{"text_format":"3","workbook":"xls","n_sheets":5,"sheets":["Register","Study Data","Dosing schedule","Further Dosing Table For AQ","Further Dosing Table For AS"],"not_rendered":{"external_links":1,"defined_names":4},"read":"whole","date_system":"1900","formulas":"cached_only"}

{"sheet":"Register","index":0,"n_rows":112,"n_cols":17,"rows_kept":112,"flags":["formulas_cached_only"]}
["Reference","Authors","Year","Title","Journal","Volume","Number","Pages","Abstract","Accession Number","Region","Country","URL","Published","WWARN Repository","Pooled analysis","Comment"]
["Adjuik-2002","Adjuik, M.;Agnamey, P.;Babiker, A.;Borrmann, S.;Brasseur, P.;Cisse, M.;Cobelens, F.;Diallo, S.;Faucher, J. F.;Garner, P.;Gikunda, S.;Kremsner, P. G.;Krishna, S.;Lell, B.;Loolpapit, M.;Matsiegui, P. B.;Missinou, M. A.;Mwanza, J.;Ntoumi, F.;Olliaro, P.;Osimbo, P.;Rezbach, P.;Some, E.;Taylor, W. R.",2002,"Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial","Lancet",359,9315,"1365-72","BACKGROUND: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa. Amodiaquine still retains efficacy against P falciparum in many African countries. We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Senegal, and Gabon. METHODS: We enrolled 941 children (400 in Kenya, 321 in Senegal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria. Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days). The primary endpoints were parasitological cure rates at days 14 and 28. Analysis was by intention to treat and by an evaluability method. FINDINGS: Both regimens were well tolerated. Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment. By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (D=16.7% [95% CI 9.3-24.1], p<0.0001), 148/160 (93%) versus 147/157 (94%) in Senegal (-1.1% [-6.7 to 4.5], p=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], p=0.02). The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], p<0.0001), 130/159 (82%) versus 123/156 (79%) in Senegal (2.9% [-5.9 to 11.7], p=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], p=0.02). Similar rates were obtained by evaluability analysis. INTERPRETATION: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Senegal. Amodiaquine-artesunate is a potential combination for use in Africa. Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.",11978332,"Africa","Multicentred","http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08348-4/abstract","Yes","Available","Included"]
["Abacassamo-2004","Abacassamo, F.;Enosse, S.;Aponte, J. J.;Gomez-Olive, F. X.;Quinto, L.;Mabunda, S.;Barreto, A.;Magnussen, P.;Ronn, A. M.;Thompson, R.;Alonso, P. L.",2004,"Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria","Tropical medicine & international health",9,2,"200-8","This paper reports a two-phase study in Manhica district, Mozambique: first we assessed the clinical efficacy and parasitological response of Plasmodium falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ), then we tested the safety and efficacy in the treatment of uncomplicated malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open, randomized, clinical trials. Children aged 6-59 months with axillary body temperature > or = 37.5 degrees C and non-complicated malaria were randomly allocated to treatment groups and followed up for 21 days (first and second trial) and 28 days (first trial). The therapeutic efficacy of AQ (91.6%) was better than that of SP (82.7%) and CQ (47.1%). After 14 days, 69% of the strains were parasitologically resistant to CQ, 21.4% to SP and 26% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up.",15040556,"Africa","Mozambique","http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3156.2003.01182.x/abstract","Yes","Not Available","Not targetted","Two phase trial: First phase with 28 day follow up while second phase had 14 day follow up"]
["Barennes-2004","Barennes, H.;Nagot, N.;Valea, I.;Koussoube-Balima, T.;Ouedraogo, A.;Sanou, T.;Ye, S.",2004,"A randomized trial of amodiaquine and artesunate alone and in combination for the treatment of uncomplicated falciparum malaria in children from Burkina Faso","Tropical medicine & international health",9,4,"438-44","Combining artesunate (AR) with existing antimalarial drugs may improve cure rates, delay emergence of resistance and reduce parasite clearance time. In order to investigate the latter, we conducted a randomized clinical trial testing the AR plus amodiaquine (AQ) combination for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Children aged 1-15 years were randomly assigned to either AQ (10 mg/kg) or AR (4 mg/kg first day then half dose) or AQ + AR (AQAR) as a single daily dose under supervision for three consecutive days for all groups. Follow-up lasted 28 days. Primary endpoints were parasite and fever clearance time. Eighty-seven children were evaluated: 27 received AQ, 27 AR and 33 AQAR. Using an intention to treat analysis, fever clearance time was similar in the three groups. However, it was significantly faster in the AR (1.21 days; P = 0.02) and AQAR groups (1.19 days; P < 0.01) than in the AQ group (1.46 days) when excluding other concomitant causes of fever. Parasite clearance time was faster in AR (1.13 days; P = 0.008) and AQAR groups (1.13 days; P < 0.01) than in the AQ group (1.6 days). All children cleared their parasites by day 14, including the child with Late Parasitological Failure (LPF) at day 7 after rescue treatment. Only one child (4%) from the AR group and one (4%) from the AQ group presented with asymptomatic parasitaemia at day 7 and day 21, respectively (LPF). Gametocyte carriage was not detectable in any group during follow-up nor was any adverse reaction observed. While resistance to first-line treatment (chloroquine) is already established in the country, AQ and AR used alone or in combination therapy proved highly efficacious in our study. Burkina Faso stands in a very good situation for an internationally recommended switch to AR-containing combination as first-line treatment for uncomplicated malaria. Including AQ in this regimen seems the best option.",15078261,"Africa","Burkina Faso","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2004.01224.x/abstract","Yes","Available","Included"]
["Ndayiragije-2004","Ndayiragije, A.;Niyungeko, D.;Karenzo, J.;Niyungeko, E.;Barutwanayo, M.;Ciza, A.;Bosman, A.;Moyou-Somo, R.;Nahimana, A.;Nyarushatsi, J. P.;Barihuta, T.;Mizero, L.;Ndaruhutse, J.;Delacollette, C.;Ringwald, P.;Kamana, J.",2004,"Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi","Tropical medicine & international health",9,6,"673-9","Faced with the problem of resistance to chloroquine and sulfadoxine-pyrimethamine, the Ministry of Public Health of Burundi decided to study the efficacy of two artemisinin-based combinations, the fixed combination of artemether-lumefantrine and the combination of amodiaquine + artesunate. The efficacy of these combinations for the treatment of uncomplicated falciparum malaria was studied in two sites representative of the country, in Kigobe neighbourhood of Bujumbura, the capital city, and in Buhiga, a rural area. The study followed the standardized WHO protocol from October 2001 to November 2002. A total of 295 children under 5 years were included; 153 children were treated with artesunate and amodiaquine (77 at Buhiga and 76 at Kigobe), and 142 children with the combination of artemether-lumefantrine (64 at Buhiga and 78 at Kigobe). Among the 295 children, 290 were followed up to 14 days. In the group of 149 children treated with artesunate and amodiaquine, 142 (95.3%, 95% CI: 91.9-98.7%) presented with adequate clinical and parasitological response, five (3.3%) with late parasitological failure, one (0.7%) with late clinical failure and one (0.7%) with early treatment failure. Among the 141 children treated with artemether-lumefantrine, 140 (99.3%, 95% CI: 97.9-100%) presented with adequate clinical and parasitological response and one (0.7%) with late parasitological failure at Buhiga. Side-effects were comparable in both groups except for the vomiting. Vomiting was more frequent in the artesunate + amodiaquine on D1 and D2. Both treatments decreased the gametocyte carriage but without getting full clearance in all the patients. During a consensus workshop, the Ministry of Public Health agreed on the combination of artesunate and amodiaquine as the first line drug for the treatment of uncomplicated falciparum malaria in Burundi including epidemic outbreak.",15189457,"Africa","Burundi","http://web.ebscohost.com/ehost/detail?sid=244a9a4c-bb8d-4b17-af13-1c360b816e73%40sessionmgr110&vid=8&hid=106&bdata=JkF1dGhUeXBlPWlwLHVybCxjb29raWUsdWlkJnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=mnh&AN=15189457","Yes","Not Available","Not targetted","Patients followed up to 14 days (290/295 patients followed up only up to 14 days)"]
["Rwagacondo-2004","Rwagacondo, C. E.;Karema, C.;Mugisha, V.;Erhart, A.;Dujardin, J. C.;Van, O. C.;Ringwald, P.;D'Alessandro, U.",2004,"Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria","Tropical medicine & international health",9,10,"1091-8","We investigated the safety and efficacy of amodiaquine alone (AQ) and combined with artesunate (AQ + AS) in 308 Rwandan children 6-59 months old with uncomplicated Plasmodium falciparum malaria attending three sentinel sites. The two treatment regimes were well tolerated and no serious adverse events were recorded. After excluding new infections, children treated with AQ + AS had fewer clinical failures at day 28 after treatment than those treated with AQ alone: OR = 0.20 [95% CI: 0.06-0.57 (P = 0.001)]. Total (parasitological and clinical) failure was also significantly less frequent in the AQ + AS group: OR = 0.34 [95% CI: 0.17-0.67 (P = 0.001)]. When adjusting for study site, the hazard ratio for treatment failure was 0.37 [95% CI: 0.20-0.68 (P = 0.001)]. Combining AQ with AS increases the efficacy of the treatment but the apparent increase of AQ resistance observed in just a 1-year period is worrying and casts doubts on the suitability of implementing AQ + AS as first-line treatment in Rwanda. Alternative treatments should be identified and tested.",15482401,"Africa","Rwanda","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2004.01316.x/abstract","Yes","Available","Included"]
["Staedke-2004","Staedke, S. G.;Mpimbaza, A.;Kamya, M. R.;Nzarubara, B. K.;Dorsey, G.;Rosenthal, P. J.",2004,"Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial","Lancet",364,9449,"1950-7","BACKGROUND: Plasmodium falciparum resistance has rendered chloroquine monotherapy ineffective in much of Africa, but data on alternative regimens are limited. We compared chloroquine+sulfadoxine-pyrimethamine, amodiaquine+sulfadoxine-pyrimethamine, and amodiaquine+artesunate for treatment of uncomplicated malaria in Kampala, Uganda. METHODS: Of 1017 consecutive patients aged 6 months to 10 years with uncomplicated malaria who were screened, 418 were randomised to receive: chloroquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine, single dose); amodiaquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine; or amodiaquine and artesunate (4 mg/kg daily for 3 days). Primary efficacy outcomes were 28-day clinical failure risks, adjusted and unadjusted by genotyping to distinguish new infection and recrudescence. The primary safety endpoint was incidence of serious adverse events during follow-up. Analysis was intention to treat and per protocol. FINDINGS: 18 patients were excluded before enrollment. Of those enrolled, 384 of 400 (96%) were assigned an efficacy outcome and 396 (99%) were assessed for safety. Risk of 28-day clinical treatment failure was significantly higher with chloroquine+sulfadoxine-pyrimethamine (44/125 [35%]) than with amodiaquine+sulfadoxine-pyrimethamine (12/129 [9%]; risk difference 26% [95% CI 16-36]; p<0.0001) or amodiaquine+artesunate (3/130 [2%]; 33% [24-42]; p<0.0001). The greater risk of clinical treatment failure with amodiaquine+sulfadoxine-pyrimethamine was balanced by a lower risk of new infection, resulting in a similar need for retreatment over 28 days for amodiaquine+sulfadoxine-pyrimethamine (17/129 [13%]) and amodiaquine+artesunate (16/130 [12%]; p=0.854). Serious adverse events were uncommon with all regimens. INTERPRETATION: Risk of treatment failure with chloroquine+sulfadoxine-pyrimethamine was unacceptably high. Combinations of amodiaquine and sulfadoxine-pyrimethamine or artesunate were significantly more efficacious, and each regimen could be an appropriate alternative for treatment of uncomplicated malaria in Africa.",15567011,"Africa","Uganda","http://www.sciencedirect.com/science/article/pii/S0140673604174783","Yes","Available","Included"]
["Durrani-2005","Durrani, N.;Leslie, T.;Rahim, S.;Graham, K.;Ahmad, F.;Rowland, M.",2005,"Efficacy of combination therapy with artesunate plus amodiaquine compared to monotherapy with chloroquine, amodiaquine or sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum in Afghanistan","Tropical medicine & international health",10,6,"521-9","INTRODUCTION: In South and Central Asia resistance to chloroquine (CQ) has reached unmanageable levels, and resistance to sulfadoxine-pyrimethamine (SP) is emerging. Amodiaquine (AQ) is widely used in the region, and elsewhere shows only partial resistance to CQ. In Afghanistan, one option for slowing the spread of resistance and improving treatment outcomes is the use of artemisinin combination therapy (ACT). METHODS: The efficacy of CQ, AQ, SP and amodiaquine plus artesunate (AQ/AS) in the treatment of uncomplicated falciparum malaria was investigated using standard World Health Organization (WHO) procedures. Malaria patients were randomized to four treatment groups: 268 were enrolled and 240 completed the trial. RESULTS: There was a high level of cross-resistance between CQ and AQ resistance: adequate clinical and parasitological response by day 42 was 11% after CQ treatment and 9% after AQ treatment. The trend of treatment failure between AQ and CQ was almost identical. Cure rates were considerably improved by the addition of artesunate to AQ or by use of SP; adequate clinical and parasitological response being 72% for AQ/AS and 92% for SP. The combination of AS/AQ substantially reduced the odds of treatment failure relative to AQ monotherapy by day 42 [odds ratio (OR) = 0.03, 95% confidence interval (CI) 0.01-0.1] in addition to reducing the proportion of patients with gametocytes throughout the 42-day period. Gametocyte carriage rate was only marginally higher in the SP than in the CQ- and AQ-treated groups. CONCLUSION: The therapeutic and parasitological cure rates with AS/AQ were inadequate, and the criteria for deploying ACT - namely to prevent further selection of drug resistance from a position of low frequency - was not met in the region. An alternative drug combination to AQ/AS is required for Afghanistan.",15941414,"Asia","Afghanistan","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2005.01429.x/abstract","Yes","Available","Not Targetted","PCR Not Carried Out"]
["Guthmann-2005","Guthmann, J. P.;Ampuero, J.;Fortes, F.;van, O. C.;Gaboulaud, V.;Tobback, S.;Dunand, J.;Saraiva, N.;Gillet, P.;Franco, J.;Denoncin, A.;van, H. M.;Balkan, S.;Dujardin, J. C.;D'Alessandro, U.;Legros, D.",2005,"Antimalarial efficacy of chloroquine, amodiaquine, sulfadoxine-pyrimethamine, and the combinations of amodiaquine + artesunate and sulfadoxine-pyrimethamine + artesunate in Huambo and Bie provinces, central Angola","Transactions of the Royal Society of Tropical Medicine and Hygiene",99,7,"485-92","We studied three antimalarial treatments in Caala and Kuito, Angola, in 2002 and 2003. We tested chloroquine (CQ), amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) in Caala, and AQ, SP and the combinations AQ+artesunate (AQ+AS) and SP+artesunate (SP+AS) in Kuito. A total of 619 children (240 in Caala, 379 in Kuito) with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days, with PCR genotyping to distinguish recrudescence from reinfection. PCR-corrected failure proportions at day 28 were very high in the CQ group (83.5%, 95% CI 74.1-90.5), high in the SP groups (Caala: 25.3%, 95% CI 16.7-35.8; Kuito: 38.8%, 95% CI 28.4-50.0), around 20% in the AQ groups (Caala: 17.3%, 95% CI 10.0-27.2; Kuito: 21.6%, 95% CI 14.3-30.6) and very low in the artemisinin-based combination groups (1.2%, 95% CI 0.0-6.4 for each combination AQ+AS and SP+AS). These results show that CQ and SP are no longer efficacious in Caala and Kuito and that the moderate efficacy of AQ is likely to be compromised in the short term if used as monotherapy. We recommend the use of AQ with AS, though this combination might not have a long useful therapeutic life because of AQ resistance.",15876443,"Africa","Angola","http://www.sciencedirect.com/science/article/pii/S0035920305000404","Yes","Available","Included"]
["Hamour-2005","Hamour, S.;Melaku, Y.;Keus, K.;Wambugu, J.;Atkin, S.;Montgomery, J.;Ford, N.;Hook, C.;Checchi, F.",2005,"Malaria in the Nuba Mountains of Sudan: baseline genotypic resistance and efficacy of the artesunate plus sulfadoxine-pyrimethamine and artesunate plus amodiaquine combinations","Transactions of the Royal Society of Tropical Medicine and Hygiene",99,7,"548-54","Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria (artesunate+sulfadoxine-pyrimethamine [AS+SP] in the north, artesunate+amodiaquine [AS+AQ] in the south). In 2003, we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated, seasonally endemic Nuba Mountains region (the first study of AS combinations in southern Sudan). We also analysed pre-treatment blood samples for mutations at the P. falciparum chloroquine transporter (Pfcrt) gene (associated with CQ resistance), and at the dihydrofolate reductase (Dhfr) gene (associated with pyrimethamine resistance). Among 161 randomized children under 5 years, PCR-corrected cure rates after 28 days were 91.2% (52/57, 95% CI 80.7-97.1) for AS+SP and 92.7% (51/55, 95% CI 82.4-98.0) for AS+AQ, with equally rapid parasite and fever clearance. The Pfcrt K76T mutation occurred in 90.0% (144/160) of infections, suggesting CQ would work poorly in this region. Overall, 82.5% (132/160) carried mutations at Dhfr (N51I, C59R or S108N, but not I164L), but triple mutants (more predictive of in vivo SP failure) were rare (3.1%). CQ use should be rapidly discontinued in this region. SP resistance may propagate rapidly, and AS+AQ is likely to be a better long-term option, provided AQ use is limited to the combination.",15869770,"Africa","Sudan","http://trstmh.oxfordjournals.org/content/99/7/548.long","Yes","Available","Included"]
["Koram-2005","Koram, K. A.;Abuaku, B.;Duah, N.;Quashie, N.",2005,"Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana","Acta tropica",95,3,"194-203","The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control in sub-Saharan Africa. We undertook a study on the efficacy of some antimalarial drugs in 2003 with the view of supporting the National Malaria Control Programme in the review of the antimalarial drug treatment policy in Ghana. Children aged 6-59 months with signs/symptoms of uncomplicated malaria including axillary temperature > or =37.5 degrees C; mono infection with P. falciparum; and parent's willingness to give consent, were randomized into four treatment groups and followed up for a maximum of 28 days. The treatment groups were chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine+artesunate (ADQ+ART) combination, and artemether+lumefantrine (Coartem) combination. Clinical evaluation of 168 children studied showed that cumulative pcr-corrected cure rates on day 28 were 100% for ADQ+ART; 97.5% for coartem, 60% for SP and 25% for CHQ. The artemisinin-based combinations effected rapid fever and parasite clearance. Prevalence of gametocytaemia was highest in the SP group whilst the CHQ group did not show any significant changes in haemoglobin levels during the follow-up period. The findings are in agreement with current recommendations for using artemisinin-based combinations for treating uncomplicated malaria in areas of high CHQ failure such as Ghana.",16054584,"Africa","Ghana","http://www.sciencedirect.com/science/article/pii/S0001706X05001579","Yes","Not Available","Not Available"]
["Martensson-2005","Martensson, A.;Stromberg, J.;Sisowath, C.;Msellem, M. I.;Gil, J. P.;Montgomery, S. M.;Olliaro, P.;Ali, A. S.;Bjorkman, A.",2005,"Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania","Clinical infectious diseases",41,8,"1079-86","BACKGROUND: This is the first clinical trial comparing the efficacy of artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--the major artemisinin-based combination therapy (ACT) candidates for treatment of malaria in Africa--that involved an extended, 42-day follow-up period, polymerase chain reaction-adjusted parasitological cure rates (PCR APCRs), and systematic analyses of genetic markers related to quinoline resistance. METHODS. A total of 408 children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania, were enrolled. Children who were 6-8 months of age and/or who weighed 6-8 kg were assigned to receive ASAQ for 3 days. Children who were 9-59 months of age and who weighted > or =9 kg were randomly assigned to receive either ASAQ or AL for 3 days in standard doses. Intention-to-treat analyses were performed. RESULTS: Age- and weight-adjusted PCR-APCRs by follow-up day 42 were 91% (188 of 206 patients) in the ASAQ group and 94% (185 of 197 patients) in the AL group (odds ratio [OR] for the likelihood of cure, 2.07; 95% confidence interval [CI], 0.84-5.10; P=.115). A total of 5 and 7 recrudescences occurred after day 28 in the ASAQ and AL groups, respectively. On the assumption that 10 malaria episodes with uncertain PCR results were recrudescences, PCR-APCRs decreased to 88% in the ASAQ group and to 92% in the AL group. Unadjusted cure rates by day 42 were 56% (116 of 206 patients) in the ASAQ group versus 77% (151 of 197 patients) in the AL group (OR, 2.55; 95% CI, 1.66-3.91; P<.001). Rates of reinfection by day 42 were 36% (65 of 181 patients) in the ASAQ arm versus 17% (31 of 182 patients) in the AL arm (OR, 0.37; 95% CI, 0.22-0.60; P<.001). A significant selection of P. falciparum multidrug resistance gene 1 allele 86N was found in isolates associated with reinfection after AL treatment, compared with isolates at baseline (2.2-fold increase; P<.001). CONCLUSIONS: Both treatments were highly efficacious, but AL provided stronger prevention against reinfection. The high proportion of recrudescences found after day 28 and the genetic selection by the long-acting partner drug underlines the importance of long follow-up periods in clinical trials. A long follow-up duration and performance of PCR genotyping should be implemented in programmatic surveillance of antimalarial drugs.",16163624,"Africa","Tanzania","http://cid.oxfordjournals.org/content/41/8/1079.long","Yes","Available","Included"]
["Mutabingwa-2005","Mutabingwa, T. K.;Anthony, D.;Heller, A.;Hallett, R.;Ahmed, J.;Drakeley, C.;Greenwood, B. M.;Whitty, C. J.",2005,"Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial","Lancet",365,9469,"1474-80","BACKGROUND: Many countries in Africa are considering a change to combination treatment for falciparum malaria because of the increase in drug resistance. However, there are few effectiveness data for these combinations. Our aim was to study the effectiveness of three drug combinations that have proven efficacious in east Africa compared with amodiaquine monotherapy. METHODS: We undertook a randomised trial of antimalarial drug combinations for children (aged 4-59 months) with uncomplicated malaria in Muheza, Tanzania, an area with a high prevalence of resistance to sulfadoxine-pyrimethamine and chloroquine. Children were randomly allocated 3 days of amodiaquine (n=270), amodiaquine +sulfadoxine-pyrimethamine (n=507), or amodiaquine+artesunate (n=515), or a 3-day six-dose regimen of artemether-lumefantrine (n=519). Drugs were taken orally, at home, unobserved by medical staff. The primary endpoint was parasitological failure by day 14 assessed blind to treatment allocation. Secondary endpoints included day 28 follow-up and gametocyte carriage. Analysis was by intention to treat. FINDINGS: Of 3158 children screened, 1811 were randomly assigned treatment and 1717 (95%) reached the 14-day follow-up. The amodiaquine group was stopped early by the data and safety monitoring board. By day 14, the parasitological failure rates were 103 of 248 (42%) for amodiaquine, 97 of 476 (20%) for amodiaquine+sulfadoxine-pyrimethamine, 54 of 491 (11%) for amodiaquine+artesunate, and seven of 502 (1%) for artemether-lumefantrine. By day 28, the parasitological failure rates were 182 of 239 (76%), 282 of 476 (61%), 193 of 472 (40%), and 103 of 485 (21%), respectively. The difference between individual treatment groups and the next best treatment combination was significant (p<0.001) in every case. Recrudescence rates by day 28, after correction by genotyping, were 48.4%, 34.5%, 11.2%, and 2.8%, respectively. INTERPRETATION: The study shows how few the options are for treating malaria where there is already a high level of resistance to sulfadoxine-pyrimethamine and amodiaquine. The WHO-packaged six-dose regimen of artemether-lumefantrine is effective taken unsupervised, although cost is a major limitation.",15850631,"Africa","Tanzania","http://www.lancet.com/journals/lancet/article/PIIS0140-6736(05)66417-3/abstract","Yes","Available","Excluded","Missing Dosing Plan"]
["Sowunmi-2005","Sowunmi, A.;Fehintola, F. A.;Adedeji, A. A.;Gbotosho, G. O.;Tambo, E.;Fateye, B. A.;Happi, T. C.;Oduola, A. M.",2005,"Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children","Tropical medicine & international health",10,11,"1161-70","BACKGROUND: Artemisinin-based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine-sulfadoxine in children. METHODS: We evaluated 153 children who were aged 12 years or younger who had uncomplicated Plasmodium falciparum malaria. Patients were randomly assigned a combination of artesunate (4 mg/kg of body weight daily for 3 days) plus amodiaquine (30 mg/kg over 3 days), or chloroquine (25 mg/kg over 3 days) plus pyrimethamine-sulfadoxine (25 mg/kg of the sulfadoxine component at presentation). The primary endpoints were the proportions of children with adequate clinical and parasitological response, late parasitological failure, late clinical failure and early treatment failure. The parasitological cure rates on days 14-28 were also used as the primary endpoints. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. All children treated with artesunate plus amodiaquine had adequate clinical and parasitological response (ACPR), while all but five children treated with chloroquine plus pyrimethamine-sulfadoxine had similar response. Fever clearance times were similar in the two treatment groups. However, the proportion of patients whose parasitaemia cleared by day 2 was significantly higher (100 vs. 50%, P = 0.00001) and parasite clearance was significantly faster (1.7 +/- 0.4 vs. 2.5 +/- 0.8 days, P = 0.0001) in children treated with artesunate plus amodiaquine. The cure rates on days 21 (100%vs. 94%, P = 0.03) and 28 (100%vs. 90%, P = 0.003) were also significantly higher in children treated with artesunate plus amodiaquine than in those treated with chloroquine plus pyrimethamine-sulfadoxine. Overall, a significantly higher proportion of children treated with chloroquine plus pyrimethamine-sulfadoxine carried gametocytes at least once during follow-up compared with those treated with artesunate plus amodiaquine [5 of 50 (10%) vs. 1 of 103 (0.97%), P = 0.01]. CONCLUSION: The combination of artesunate plus amodiaquine is therapeutically superior to a combination of chloroquine plus pyrimethamine-sulfadoxine, and significantly reduced gametocyte carriage following treatment.",16262741,"Africa","Nigeria","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2005.01503.x/abstract","Yes","Not Available","Not Available"]
["van den Broek-2005","van den Broek, I; Amsalu, R; Balasegaram, M; Hepple P; Alemu E; Hussein el B; Al-Faith M; Montgomery J; Checchi F.",2005,"Efficacy of two artemisinin combination therapies for uncomplicated falciparum malaria in children under 5 years, Malakal, Upper Nile, Sudan","Malaria journal",4,14,"doi:10.1186/1475-2875-4-14","BACKGROUND: The treatment for Plasmodium falciparum malaria in Sudan has been in process of change since 2003. Preceding the change, this study aimed to determine which artemisinin-based combination therapies is more effective to treat uncomplicated malaria in Malakal, Upper Nile, Sudan. METHODS: Clinical trial to assess the efficacy of 2 antimalarial therapies to treat P. falciparum infections in children aged 6-59 months, in a period of 42 days after treatment. RESULTS: A total of 269 children were followed up to 42 days. Artesunate plus Sulfadoxine/Pyrimethamine (AS+SP) and Artesunate plus Amodiaquine (AS+AQ) were both found to be efficacious in curing malaria infections by rapid elimination of parasites and clearance of fever, in preventing recrudescence and suppressing gametocytaemia. The combination of AS+SP appeared slightly more efficacious than AS+AQ, with 4.4% (4/116) versus 15% (17/113) of patients returning with malaria during the 6-week period after treatment (RR = 0.9, 95% CI 0.81-0.96). PCR analysis identified only one recrudescence which, together with one other early treatment failure, gave efficacy rates of 99.0% for AS+AQ (96/97) and 99.1% for AS+SP (112/113). However, PCR results were incomplete and assuming part of the indeterminate samples were recrudescent infections leads to an estimated efficacy ranging 97-98% for AS+SP and 88-95% for AS+AQ. CONCLUSION: These results lead to the recommendation of ACT, and specifically AS+SP, for the treatment of uncomplicated falciparum malaria in this area of Sudan. When implemented, ACT efficacy should be monitored in sentinel sites representing different areas of the country.",15730557,"Africa","Sudan","http://www.malariajournal.com/content/4/1/14/comments","Yes","Available","Excluded","Missing Dosing Plan"]
["Yeka-2005","Yeka, A.;Banek, K.;Bakyaita, N.;Staedke, S. G.;Kamya, M. R.;Talisuna, A.;Kironde, F.;Nsobya, S. L.;Kilian, A.;Slater, M.;Reingold, A.;Rosenthal, P. J.;Wabwire-Mangen, F.;Dorsey, G.",2005,"Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda","PLoS medicine",2,7,"e190","BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003). CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).",16033307,"Africa","Uganda","http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020190","Yes","Available","Included"]
["Bukirwa-2006","Bukirwa, H.;Yeka, A.;Kamya, M. R.;Talisuna, A.;Banek, K.;Bakyaita, N.;Rwakimari, J. B.;Rosenthal, P. J.;Wabwire-Mangen, F.;Dorsey, G.;Staedke, S. G.",2006,"Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda","PLoS clinical trials",1,1,"e7","OBJECTIVES: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blind controlled trial. SETTING: Tororo, Uganda, an area of high-level malaria transmission. PARTICIPANTS: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria. INTERVENTIONS: Amodiaquine + artesunate or artemether-lumefantrine. OUTCOME MEASURES: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens. CONCLUSIONS: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.",16871329,"Africa","Uganda","http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1488893/","Yes","Available","Included"]
["Grandesso-2006","Grandesso, F.;Hagerman, A.;Kamara, S.;Lam, E.;Checchi, F.;Balkan, S.;Scollo, G.;Durand, R.;Guthmann, J. P.",2006,"Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 years in Kailahun, Sierra Leone","Tropical medicine & international health",11,7,"1017-21","OBJECTIVE: In 2004, Sierra Leone adopted artesunate plus amodiaquine as first-line antimalarial treatment. We evaluated the efficacy of this combination in Kailahun, where a previous study had shown 70.2% efficacy of amodiaquine in monotherapy. METHODS: Method and outcome classification of the study complied with WHO guidelines. Children 6-59 months with uncomplicated malaria were followed-up for 28 days. PCR genotyping was used to distinguish recrudescence from reinfection. Reinfections were reclassified as cured. RESULTS: Of 172 children who were referred to the study clinic, 126 satisfied inclusion criteria and were enrolled. No early treatment failures were reported. The day 14, efficacy was 98.2% (95% CI: 93.8-99.8). Of 65 recurrent parasitaemias analysed by PCR, 17 were recrudescences. The PCR-adjusted day 28 efficacy was 84.5% (95% CI: 76.4-90.7). All true failures occurred in the last 8 days of follow-up. Of 110 children who completed the 28-day follow-up, 54 (49.1%) experienced a novel infection. CONCLUSION: The efficacy of this combination was disappointing. The high reinfection rate suggested little prophylactic effect. In Kailahun a more efficacious combination might be necessary in the future. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone.",16827702,"Africa","Sierra Leone","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2006.01655.x/full","Yes","Available","Included"]
["Guthmann-2006","Guthmann, J. P.;Cohuet, S.;Rigutto, C.;Fortes, F.;Saraiva, N.;Kiguli, J.;Kyomuhendo, J.;Francis, M.;Noel, F.;Mulemba, M.;Balkan, S.",2006,"High efficacy of two artemisinin-based combinations (artesunate + amodiaquine and artemether + lumefantrine) in Caala, Central Angola","The American journal of tropical medicine and hygiene",75,1,"143-5","In April 2004, 137 children 6-59 months of age with uncomplicated Plasmodium falciparum (Pf) malaria (Caala, Central Angola) were randomized to receive either artemether-lumefantrine (Coartem) or artesunate + amodiaquine (ASAQ). After 28 days of follow-up, there were 2/61 (3.2%) recurrent parasitemias in the Coartem group and 4/64 (6.2%) in the ASAQ group (P = 0.72), all classified as re-infections after PCR genotyping (cure rate = 100% [95%CI: 94-100] in both groups). Only one patient (ASAQ group) had gametocytes on day 28 versus five (Coartem) and three (ASAQ) at baseline. Compared with baseline, anemia was significantly improved after 28 days of follow-up in both groups (Coartem: from 54.1% to 13.4%; ASAQ: from 53.1% to 15.9%). Our findings are in favor of a high efficacy of both combinations in Caala. Now that Coartem has been chosen as the new first-line anti-malarial, the challenge is to insure that this drug is available and adequately used.",16837721,"Africa","Angola","http://www.ajtmh.org/content/75/1/143.full","Yes","Available","Included"]
["Karema-2006","Karema, C.;Fanello, C. I.;van, O. C.;van, G. J. P.;van, D. W.;Ngamije, D.;D'Alessandro, U.",2006,"Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children","Transactions of the Royal Society of Tropical Medicine and Hygiene",100,12,"1105-11","In Rwanda, amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) is the current first-line treatment for malaria, introduced in 2001 as an interim strategy before the future deployment of an artemisinin-based combination treatment (ACT). Dihydroartemisinin/piperaquine (DHA-PQP) is a new co-formulated and well tolerated ACT increasingly used in Southeast Asia where it has proved to be highly effective against Plasmodium falciparum malaria. We tested the efficacy, safety and tolerability of DHA-PQP in children with uncomplicated P. falciparum malaria. A randomised, open trial was carried out in 2003-2004. Seven hundred and sixty-two children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to one of the following treatments: amodiaquine+artesunate; AQ+SP; or DHA-PQP. Patients were followed-up until Day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Children treated with DHA-PQP or AQ+AS had a significantly higher cure rate compared with those treated with amodiaquine+sulfadoxine/pyrimethamine (95.2% and 92.0% vs. 84.7%, respectively). Parasite clearance was significantly faster in children treated with DHA-PQP and AQ+AS compared with those treated with amodiaquine+sulfadoxine/pyrimethamine. The frequency of adverse events was significantly lower in patients treated with DHA-PQP than in those treated with combinations containing amodiaquine. A 3-day treatment with DHA-PQP proved to be efficacious with a good safety and tolerability profile and could be a good candidate for the next first-line treatment.",16766006,"Africa","Burkina Faso","http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055852/","Yes","Available","Included"]
["Meremikwu-2006","Meremikwu, M.;Alaribe, A.;Ejemot, R.;Oyo-Ita, A.;Ekenjoku, J.;Nwachukwu, C.;Ordu, D.;Ezedinachi, E.",2006,"Artemether-lumefantrine versus artesunate plus amodiaquine for treating uncomplicated childhood malaria in Nigeria: randomized controlled trial","Malaria journal",5,43,"doi:10.1186/1475-2875-5-43","BACKGROUND: The therapeutic efficacy of artesunate plus amodiaquine and artemether/lumefantrine were assessed in an area of Nigeria with high levels of Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine. PARTICIPANTS: Children aged 6 to 59 months with uncomplicated P. falciparum infection and parasite density 1,000 to 200,000 parasites/microL enrolled following informed consent by parents. METHODS: Eligible children were randomly assigned to receive either a 3-day course of artesunate (4 mg/kg) plus amodiaquine (10 mg/kg) or 6-dose course of artemether/lumefantrine (20/120 mg tablets) over three days. Patients were followed up with clinical and laboratory assessments until day 14 using standard WHO in-vivo antimalarial drug test protocol. RESULTS: A total 119 eligible children were enrolled but 111 completed the study. Adequate clinical and parasitological response (ACPR) was 47 (87.0%) and 47 (82.5%) for artemether-lumefantrine (AL) and artesunate+amodiaquine (AAMQ) respectively (OR 0.7, 95% confidence interval 0.22 to 2.22). Early treatment failure (ETF) occurred in one participant (1.8%) treated with AAQ but in none of those with AL. Two (3.7%) patients in the AL group and none in the AAQ group had late clinical failure. Late parasitological failure was observed in 9 (15.8) and 5 (9.3%) of patients treated with AAQ and AL respectively. None of participants had a serious adverse event. CONCLUSION: Artemether-lumenfantrine and artesunate plus amodiaquine have high and comparable cure rates and tolerability among under-five children in Calabar, Nigeria.",16704735,"Africa","Nigeria","http://www.malariajournal.com/content/5/1/43","Yes","Not Available","Not targetted","<28 days follow up [14 day follow up study]"]
["Swarthout-2006","Swarthout, T. D.;van, d. B. I. V.;Kayembe, G.;Montgomery, J.;Pota, H.;Roper, C.",2006,"Artesunate + amodiaquine and artesunate + sulphadoxine-pyrimethamine for treatment of uncomplicated malaria in Democratic Republic of Congo: a clinical trial with determination of sulphadoxine and pyrimethamine-resistant haplotypes","Tropical medicine & international health",11,10,"1503-11","We undertook a trial of artesunate + amodiaquine (AS + AQ) and artesunate + sulphadoxine-pyrimethamine (AS + SP) in 180 children of age 6-59 months with uncomplicated malaria in Democratic Republic of Congo. Children were randomly allocated to receive 3 days observed treatment of AS + AQ (n = 90) or 3 days of AS + SP (n = 90). Primary efficacy outcomes were 28-day parasite recurrence rates, and recrudescence rates were adjusted by genotyping to distinguish new infection and recrudescence. In addition, we determined the prevalence of molecular markers of resistance to sulphadoxine and pyrimethamine. Day 28 parasite recurrence rates were 16.9% (14/83; 95% CI: 9.5-26.7) in the AS + AQ group and 34.6% (28/81; 95% CI: 24.3-46.0) in the AS + SP group (P = 0.009). After PCR correction, recrudescence rates were 6.7% (5/74; 95% CI: 2.2-15.1) for AS + AQ and 19.7% (13/66; 95% CI: 10.9-31.3) for AS + SP (P = 0.02). There was no significant difference between the two arms in time to parasite clearance, fever clearance and gametocyte clearance. Parasite genotyping showed high frequencies of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) molecular SP-resistance markers, with 57% of the samples showing more than three mutations linked to SP resistance, and 27% with triple-dhfr/double-dhps haplotype, confirming that SP treatment failure rates are likely to be high. AS + AQ had significantly higher efficacy than AS + SP. These results contributed to the subsequent change to AS + AQ as first-line regimen in the country. Efforts to properly implement the new protocol and maintain adherence at acceptable levels should include health staff and patient sensitization. The 6.8% recrudescence rate indicates that AS + AQ should be monitored closely until a more effective artemisinin combination therapy regimen is needed and can be introduced.",17002724,"Africa","Democratic Republic of Congo","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2006.01710.x/full","Yes","Available","Included"]
["van den Broek-2006","van den Broek, I; Kitz, C; Al Attas, S; Libama F; Balasegaram M; Guthmann JP.",2006,"Efficacy of three artemisinin combination therapies for the treatment of uncomplicated Plasmodium falciparum malaria in the Republic of Congo","Malaria journal",5,113,"doi:10.1186/1475-2875-5-113","BACKGROUND: Presented here are the results of a comparative trial on the efficacy of three artemisinin-based combinations conducted from May to October 2004, in Pool Province, Republic of Congo. METHODS: The main outcome was the proportion of cases of true treatment success at day 28. Recrudescences were distinguished from re-infections by PCR analysis. A total of 298 children of 6-59 months were randomized to receive either artesunate + SP (AS+SP), artesunate + amodiaquine (AS+AQ) or artemether + lumefantrine (AL), of which 15 (5%) were lost to follow-up. RESULTS: After 28 days, there were 21/85 (25%) recurrent parasitaemias in the AS+SP group, 31/97 (32%) in the AS+AQ group and 13/100 (13%) in the AL group. The 28-day PCR-corrected cure rate was 90.1% [95% CI 80.7-95.9] for AS+SP, 98.5% [95% CI 92.0-100] for AS+AQ and 100% [95.8-100] for AL, thereby revealing a weaker response to AS+SP than to AL (p = 0.003) and to AS+AQ (p = 0.06). A potential bias was the fact that children treated with AL were slightly older and in better clinical condition, but logistic regression did not identify these as relevant factors. There was no significant difference between groups in fever and parasite clearance time, improvement of anaemia and gametocyte carriage at day 28. No serious adverse events were reported. CONCLUSION: Considering the higher efficacy of AL as compared to AS+SP and the relatively high proportion of cases with re-infections in the AS+AQ group, we conclude that AL is clinically more effective than AS+SP and AS+AQ in this area of the Republic of Congo. Implementation of the recently chosen new national first-line AS+AQ should be monitored closely.",17125496,"Africa","Republic of Congo","http://www.malariajournal.com/content/5/1/113","Yes","Available","Included"]
["Bonnet-2007","Bonnet, M.;Roper, C.;Felix, M.;Coulibaly, L.;Kankolongo, G. M.;Guthmann, J. P.",2007,"Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zerekore","Malaria journal",6,54,"doi:10.1186/1475-2875-6-54","BACKGROUND: In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT), many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS)/sulphadoxine-pyrimethamine (SP) had been used in refugee camps for two years. METHODS: In Dabola (central Guinea), 220 children aged 6-59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ) or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea), where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr) (codons 108, 51, 59) and dihydropteroate synthase (dhps) (codons 436, 437, 540) genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively. RESULTS: In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR)-adjusted failure rates were 1.0% (95%CI 0-5.3) for AS/AQ and 1.0% (95%CI 0-5.5) for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2-90.7) patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2-15.9). CONCLUSION: Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of implementing ACTs, but cannot predict how long their therapeutic life will be, especially in countries which have chosen drugs also available as monotherapies.",17477865,"Africa","Guinea","http://www.malariajournal.com/content/6/1/54","Yes","Available","Included"]
["Brasseur-2007","Brasseur P, Agnamey P, Gaye O, Vaillant M, Taylor WR, Olliaro PL",2007,"Efficacy and safety of artesunate plus amodiaquine in routine use for the treatment of uncomplicated malaria in Casamance, southern Sénégal","Malaria journal",6,150,"doi:10.1186/1475-2875-6-150","Abstract BACKGROUND: There are no data on the long term use of an artemisinin combination treatment in moderate or high transmission areas of Africa.\nMETHODS AND FINDINGS: Artesunate plus amodiaquine (AS+AQ) was used to treat slide-proven Plasmodium falciparum-infected patients of all ages in the Oussouye district, Casamance, Senegal, over a period of six years (2000 to 2005). Efficacy, by Kaplan Meier survival analysis (n = 966), and safety (adverse event rates, n = 752) were determined over 28 days. A weight-based dosing regimen was used for the loose tablets during 2000-2003 (n = 731) and a commercially available co-blister was used during 2004-2005 (n = 235). Annual crude (non PCR corrected) rates remained stable over the study period [range 88.5-96.7%; overall 94.6 (95% CI 92.9-95.9)]. Nine co-blister treated patients (0.9%) withdrew because of drug-related adverse events; seven had gastrointestinal complaints of whom two were hospitalized for vomiting. By Day 28, the mean total bilirubin (n = 72), AST (n = 94) and ALT (n = 95) values decreased. Three patients had Day 28 AST/ALT values > 40 < 200 IU/L. Changes in white cell counts were unremarkable (n = 87).\nCONCLUSION: AS+AQ in combination was highly efficacious and well-tolerated in this area and justifies the decision to use it as first line treatment. Long-term monitoring of safety and efficacy should continue.",18005408,"Africa","Senegal","http://www.malariajournal.com/content/6/1/150","Yes","Available","Excluded","Subset of Brasseur-2009"]
["Dorsey-2007","Dorsey, G.;Staedke, S.;Clark, T. D.;Njama-Meya, D.;Nzarubara, B.;Maiteki-Sebuguzi, C.;Dokomajilar, C.;Kamya, M. R.;Rosenthal, P. J.",2007,"Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial","JAMA : the journal of the American Medical Association",297,20,"2210-9","CONTEXT: Combination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas. OBJECTIVE: To compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria. DESIGN, SETTING, AND PARTICIPANTS: Single-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic. INTERVENTIONS: Study participants were randomized to receive 1 of 3 combination therapies (amodiaquine plus sulfadoxine-pyrimethamine, amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes. MAIN OUTCOME MEASURE: 28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs. RESULTS: Of enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P< or =.008 for all pairwise comparisons, except amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing. CONCLUSIONS: Artemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN37517549.",17519410,"Africa","Uganda","http://jama.ama-assn.org/content/297/20/2210.abstract","Yes","Available","Included"]
["Faye-2007","Faye, B.;Ndiaye, J. L.;Ndiaye, D.;Dieng, Y.;Faye, O.;Gaye, O.",2007,"Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal","Malaria journal",6,80,"doi:10.1186/1475-2875-6-80","BACKGROUND: In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam), artesunate plus mefloquine (Artequin), artemether plus lumefantrine (Coartem; four doses and six doses), and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. METHODS: This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. RESULTS: All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%). Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%.The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. CONCLUSION: The four combinations are effective and well-tolerated.",17570848,"Africa","Senegal","http://www.malariajournal.com/content/6/1/80","Yes","Available","Excluded","Missing Dosing Table and Missing PCR Results"]
["Hasugian-2007","Hasugian, A. R.;Purba, H. L.;Kenangalem, E.;Wuwung, R. M.;Ebsworth, E. P.;Maristela, R.;Penttinen, P. M.;Laihad, F.;Anstey, N. M.;Tjitra, E.;Price, R. N.",2007,"Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria","Clinical infectious diseases",44,8,"1067-74","BACKGROUND: Antimalarial drug resistance is now well established in both Plasmodium falciparum and Plasmodium vivax. In southern Papua, Indonesia, where both strains of plasmodia coexist, we have been conducting a series of studies to optimize treatment strategies. METHODS: We conducted a randomized trial that compared the efficacy and safety of dihydroartemisinin-piperaquine (DHP) with artesunate-amodiaquine (AAQ). The primary end point was the overall cumulative parasitological failure rate at day 42. RESULTS: Of the 334 patients in the evaluable patient population, 185 were infected with P. falciparum, 80 were infected with P. vivax, and 69 were infected with both species. The overall parasitological failure rate at day 42 was 45% (95% confidence interval [CI], 36%-53%) for AAQ and 13% (95% CI, 7.2%-19%) for DHP (hazard ratio [HR], 4.3; 95% CI, 2.5-7.2; P<.001). Rates of both recrudescence of P. falciparum infection and recurrence of P. vivax infection were significantly higher after receipt of AAQ than after receipt of DHP (HR, 3.4 [95% CI, 1.2-9.4] and 4.3 [95% CI, 2.2-8.2], respectively; P<.001). By the end of the study, AAQ recipients were 2.95-fold (95% CI, 1.2- to 4.9-fold) more likely to be anemic and 14.5-fold (95% CI, 3.4- to 61-fold) more likely to have carried P. vivax gametocytes. CONCLUSIONS: DHP was more effective and better tolerated than AAQ against multidrug-resistant P. falciparum and P. vivax infections. The prolonged therapeutic effect of piperaquine delayed the time to P. falciparum reinfection, decreased the rate of recurrence of P. vivax infection, and reduced the risk of P. vivax gametocyte carriage and anemia.",17366451,"Asia","Indonesia","http://cid.oxfordjournals.org/content/44/8/1067.abstract","Yes","Available","Included"]
["Ibrahium-2007","Ibrahium, A. M.;Kheir, M. M.;Osman, M. E.;Khalil, I. F.;Alifrangis, M.;Elmardi, K. A.;Malik, E. M.;Adam, I.",2007,"Efficacies of artesunate plus either sulfadoxine-pyrimethamine or amodiaquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan","Annals of tropical medicine and parasitology",101,1,"15-21","Artemisinin-based combination therapy (ACT) is increasingly being adopted as the first-line treatment for malaria in sub-Saharan Africa. In September-November 2005, in New Halfa, eastern Sudan, the efficacy of artesunate-sulfadoxine-pyrimethamine (AS-SP) for the treatment of uncomplicated, Plasmodium falciparum was compared with that of artesunate-amodiaquine (AS-AQ). The artesunate was given at 4 mg/kg. day on days 0-2, with either a single dose of SP (25 mg sulfadoxine/kg) given on day 0, or AQ, at 10 mg/kg. day, given on days 0-2. Eighty-two of the patients treated (40 given AS-SP and 42 given AS-AQ) completed the 28 days of follow-up. On day 3 all the patients were afebrile and only one patient, in the AS-AQ group, was still parasitaemic. AS-SP appeared slightly more efficacious than AS-AQ but the differences were not statistically significant. Only one patient (2.5%) given AS-SP but four (9.5%) of those given AS-AQ were initially considered to be late treatment and parasitological failures, with all other patients showing an adequate treatment response. The PCR-corrected frequencies of cure were 97.5% for AS-SP and 95.2% for AS-AQ (P>0.05). No gametocytaemias were observed during the follow-up and, although mild adverse effects (nausea, vomiting, abdominal pain, dizziness and/or rash) were detected in 14 patients, they occurred at the same frequency in each treatment arm. It therefore appears that the AS-SP and AS-AQ combinations were both effective and safe for the treatment of uncomplicated, P. falciparum malaria in eastern Sudan.",17244406,"Africa","Sudan","http://www.maneyonline.com/doi/abs/10.1179/136485907X156924?token=004f100d6e58654624316342386b792136663470535e4e26634a492f2530332976e5b178f319c53&","Yes","Not Available","Not Available"]
["Kabanywanyi-2007","Kabanywanyi, A. M.;Mwita, A.;Sumari, D.;Mandike, R.;Mugittu, K.;Abdulla, S.",2007,"Efficacy and safety of artemisinin-based antimalarial in the treatment of uncomplicated malaria in children in southern Tanzania","Malaria journal",6,146,"doi:10.1186/1475-2875-6-146","BACKGROUND: Tanzania switched the antimalarial first line to sulphadoxine-pyrimethamine (SP) in 2001 from ineffective chloroquine (CQ). By 2003 higher levels of SP resistance were recorded, prompting an urgent need for replacing the first line drug with ACT, as currently recommended by the World Health Organization. Despite this recommendation country-specific evidence-based data to support efficacy and safety profile of ACT is still limited. A study on the efficacy and safety of artesunate plus amodiaquine (AS+AQ) and artemether plus lumefantrine (AL)(Coartem) was carried out in 2004 with the view of supporting the National Malaria Control Programme in the review of the policy in mainland Tanzania. METHODS: An in vivo efficacy study was conducted at Ipinda and Mlimba health facilities between May and November 2004. The study recruited children aged 6-59 months presenting with symptoms of uncomplicated malaria, history of fever or an axillary temperature > or =37.5 degrees C; mono infection with Pasmodium falciparum (2,000-200,000 parasites/microl). Patients were randomized to received either SP or amodiaquine monotherapy or treated with standard doses of AS+AQ in Mlimba and Coartem in Kyela and followed-up for 28 days to assess treatment responses. This study reports results of the combination therapies. RESULTS: A total of 157 children (76 in Mlimba and 99 in Kyela) who were enrolled in to the study and treated with either AL or AS+AQ were successfully followed-up. Both combinations were tolerated and effected rapid fever and parasite clearance. The crude ACPRs were 80 (87%) and 41 (63%) for AL and AS+AQ respectively. However, after PCR adjustments the corresponding figures raised to 100% (n = 86) and 93.8% (n = 45) in AL and AS+AQ groups, respectively. The mean haemoglobin improved moderately from day 0 to day 28 by 1 g/dl in AL and 0.4 g/dl in AS+AQ treatment group and was statistically significant (p < 0.001 both). CONCLUSION: These findings provide substantial evidence that AL is highly efficacious in areas of high resistance of SP and supported the country's decision to switch from SP monotherapy to AL.",17996121,"Africa","Tanzania","http://www.malariajournal.com/content/6/1/146","Yes","Not Available","Not Available"]
["Menard-2007","Menard, D.;Andrianina, N. N.;Ramiandrasoa, Z.;Randriamanantena, A.;Rasoarilalao, N.;Jahevitra, M.;Ratsimbasoa, A.;Tuseo, L.;Raveloson, A.",2007,"Randomized clinical trial of artemisinin versus non-artemisinin combination therapy for uncomplicated falciparum malaria in Madagascar","Malaria journal",6,65,"doi:10.1186/1475-2875-6-65","BACKGROUND: Data concerning antimalarial combination treatment for uncomplicated malaria in Madagascar are largely lacking. Randomized clinical trial was designed to assess therapeutic efficacies of chloroquine (CQ), amodiaquine (AQ), sulphadoxine-pyrimethamine (SP), amodiaquine plus sulphadoxine-pyrimethamine combination (AQ+SP) and artesunate plus amodiaquine combination (AQ+AS). METHODS: 287 children between 6 months and 15 years of age, with uncomplicated falciparum malaria, were enrolled in the study. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. RESULTS: All treatment regimens, except for CQ treatment, gave clinical cure rates above 97% by day-14 and 92% by day-28 (PCR-corrected). AQ+SP was as effective as AQ+AS. The risk of new infection within the month after therapy was generally higher for AQ+AS than AQ+SP. CONCLUSION: These findings show that the inexpensive and widely available combination AQ+SP may be valuable in for the treatment of uncomplicated malaria in Madagascar and could have an important role in this country, where much of the drugs administered go to patients who do not have malaria.",17519010,"Africa","Madagascar","http://www.malariajournal.com/content/6/1/65","Yes","Available","Excluded","Subset of Menard-2008 Study"]
["Osorio-2007","Osorio, L.;Gonzalez, I.;Olliaro, P.;Taylor, W. R.",2007,"Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia","Malaria journal",6,25,"doi:10.1186/1475-2875-6-25","BACKGROUND: Artemisinin-based combination therapy (ACT) is being widely promoted as a strategy to counteract the increase in Plasmodium falciparum antimalarial drug resistance. METHODS: A randomized, double-blind, placebo-controlled, clinical trial of the efficacy, effect on gametocytes and safety of the addition of artesunate/placebo (4 mg/kg/day x 3 d) to amodiaquine (10 mg/kg/day x 3 d) was conducted in Choco department, a low intensity transmission area in northwest Colombia. RESULTS: From 2,137 screened subjects, 85 entered the study: 43 in the amodiaquine plus placebo and 42 in the amodiaquine plus artesunate groups. Potentially eligible cases failed to qualify mostly because they were not available for follow-up visits (73%). Based on a per protocol analysis, the therapeutic response to both treatments was high: amodiaquine/placebo 35/36, 97.2% (95% CI 85.5-99.9), and amodiaquine/artesunate 32/32, 100% (89.1-100) after PCR genotyping. The Kaplan-Meier survival estimates based on all eligible patients enrolled (amodiaquine/placebo: n = 42; amodiaquine/artesunate: n = 41) were similar in the two study groups (P = 0.3). The addition of artesunate significantly decreased gametocyte carriage on Day 4 (OR = 0.1 95% CI 0.02-0.6), Day 7 (OR = 0.2 95%CI 0.04-0.9), Day 14 (OR = 0.09 95% CI 0-0.8), and Day 21 (OR95%CI 0-0.9). Most subjects in both groups (81% in amodiaquine/placebo and 75.6% in amodiaquine/artesunate) reported at least one drug related adverse event. Symptoms were generally mild and self-limiting and there was no serious adverse event. Two patients on amodiaquine/artesunate voluntarily withdrew from study because they could not tolerate the medication. CONCLUSION: Both drug regimens were effective in this area of Colombia. The addition of artesunate reduced gametocyte carriage and did not adversely affect tolerability. In this set of patients, the rate of adverse events was higher than in other studies. Patients' follow-up is problematic in areas with dispersed population and affects the conduct of clinical studies and monitoring of treatment effects. The results are discussed in the light of concurrent increase resistance to amodiaquine in other endemic areas in Colombia and the factors that may influence a change in the national antimalarial drug policy. ",17328806,"S.America","Colombia","http://www.malariajournal.com/content/6/1/25","Yes","Available","Included"]
["Oyakhirome-2007","Oyakhirome, S.;Potschke, M.;Schwarz, N. G.;Dornemann, J.;Laengin, M.;Salazar, C. O.;Lell, B.;Kun, J. F.;Kremsner, P. G.;Grobusch, M. P.",2007,"Artesunate--amodiaquine combination therapy for falciparum malaria in young Gabonese children","Malaria journal",6,29,"doi:10.1186/1475-2875-6-29","BACKGROUND: Artesunate-amodiaquine combination for the treatment of childhood malaria is one of the artemisinin combination therapies (ACTs) recommended by National authorities in many African countries today. Effectiveness data on this combination in young children is scarce. METHODS: The effectiveness of three daily doses of artesunate plus amodiaquine combination given unsupervised (n = 32), compared with the efficacy when given under full supervision (n = 29) to children with falciparum malaria were assessed in an unrandomized study. RESULTS: 61 patients analysed revealed a PCR-corrected day-28 cure rate of 86 % (25 of 29 patients; CI 69-95 %) in the supervised group and 63 % (20 of 32 patients; CI 45-77 %) in the unsupervised group. The difference in outcome between both groups was statistically significant (p = 0.04). No severe adverse events were reported. CONCLUSION: The effectiveness of this short course regimen in young children with falciparum malaria could be augmented by increased adherence and improved formulation.",17352806,"Africa","Gabon","http://www.malariajournal.com/content/6/1/29/abstract","Yes","Not Available","Not targetted","Patients followed up on day2 and day28 only"]
["Sowunmi-2007","Sowunmi, A.;Balogun, T.;Gbotosho, G. O.;Happi, C. T.;Adedeji, A. A.;Fehintola, F. A.",2007,"Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites in falciparum malaria in children","Antimicrobial agents and chemotherapy",51,5,"1694-9","The activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites were evaluated in 360 Nigerian children with uncomplicated Plasmodium falciparum malaria randomized to the standard dose regimens of the three drugs/combination. Clinical recovery from illness occurred in all children. There were no significant differences in fever clearance times. Patients treated with artesunate or artesunate-amodiaquine had significantly shorter parasite clearance times (1.4 +/- 0.5 days or 1.4 +/- 0.6 days versus 3.2 +/- 2.3 days, P = 0.0001) and lower gametocyte carriage rates (3.3 or 1.7% versus 11.7%, P = 0.001) than those treated with amodiaquine alone. Gametocytemia was detected in 62 patients (11.7% before treatment and 5.6% after treatment). The pretreatment gametocyte sex ratio, which was female biased, increased significantly during the course of treatment with amodiaquine but not with artesunate and artesunate-amodiaquine. These results suggest that artesunate and artesunate-amodiaquine reduce gametocyte carriage and may reduce transmissibility in P. falciparum malaria by accelerating asexual clearance and influencing gametocyte sex ratio.",17325222,"Africa","Nigeria","http://aac.asm.org/content/51/5/1694.abstract","Yes","Not Available","Not targetted","PCR Not Carried Out"]
["Tall-2007","Tall, A.;Rabarijaona, L. P.;Robert, V.;Bedja, S. A.;Ariey, F.;Randrianarivelojosia, M.",2007,"Efficacy of artesunate plus amodiaquine, artesunate plus sulfadoxine-pyrimethamine, and chloroquine plus sulfadoxine-pyrimethamine in patients with uncomplicated Plasmodium falciparum in the Comoros Union","Acta tropica",102,3,"176-81","Health policy makers in Comoros Union have considered a policy change recommending combination treatment to control malaria. We evaluated the efficacy of three antimalarial drug combinations, taken orally, to enable the authorities to make an evidence-based choice. The study was carried out in patients of 2-70 years old in Moroni, Moheli and Anjouan in 2003. We enrolled 168 patients with uncomplicated malaria from 1097 outpatients screened at the health centres. One hundred and fifty-eight patients, of whom half were under five years old, (mean age=11.1+/-13.9 years), were followed up for 14 days. According to PCR adjusted outcome, the therapeutic efficacy of artesunate+amodiaquine (AS+AQ) (n=54) and artesunate+sulfadoxine-pyrimethamine (AS+SP) (n=53) was 100%, whereas that of chloroquine+sulfadoxine-pyrimethamine (CQ+SP) was 98% (50/51). The key difference between these treatments was the higher parasite clearance rate on Day 2 obtained with artesunate-containing combinations (P<0.001). These results provide a baseline for monitoring changes in the susceptibility of Plasmodium falciparum to artesunate+amodiaquine and artesunate+sulfadoxine-pyrimethamine (ACTs) in the Comoros Union. Health policy changes involving the replacement of chloroquine in the Indian Ocean subregion are discussed.",17568549,"Africa","Comoros","http://www.sciencedirect.com/science/article/pii/S0001706X07001180","Yes","Not Available","Not targetted","<28 days follow up [14 day follow up study]"]
["Adjei-2008a","Adjei, G. O.;Kurtzhals, J. A.;Rodrigues, O. P.;Alifrangis, M.;Hoegberg, L. C.;Kitcher, E. D.;Badoe, E. V.;Lamptey, R.;Goka, B. Q.",2008,"Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up","Malaria journal",7,127,"doi: 10.1186/1475-2875-7-127","BACKGROUND: Artesunate-amodiaquine (AS+AQ) and artemether-lumefantrine (AM-L) are efficacious artemisinin combination therapy (ACT) regimens that have been widely adopted in sub-Saharan Africa. However, there is little information on the efficacy of these regimens on subsequent episodes beyond 28 days, or on the safety of repeated treatments. METHODS: Children aged six months to 14 years with uncomplicated malaria were randomly assigned to treatment with AS+AQ (n = 116), or AM-L (n = 111). Recruited subjects were followed-up, initially for 28 days, and then monthly for up to one year. All subsequent attacks of uncomplicated malaria after 28 days were treated with the same regimen as at randomization. Investigations aimed at determining efficacy and side effects were conducted. RESULTS: Adequate clinical and parasitological response in subjects with evaluable end-points were, 97.1% (100/103) and 98.2% (107/109) on day 14, and 94.2% (97/103) and 95.3% (102/107) on day 28 in the AM-L and AS+AQ groups, respectively. Similar results were obtained after PCR correction. The incidence of malaria attacks in the year following recruitment was similar between the two treatment groups (p = 0.93). There was a high incidence of potentially AQ-resistant parasites in the study area. The incidence of adverse events, such as pruritus, fatigue and neutropaenia were similar in the two treatment groups. No patient showed signs of hearing impairment, and no abnormal neurological signs were observed during one year of follow-up. Other adverse events were mild in intensity and overlapped with known malaria symptomatology. No adverse event exacerbation was observed in any of the subjects who received multiple treatment courses with these ACT regimens during one year follow-up. CONCLUSION: AS+AQ and AM-L were efficacious for treatment of children with uncomplicated malaria in Ghana and drug-related adverse events were rare in treated subjects during one year of follow-up. The high prevalence of potentially AQ resistant parasites raises questions about the utility of AQ as a partner drug for ACT in Ghana. The efficacy of AS+AQ in Ghana requires, therefore, continuous monitoring and evaluation. TRIAL REGISTRATION: NCT 00406146 http://www.clinicaltrials.gov.",18620577,"Africa","Ghana","http://www.malariajournal.com/content/7/1/127","Yes","Available","Excluded","Missing PCR and Dosing Information"]
["Adjei-2008b","Adjei GO, Kristensen K, Goka BQ, Hoegberg LC, Alifrangis M, Rodrigues OP, Kurtzhals JA",2008,"Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria.","ANTIMICROBIAL AGENTS AND CHEMOTHERAPY",52,12,"4400–4406","Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n = 15) or with AS plus AQ (n = 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentration-time curves (P = 0.68) and elimination half-lives (P = 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.",18779360,"Africa","Ghana",null,"Yes","Available","Excluded","Subset of Adjei-2008a (18620577): PK Patients"]
["Djimde-2008","Djimde, A. A.;Fofana, B.;Sagara, I.;Sidibe, B.;Toure, S.;Dembele, D.;Dama, S.;Ouologuem, D.;Dicko, A.;Doumbo, O. K.",2008,"Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali","The American journal of tropical medicine and hygiene",78,3,"455-61","We conducted a randomized single-blinded trial comparing the efficacy and safety of artesunate (AS) + amodiaquine (AQ, 3 days) versus AS (3 days) + sulfadoxine-pyrimethamine (SP, single dose) versus AS monotherapy (5 days) in Southern Mali. Uncomplicated malaria cases were followed for 28 days. Molecular markers of drug resistance were determined. After identification of recrudescences by genotyping, both artemisinin-based combination therapies (ACTs) reached nearly 100% efficacy at Day 14 and Day 28 versus 98.3% and 96.5% for AS, respectively (P > 0.05). AS + SP significantly selected DHFR and DHPS mutations associated with sulfadoxine and pyrimethamine resistance (P < 0.001), and AS + AQ equally selected PfCRT and PfMDR1 point mutations associated with chloroquine and AQ resistance (P < 0.001). No significant adverse event attributable to any of the study drugs was found. The ACTs were efficacious and safe, but the selection of markers for resistance to the partner drugs raises concerns over their lifespan in areas of intense malaria transmission.",18337343,"Africa","Mali","http://www.ajtmh.org/content/78/3/455","Yes","Available","Excluded","Missing Dosing Plan"]
["Falade-2008b","Falade, C. O.;Ogundele, A. O.;Yusuf, B. O.;Ademowo, O. G.;Ladipo, S. M.",2008,"High efficacy of two artemisinin-based combinations (artemether-lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria","Tropical medicine & international health",13,5,"635-43","OBJECTIVE: To test the hypothesis that artesunate plus amodiaquine (ASAQ) is as effective as artemether-lumefantrine (AL) in the treatment of acute uncomplicated malaria in Nigerian children. METHODS: In an open label, randomized controlled clinical trial, children aged 6 months to 10 years were randomized to receive artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) or AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily). Both drug regimens were given for 3 days and follow-up was for 28 days. RESULTS: A total of 132 children (66 in each group) were randomized to receive either ASAQ or AL. Day 28 cure rates in the per protocol (PP) population were 93% for ASAQ and 95% for AL (OR = 0.71, 95% CI = 0.12-3.99, rho = 0.66). Using Kaplan-Meier product-limit estimates of failure, the median survival time for ASAQ was 21 days and for AL 28 days (P = 0.294). PCR corrected day 28 cure rate for PP populations were 98.4% for ASAQ and 100% for AL. Both drugs were well-tolerated. CONCLUSION: ASAQ is as effective as AL and both combinations were efficacious and safe.",18346028,"Africa","Ghana","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2008.02043.x/abstract","Yes","Not Available","Not Available"]
["Fehintola-2008","Fehintola, F. A.;Adedeji, A. A.;Gbotosho, G. O.;Happi, C. T.;Balogun, S. T.;Folarin, O. A.;Sijuade, A. O.;Sowunmi, A.",2008,"Effects of artesunate-cotrimoxazole and amodiaquine-artesunate against asexual and sexual stages of Plasmodium falciparum malaria in Nigerian children","Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",14,3,"188-94","The activities of artesunate-cotrimoxazole and artesunate-amodiaquine combinations against asexual-and sexual-stage parasites were evaluated in 182 Nigerian children with uncomplicated Plasmodium falciparum malaria. One hundred and twenty-one children received artesunate-cotrimoxazole and 61 received artesunate-amodiaquine and all were followed up for 28 days. Clinical recovery from illness occurred in all children. There was no significant difference in fever clearance time (P = 0.35). Both treatment groups achieved a parasite clearance time of less than 2 days (1.84 +/- 0.66 days and 1.31 +/- 0.48 days); gametocyte carriage rates were comparable in the two treatment groups prior to and following treatment; both treatments appeared to reduce gametocyte carriage. The pretreatment gametocyte sex ratio, which was female-biased, was maintained throughout the period of follow up in both treatment groups. Reduction of gametocyte carriage by these two treatment regimens may reduce transmissibility in P. falciparum malaria, and this reduction is presumed to be related to the accelerated clearance of the asexual forms of the parasite.",18574653,"Africa","Nigeria","http://www.springerlink.com/content/u20x278761mq2734/","Yes","Not Available","Not Available"]
["Kobbe-2008","Kobbe, R.;Klein, P.;Adjei, S.;Amemasor, S.;Thompson, W. N.;Heidemann, H.;Nielsen, M. V.;Vohwinkel, J.;Hogan, B.;Kreuels, B.;Buhrlen, M.;Loag, W.;Ansong, D.;May, J.",2008,"A randomized trial on effectiveness of artemether-lumefantrine versus artesunate plus amodiaquine for unsupervised treatment of uncomplicated Plasmodium falciparum malaria in Ghanaian children","Malaria journal",7,261,"doi: 10.1186/1475-2875-7-261","BACKGROUND: Numerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria. METHODS: A randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam) or AL (Coartem). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews. RESULTS: Adequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00-5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05). CONCLUSION: Unobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.",19099594,"Africa","Ghana","http://www.malariajournal.com/content/7/1/261","Yes","Not Available","Not Available"]
["Koram-2008","Koram, K.;Quaye, L.;Abuaku, B.",2008,"Efficacy of amodiaquine/artesunate combination therapy for uncomplicated malaria in children under five years in ghana","Ghana medical journal",42,2,"55-60","BACKGROUND: In 2005, following several years of declining efficacy of chloroquine, the Ministry of Health recommended the use of Amodiaquine/Artesunate combination therapy for the treatment of uncomplicated malaria. A system of continuous monitoring of therapeutic responses has been established in 10 district hospitals across the country. The data gathered will enable National Malaria Control Programme (NMCP) to respond to changes in the efficacy of the new treatment in a timely manner. OBJECTIVES: To determine the 28 day therapeutic efficacy of Amodiaquine/Artesunate (AQ/AS) combination treatment in children with uncomplicated malaria in Ghana. METHODS: Children aged 6 - 59 months attending clinic with signs/symptoms of uncomplicated malaria at 9 district hospitals (3 in each of the 3 eco-epidemiological zones of the country) were eligible for enrolment. Enrolled children were followed up after treatment for a total of 28 days to record the clinical and parasitological resolution of their malaria episode as well as any adverse drug reactions. RESULTS: Treatment resulted in rapid and complete cure in almost all the children; 99.3% 14 days after treatment and 93.0%, 28 days after treatment. The majority of treatment failures on D28 were seen in the 3 sites located in the forest zones (Sunyani, Bekwai and Begoro). There was no case of Early Treatment Failure at both D14 and D28 assessments. Adverse events (AE's) were minimal, less than 4%, with the most common complaint being vomiting. CONCLUSION: AQ/AS combination for uncomplicated malaria is efficacious and safe in children less than 5 years.",19180204,"Africa","Ghana","http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631265/?report=abstract","Yes","Not Available","Not targetted","PCR results not carried out for this priliminary report"]
["Maiteki-Sebuguzi-2008","Maiteki-Sebuguzi, C.;Jagannathan, P.;Yau, V. M.;Clark, T. D.;Njama-Meya, D.;Nzarubara, B.;Talisuna, A. O.;Kamya, M. R.;Rosenthal, P. J.;Dorsey, G.;Staedke, S. G.",2008,"Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children","Malaria journal",7,106,"doi: 10.1186/1475-2875-7-106","BACKGROUND: Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. METHODS: A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. RESULTS: Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings. CONCLUSION: This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential. TRIAL REGISTRATION: Current Controlled Trials Identifier ISRCTN37517549.",18547415,"Africa","Uganda","http://www.malariajournal.com/content/7/1/106","Yes","Not Available","Not targetted","<28 days follow up [14 day follow up study]"]
["Menard-2008","Menard, D.;Ratsimbasoa, A.;Randrianarivelojosia, M.;Rabarijaona, L. P.;Raharimalala, L.;Domarle, O.;Randrianasolo, L.;Randriamanantena, A.;Jahevitra, M.;Andriantsoanirina, V.;Rason, M. A.;Raherinjafy, R.;Rakotomalala, E.;Tuseo, L.;Raveloson, A.",2008,"Assessment of the efficacy of antimalarial drugs recommended by the National Malaria Control Programme in Madagascar: up-dated baseline data from randomized and multi-site clinical trials","Malaria journal",7,55,"doi: 10.1186/1475-2875-7-55.","BACKGROUND: In order to improve the monitoring of the antimalarial drug resistance in Madagascar, a new national network based on eight sentinel sites was set up. In 2006/2007, a multi-site randomized clinical trial was designed to assess the therapeutic efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP), amodiaquine (AQ) and artesunate plus amodiaquine combination (ASAQ), the antimalarial therapies recommended by the National Malaria Control Programme (NMCP). METHODS: Children between six months and 15 years of age, with uncomplicated falciparum malaria, were enrolled. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Risks of clinical and parasitological treatment failure after adjustment by genotyping were estimated using Kaplan-Meier survival analysis. Secondary outcomes included fever clearance, parasite clearance, change in haemoglobin levels between Day 0 and the last day of follow-up, and the incidence of adverse events. RESULTS: A total of 1,347 of 1,434 patients (93.9%) completed treatment and follow-up to day 28. All treatment regimens, except for the chloroquine (CQ) treatment group, resulted in clinical cure rates above 97.6% by day-14 and 96.7% by day-28 (adjusted by genotyping). Parasite and fever clearance was more rapid with artesunate plus amodiaquine, but the extent of haematological recovery on day-28 did not differ significantly between the four groups. No severe side-effects were observed during the follow-up period. CONCLUSION: These findings (i) constitute an up-dated baseline data on the efficacy of antimalarial drugs recommended by the NMCP, (ii) show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago and (iii) support the current policy of ASAQ as the first-line treatment in uncomplicated falciparum malaria.",18394169,"Africa","Madagascar","http://www.malariajournal.com/content/7/1/55","Yes","Available","Included"]
["Ndiaye-2008","Ndiaye, J. L.;Faye, B.;Diouf, A. M.;Kuete, T.;Cisse, M.;Seck, P. A.;Brasseur, P.;Same-Ekobo, A.;Lameyre, V.;Gaye, O.",2008,"Randomized, comparative study of the efficacy and safety of artesunate plus amodiaquine, administered as a single daily intake versus two daily intakes in the treatment of uncomplicated falciparum malaria","Malaria journal",7,16,"doi: 10.1186/1475-2875-7-16.","BACKGROUND: Artesunate plus amodiaquine is a coblistered ACT, given as a single daily intake. It has been suggested that, in view of the number of tablets to be taken (particularly in adults), it may be possible to improve compliance by allowing patients to divide the daily dose. The objectives of this randomized, comparative, open-label, multicentre study, conducted in Senegal and in Cameroon in 2005, was to demonstrate the non-inferiority and to compare the safety of artesunate plus amodiaquine, as a single daily intake versus two daily intakes. METHODS: A three-day treatment period and 14-day follow-up period was performed in any subject weighting more than 10 kg, presenting with a malaria paroxysm confirmed by parasitaemia > or = 1,000/microl, after informed consent. Patients were randomly allocated into one of the two regimens, with dosage according to bodyweight range. All products were administered by an authorized person, blinded to both the investigating physician and the biologist. The primary endpoint was an adequate response to treatment on D14 (WHO definition). The two-sided 90% confidence interval of the difference was calculated on intent to treat (ITT) population; the acceptance limit for non-inferiority was 3%. The safety was evaluated by incidence of adverse events. RESULTS: Three-hundred and sixteen patients were included in the study. The two patient groups were strictly comparable on D0. The adequate responses to treatment were similar for the two treatment regimens on D14, PCR-corrected (99,4% in the one-daily intake group versus 99,3% in the comparative group). The statistical analyses demonstrated the non-inferiority of administering artesunate/amodiaquine as two intakes. The drug was well tolerated. The main adverse events were gastrointestinal disorders (2.5%) and pruritus (2.5%); safety profiles were similar in the two groups. CONCLUSION: This pilot study confirms the efficacy and good tolerability of artesunate plus amodiaquine, administrated either in one or in two daily intakes.",18205945,"Africa","Multicentred","http://www.malariajournal.com/content/7/1/16","Yes","Available","Not targetted","<28 days follow up [14 day follow up study]"]
["Oduro-2008","Oduro, A. R.;Anyorigiya, T.;Anto, F.;Amenga-Etego, L.;Ansah, N. A.;Atobrah, P.;Ansah, P.;Koram, K.;Hodgson, A.",2008,"A randomized, comparative study of supervised and unsupervised artesunate-amodiaquine, for the treatment of uncomplicated malaria in Ghana","Annals of tropical medicine and parasitology",102,7,"565-76","Although the use of artesunate-amodiaquine treatment is growing in Africa, data on its effectiveness are limited. In only the second published comparison of supervised and unsupervised treatments with this combination, Ghanaian children with uncomplicated malaria have recently been investigated in an open-label, randomized, comparative study. Children aged 6-120 months attending the Navrongo War Memorial hospital between November 2005 and December 2006 were enrolled if they had uncomplicated Plasmodium falciparum malaria and at least one of their parents/guardians gave their informed consent. Overall, 638 patients were screened, 357 were found to have P. falciparum infection, and 308 of these satisfied the other selection criteria and were enrolled. The subjects were divided randomly into two treatment arms. All the children were scheduled to receive 10 mg amodiaquine/kg and 4 mg artesunate/kg daily for 3 days but only 154 (the 'supervised') were given all their treatments in hospital, with each dose directly observed. Although the other 154 children (the 'unsupervised') were given their first dose in hospital, under supervision, they were then sent home with the tablets they required to complete treatment. Study participation lasted for 28 days, with follow-up on days 3, 7, 14, 21 and 28. During follow-up, axillary temperatures, any emergent signs and symptoms, and concomitant drug consumption were recorded and haemoglobin concentrations and malarial parasitaemias and gametocytaemias were measured. All but seven of the 308 subjects completed the study. At enrolment the subjects had a mean age of 45.0 months, a mean weight of 14.8 kg, a mean axillary temperature of 37.9 degrees C and a geometric mean parasitaemia of 11,367 asexual stages/microl. About 55% of the children investigated were girls. There were no significant baseline difference between the two treatment arms. Although there was also no difference in the clearance of fever and parasitaemia between the two arms by day 14, a supervised child was significantly more likely to show an adequate clinical and parasitological response, by day 21 (91.3% v. 84.1%; P= 0.05) or day 28 (80.0% v. 64.9%; P<0.01), than an unsupervised child. The reported adverse effects following treatment and the trend in haemoglobin recovery were, however, similar in the two arms. Although artesunate-amodiaquine appeared very effective in the treatment of uncomplicated P. falciparum malaria in children, whether supervised or not, it appears that supervised treatment provided stronger prevention against re-infection and recrudescence. At least in the present study, treatment at home, without medical supervision, probably led to relatively poor compliance.",18817597,"Africa","Ghana","http://www.maneyonline.com/doi/abs/10.1179/136485908X337508?token=00601f4f9ef9b91a34af9117e2a46762c6b795d7a6646706a494a5f24673f7b2f27375f2a72752d704254a57d61b6cde","Yes","Not Available","Not Available"]
["Owusu-Agyei-2008","Owusu-Agyei, S.;Asante, K. P.;Owusu, R.;Adjuik, M.;Amenga-Etego, S.;Dosoo, D. K.;Gyapong, J.;Greenwood, B.;Chandramohan, D.",2008,"An open label, randomised trial of artesunate+amodiaquine, artesunate+chlorproguanil-dapsone and artemether-lumefantrine for the treatment of uncomplicated malaria","PloS one",3,6,"e2530","BACKGROUND: Artesunate+amodiaquine (AS+AQ) and artemether-lumefantrine (AL) are now the most frequently recommended first line treatments for uncomplicated malaria in Africa. Artesunate+chlorproguanil-dapsone (AS+CD) was a potential alternative for treatment of uncomplicated malaria. A comparison of the efficacy and safety of these three drug combinations was necessary to make evidence based drug treatment policies. METHODS: Five hundred and thirty-four, glucose-6-phosphate dehydrogenase (G6PD) normal children were randomised in blocks of 15 to the AS+AQ, AL or AS+CD groups. Administration of study drugs was supervised by project staff and the children were followed up at r home on days 1,2,3,7,14 and 28 post treatment. Parasitological and clinical failures and adverse events were compared between the study groups. MAIN FINDINGS: In a per-protocol analysis, the parasitological and clinical failure rate at day 28 post treatment (PCF28) was lower in the AS+AQ group compared to the AL or AS+CD groups (corrected for re-infections: 6.6% vs 13.8% and 13.8% respectively, p = 0.08; uncorrected: 14.6% vs 27.6% and 28.1% respectively, p = 0.005). In the intention to treat analysis, the rate of early treatment failure was high in all three groups (AS+AQ 13.3%; AL 15.2%; and AS+CD 9.3%, p = 0.2) primarily due to vomiting. However, the PCF28 corrected for re-infection was lower, though not significantly, in the AS+AQ group compared to the AL or the AS+CD groups (AS+AQ 18.3%; AL 24.2%; AS+CD 20.8%, p = 0.4) The incidence of adverse events was comparable between the groups. CONCLUSIONS: AS+AQ is an appropriate first line treatment for uncomplicated malaria in Ghana and possibly in the neighbouring countries in West Africa. The effectiveness of AL in routine programme conditions needs to be studied further in West Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119145.",18575626,"Africa","Ghana","http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002530","Yes","Not Available","Not Available"]
["Zoungrana-2008","Zoungrana, A.;Coulibaly, B.;Sie, A.;Walter-Sack, I.;Mockenhaupt, F. P.;Kouyate, B.;Schirmer, R. H.;Klose, C.;Mansmann, U.;Meissner, P.;Muller, O.",2008,"Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso","PloS one",3,2,"e1630","BACKGROUND: Besides existing artemisinin-based combination therapies, alternative safe, effective and affordable drug combinations against falciparum malaria are needed. Methylene blue (MB) was the first synthetic antimalarial drug ever used, and recent studies have been promising with regard to its revival in malaria therapy. The objective of this study was to assess the safety and efficacy of two MB-based malaria combination therapies, MB-artesunate (AS) and MB-amodiaquine (AQ), compared to the local standard of care, AS-AQ, in Burkina Faso. METHODS AND FINDINGS: Open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria in Nouna, north-western Burkina Faso. Follow-up was for 28 days and analysis by intention-to-treat. The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. No drug-related serious adverse events and no deaths occurred. MB-containing regimens were associated with mild vomiting and dysuria. No early treatment failures were observed. Parasite clearance time differed significantly among groups and was the shortest with MB-AS. By day 14, the rates of adequate clinical and parasitological response after PCR-based correction for recrudescence were 87% for MB-AS, 100% for MB-AQ (p = 0.004), and 100% for AS-AQ (p = 0.003). By day 28, the respective figure was lowest for MB-AS (62%), intermediate for the standard treatment AS-AQ (82%; p = 0.015), and highest for MB-AQ (95%; p<0.001; p = 0.03). CONCLUSIONS: MB-AQ is a promising alternative drug combination against malaria in Africa. Moreover, MB has the potential to further accelerate the rapid parasite clearance of artemisinin-based combination therapies. More than a century after the antimalarial properties of MB had been described, its role in malaria control deserves closer attention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00354380.",18286187,"Africa","Uganda","http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001630","Yes","Not Available","Not Targetted","Methylene Blue Study"]
["Asih-2009","Asih, P. B.;Dewi, R. M.;Tuti, S.;Sadikin, M.;Sumarto, W.;Sinaga, B.;van, d. V. A. J.;Sauerwein, R. W.;Syafruddin, D.",2009,"Efficacy of artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province, Indonesia, and genotypic profiles of the parasite","The American journal of tropical medicine and hygiene",80,6,"914-8","Reports on treatment failures associated with the use of first-and second-line antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have recently increased in many parts of Indonesia. The present study evaluated artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province. A total of 103 persons 1-57 years of age were enrolled, given standard artesunate-amodiaquine therapy, and followed-up for 28 days. All persons clinically recovered, but two persons were again parasitemic on day 7. This finding indicated that these two persons had recurrent parasitemias on days 21 and 28. Molecular analyses suggested both recurrences were caused by reinfections. There were no severe adverse events, but complaints of gastrointestinal upset, nausea and vomiting, and headache linked to therapy occurred among 9.7%, 5.8% and 5.8% of the persons, respectively. Artesunate-amodiaquine proved efficacious therapy for treatment of persons with uncomplicated P. falciparum malaria at one site in eastern Indonesia but it may have tolerability problems that merit further investigation.",19478248,"Asia","Indonesia","http://www.ajtmh.org/content/80/6/914","Yes","Not Available","Not Available"]
["Bonnet-2009","Bonnet, M.;Broek, I.;van, H. M.;Urrutia, P. P.;van, O. C.;Kyomuhendo, J.;Ndosimao, C. N.;Ashley, E.;Guthmann, J. P.",2009,"Varying efficacy of artesunate+amodiaquine and artesunate+sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in the Democratic Republic of Congo: a report of two in-vivo studies","Malaria journal",8,192,"doi: 10.1186/1475-2875-8-192","BACKGROUND: Very few data on anti-malarial efficacy are available from the Democratic Republic of Congo (DRC). DRC changed its anti-malarial treatment policy to amodiaquine (AQ) and artesunate (AS) in 2005. METHODS: The results of two in vivo efficacy studies, which tested AQ and sulphadoxine-pyrimethamine (SP) monotherapies and AS+SP and AS+AQ combinations in Boende (Equatorial province), and AS+SP, AS+AQ and SP in Kabalo (Katanga province), between 2003 and 2004 are presented. The methodology followed the WHO 2003 protocol for assessing the efficacy of anti-malarials in areas of high transmission. RESULTS: Out of 394 included patients in Boende, the failure rates on day 28 after PCR-genotyping adjustment of AS+SP and AS+AQ were estimated as 24.6% [95% CI: 16.6-35.5] and 15.1% [95% CI: 8.6-25.7], respectively. For the monotherapies, failure rates were 35.9% [95% CI: 27.0-46.7] for SP and 18.3% [95% CI: 11.6-28.1] for AQ. Out of 207 patients enrolled in Kabalo, the failure rate on day 28 after PCR-genotyping adjustment was 0 [1-sided 95% CI: 5.8] for AS+SP and AS+AQ [1-sided 95% CI: 6.2]. It was 19.6% [95% CI: 11.4-32.7] for SP monotherapy. CONCLUSION: The finding of varying efficacy of the same combinations at two sites in one country highlights one difficulty of implementing a uniform national treatment policy in a large country. The poor efficacy of AS+AQ in Boende should alert the national programme to foci of resistance and emphasizes the need for systems for the prospective monitoring of treatment efficacy at sentinel sites in the country.",19664280,"Africa","Democratic Republic of Congo","http://www.malariajournal.com/content/8/1/192","Yes","Available","Excluded","Missing PCR"]
["Brasseur-2009","Brasseur P, Agnamey P, Gaye O, Cisse M, Badiane M, Vaillant M, Taylor WR, Olliaro P",2009,"Dosing accuracy of artesunate and amodiaquine as treatment for falciparum malaria in Casamance, Senegal","Malaria journal",14,1,"79-87","Abstract OBJECTIVES: Several products of artesunate plus amodiaquine (AS + AQ) are being deployed in malaria-endemic countries for treating uncomplicated falciparum malaria but dosing accuracy and consequential effects on efficacy and tolerability have not been examined. METHODS: Patients with parasitologically confirmed, uncomplicated falciparum malaria were treated and followed by research teams or local health centre staff in Casamance, Senegal. AS + AQ was given as: (i) loose combination (AS 50 mg, AQ 200 mg), dosed on body weight, or (ii) co-blistered product (AS 50 mg, AQ 153 mg) dosed by weight or age. Target doses were: (i) AS 4 (2-10) mg/kg/day and (ii) AQ 10 (7.5-15) mg/kg/day. Patients receiving therapeutic doses defined dosing accuracy. Treatment-emergent signs and symptoms (TESS) were recorded. RESULTS: A total of 3277 patients were treated with loose (n = 1972, weight-dosed) or co-blistered (n = 1305, 962 age-dosed, 343 weight-dosed) AS + AQ by the research team (n = 966) or clinic staff (n = 2311). AS was dosed correctly in >99% with all regimens. Loose AQ by weight was 98% correct. The co-blister AQ overdosed 18% of patients when dosed by age and underdosed 13% by weight. Low weight was an independent risk factor for overdosing. The co-blister had significantly more TESS than the loose product [117/1305 (9%) vs. 41/1972 (2%), relative risk = 4.3 (95% CI: 3.0-6.1, P < 0.0001)]. Age-based dosing accounted for the difference. TESS occurred mostly within one day (72%) and were mild or moderate (75%).\nCONCLUSION:Artesunate is easier to dose than AQ. Currently available age-dosed, co-blistered AS + AQ tends to overdose AQ and is less well tolerated than loose tablets. It is not the optimal presentation of AS + AQ.",19021893,"Africa","Senegal","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2008.02190.x/abstract;jsessionid=23591FEA1F14AC5508DB7F948999CA58.f04t02","Yes","Available","Included"]
["Faucher-2009","Faucher, J. F.;Aubouy, A.;Adeothy, A.;Cottrell, G.;Doritchamou, J.;Gourmel, B.;Houze, P.;Kossou, H.;Amedome, H.;Massougbodji, A.;Cot, M.;Deloron, P.",2009,"Comparison of sulfadoxine-pyrimethamine, unsupervised artemether-lumefantrine, and unsupervised artesunate-amodiaquine fixed-dose formulation for uncomplicated plasmodium falciparum malaria in Benin: a randomized effectiveness noninferiority trial","The Journal of infectious diseases",200,1,"57-65","BACKGROUND: We compared sulfadoxine-pyrimethamine (SP) with unsupervised artemether-lumefantrine (AL) and unsupervised amodiaquine-artesunate (ASAQ) fixed-dose formulation for the treatment of uncomplicated malaria in children in Benin. METHODS: This open-label, noninferiority comparative trial included children aged 6-60 months. The follow-up period was 6 weeks, and the primary objective was a comparison of polymerase chain reaction (PCR)-adjusted effectiveness rates at day 28. RESULTS: The study included 240 children (48 received SP, and 96 each received AL and ASAQ). The intention-to-treat analysis showed effectiveness rates on day 28 of 20.8%, 78.1%, and 70.5% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 27.1%, 83.3%, and 87.4%, respectively. The per-protocol analysis (217 patients) showed effectiveness rates on day 28 of 21.7%, 88.0%, and 76.1% for SP, AL, and ASAQ, respectively. After adjustment for PCR results, these rates were 28.3%, 94.0%, and 93.2%, respectively. SP was less effective than the other drugs in the PCR-adjusted analysis, whereas AL and ASAQ were equally effective. The rate of new infection was higher among children treated with ASAQ than among those treated with AL. CONCLUSIONS: This was the first trial, to our knowledge, to compare unsupervised AL with unsupervised ASAQ fixed-dose formulation; both treatments provided high PCR-adjusted day 28 effectiveness rates. Efficacy rates for SP were surprisingly low. Clinical trials registration. NCT00460369.",19469703,"Africa","Benin","http://www.ncbi.nlm.nih.gov/pubmed/19469703","Yes","Available","Included"]
["Kayentao-2009","Kayentao, K.;Maiga, H.;Newman, R. D.;McMorrow, M. L.;Hoppe, A.;Yattara, O.;Traore, H.;Kone, Y.;Guirou, E. A.;Saye, R.;Traore, B.;Djimde, A.;Doumbo, O. K.",2009,"Artemisinin-based combinations versus amodiaquine plus sulphadoxine-pyrimethamine for the treatment of uncomplicated malaria in Faladje, Mali","Malaria journal",8,5,"doi: 10.1186/1475-2875-8-5","BACKGROUND: Because of the emergence of chloroquine resistance in Mali, artemether-lumefantrine (AL) or artesunate-amodiaquine (AS+AQ) are recommended as first-line therapy for uncomplicated malaria, but have not been available in Mali until recently because of high costs. METHODS: From July 2005 to January 2006, a randomized open-label trial of three oral antimalarial combinations, namely AS+AQ, artesunate plus sulphadoxine-pyrimethamine (AS+SP), and amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP), was conducted in Faladje, Mali. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish new from recrudescent Plasmodium falciparum infections. RESULTS: 397 children 6 to 59 months of age with uncomplicated Plasmodium falciparum malaria were enrolled, and followed for 28 days to assess treatment efficacy. Baseline characteristics were similar in all three treatment groups. The uncorrected rates of adequate clinical and parasitologic response (ACPR) were 55.7%, 90.8%, and 97.7% in AS+AQ, AS+SP, and AQ+SP respectively (p < 0.001); after PCR correction ACPR rates were similar among treatment groups: 95.4%, 96.9%, and 99.2% respectively (p = 0.17). Mean haemoglobin concentration increased across all treatment groups from Day 0 (9.82 +/- 1.68 g/dL) to Day 28 (10.78 +/- 1.49 g/dL) (p < 0.001), with the greatest improvement occurring in children treated with AQ+SP. On Day 2, the prevalence of parasitaemia was significantly greater among children treated with AQ+SP (50.8%) than in children treated with AS+AQ (10.5%) or AS+SP (10.8%) (p < 0.001). No significant difference in gametocyte carriage was found between groups during the follow-up period. CONCLUSION: The combination of AQ+SP provides a potentially low cost alternative for treatment of uncomplicated P. falciparum infection in Mali and appears to have the added value of longer protective effect against new infection.",19128455,"Africa","Mali","http://www.malariajournal.com/content/8/1/5/abstract","Yes","Available","Included"]
["Mutabingwa-2009","Mutabingwa, T. K.;Muze, K.;Ord, R.;Briceno, M.;Greenwood, B. M.;Drakeley, C.;Whitty, C. J.",2009,"Randomized trial of artesunate+amodiaquine, sulfadoxine-pyrimethamine+amodiaquine, chlorproguanal-dapsone and SP for malaria in pregnancy in Tanzania","PloS one",4,4,"e5138","BACKGROUND: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria. METHODS: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28. RESULTS: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site. CONCLUSIONS: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00146731.",19352498,"Africa","Tanzania","http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005138","Yes","Not Available","Not targetted","Study in pregnant women"]
["Ndiaye-2009","Ndiaye, J. L.;Randrianarivelojosia, M.;Sagara, I.;Brasseur, P.;Ndiaye, I.;Faye, B.;Randrianasolo, L.;Ratsimbasoa, A.;Forlemu, D.;Moor, V. A.;Traore, A.;Dicko, Y.;Dara, N.;Lameyre, V.;Diallo, M.;Djimde, A.;Same-Ekobo, A.;Gaye, O.",2009,"Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria","Malaria journal",8,125,"doi: 10.1186/1475-2875-8-125","BACKGROUND: The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine (ASAQ) was recently developed. To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. METHODS: A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. RESULTS: Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. CONCLUSION: The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. TRIAL REGISTRATION: The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.",19505304,"Africa","Multicentred","http://www.malariajournal.com/content/8/1/125/","Yes","Available","Included"]
["Sinou-2009","Sinou, V.;Malaika, L. T.;Taudon, N.;Lwango, R.;Alegre, S. S.;Bertaux, L.;Sugnaux, F.;Parzy, D.;Benakis, A.",2009,"Pharmacokinetics and pharmacodynamics of a new ACT formulation: Artesunate/Amodiaquine (TRIMALACT) following oral administration in African malaria patients","European journal of drug metabolism and pharmacokinetics",34,"3/4","133-42","A new fixed-dose combination of artesunate (AS) plus amodiaquine (AQ) (TRIMALACT) was recently developed for the treatment of uncomplicated falciparum malaria. The originality of this combination lies in its galenic formulation which consists of a three-layer tablet with two layers containing each of the active ingredients, i.e. AS and AQ, and these are separated by a middle layer containing an antioxidant compound. To evaluate the efficacy and tolerability of this combination, adults with uncomplicated malaria received three administrations of two tablets (100:300 mg AS/AQ) in a 24-h interval, in Democratic Republic of Congo. Parasitemia and fever were measured and the plasma levels of parent compounds and metabolites [dihydroartemisinin (DHA) and monodesethylamodiaquine (MdAQ)] were determined by high-performance liquid chromatography. In addition, we determined the prevalence of molecular markers of resistance to chloroquine (CQ) and sulfadoxine/pyrimethamine (SP). The AS/AQ combination TRIMALACT demonstrated a good efficacy resulting in an excellent clinical and parasitological response rate of 100% after correction for PCR results. Treatment regimen was well tolerated. The main disposition parameters to AS+AQ were: for DHA, AUC = 632 +/- 475 ng h/ml and Cmax = 432 +/- 325 ng/ml, and for MdAQ = 14268 +/- 4114 ng h/ml and Cmax = 336 +/- 225 ng/ml (mean +/- standard deviation). Parasite genotyping show high frequencies of molecular SP- and CQ-resistance markers with more 80% of the samples showing more than three mutations linked to SP resistance and 93.48% carrying parasite with the CQ-resistant haplotype. This study shows that the AS/AQ combination TRIMALACT is safe and effective in the treatment of highly drug-resistant falciparum malaria.",20166428,"Africa","Democratic Republic of Congo","http://www.springerlink.com/content/hu815317ru434782/","Yes","Available","Included"]
["Sirima-2009","Sirima, S. B.;Tiono, A. B.;Gansane, A.;Diarra, A.;Ouedraogo, A.;Konate, A. T.;Kiechel, J. R.;Morgan, C. C.;Olliaro, P. L.;Taylor, W. R.",2009,"The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum","Malaria journal",8,48,"doi: 10.1186/1475-2875-8-48","BACKGROUND: Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested. METHODS: A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety. RESULTS: Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients. CONCLUSION: Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07576538.",19291301,"Africa","Burkina Faso","http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662869/","Yes","Available","Included"]
["Thanh-2009","Thanh, N. X.;Trung, T. N.;Phong, N. C.;Thien, N. X.;Dai, B.;Shanks, G. D.;Chavchich, M.;Edstein, M. D.",2009,"Open label randomized comparison of dihydroartemisinin-piperaquine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam","Tropical medicine & international health",14,5,"504-11","OBJECTIVE: Artesunate-amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin-piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam. METHODS: Open, randomized clinical trial of 116 patients (36 children aged 6-14 years, 80 adults aged 15-60 years) were randomly allocated a 3-day course of either DHP (approximately 2.3 mg/kg dihydroartemisinin plus approximately 18.5 mg/kg of piperaquine per day) or AAQ (approximately 4.4 mg/kg of artesunate plus approximately 10.6 mg/kg of amodiaquine per day). The follow-up period was 42 days. RESULTS: The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49/49) and 98% (48/49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater post-treatment prophylactic activity than AAQ. CONCLUSION: AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.",19320869,"Asia","Vietnam","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2009.02269.x/abstract","Yes","Not Available","Not Available"]
["Thwing-2009","Thwing, J. I.;Odero, C. O.;Odhiambo, F. O.;Otieno, K. O.;Kariuki, S.;Ord, R.;Roper, C.;McMorrow, M.;Vulule, J.;Slutsker, L.;Newman, R. D.;Hamel, M. J.;Desai, M.",2009,"In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya","Tropical medicine & international health",14,3,"294-300","OBJECTIVES: To assess the efficacy of amodiaquine-artesunate in an area with high chloroquine resistance in western Kenya. METHODS: Twenty-eight day in-vivo efficacy trial of amodiaquine-artesunate in 103 children aged 6-59 months in western Kenya with smear-confirmed uncomplicated Plasmodium falciparum malaria. RESULTS: The 28-day uncorrected adequate clinical and parasitological response (ACPR) was 69.0%, with 15.5% Late Clinical Failure and 15.5% Late Parasitologic Failure rates. The PCR-corrected 28-day ACPR was 90.2%. Clinical risk factors for recurrent infection (recrudescences and reinfections) were lower axillary temperature at enrollment and low weight-for-age Z-score. The presence of single nucleotide polymorphisms pfcrt 76T and pfmdr1 86Y at baseline was associated with increased risk of recurrent infections, both reinfections and recrudescences. CONCLUSION: Although artemether-lumefantrine (Coartem) is the first line ACT in Kenya, amodiaquine-artesunate is registered as an option for treatment of uncomplicated P. falciparum and remains an effective alternative to Coartem in western Kenya. Continued amodiaquine monotherapy in the private sector may jeopardize the future use of amodiaquine-artesunate as an alternative artemisinin-based combination therapy.",19187521,"Africa","Kenya","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2009.02222.x/abstract","Yes","Available","Included"]
["Warsame-2009","Warsame, M.;Atta, H.;Klena, J. D.;Waqar, B. A.;Elmi, H. H.;Jibril, A. M.;Hassan, H. M.;Hassan, A. M.",2009,"Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia","Acta tropica",109,2,"146-51","In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.",19026606,"Africa","Somalia","http://www.sciencedirect.com/science/article/pii/S0001706X08002969","Yes","Not Available","Not Available"]
["Zwang-2009","Julien Zwang, Piero Olliaro, Hubert Barennes, Maryline Bonnet, Philippe Brasseur, Hasifa Bukirwa, Sandra Cohuet, Umberto D'Alessandro, Abdulaye Djimdé, Corine Karema, Jean-Paul Guthmann, Sally Hamour, Jean-Louis Ndiaye, Andreas Mårtensson, Claude Rwagacondo, Issaka Sagara, Albert Same- Ekobo, Sodiomon B Sirima, Ingrid van den Broek, Adoke Yeka, Walter RJ Taylor, Grant Dorsey and Milijaona Randrianarivelojosia",2009,"Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis.","Malaria journal",8,203,"doi:10.1186/1475-2875-8-203","BACKGROUND:Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. METHODS:An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. RESULTS:A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. CONCLUSION: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.",19698172,"Africa","Multicentred",null,"Yes","Available","Not Targetted ","Pooled Analysis"]
["Ayede-2010","Ayede, I. A.;Falade, A. G.;Sowunmi, A.;Jansen, F. H.",2010,"An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours)","Malaria journal",9,378,"doi: 10.1186/1475-2875-9-378","BACKGROUND: Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT) across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance. METHODS: Children aged one year to 13 years presenting with uncomplicated Plasmodium falciparum malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of artesunate/sulphamethoxypyrazine/pyrimethamine (AS + SMP) (12 hourly doses over 24 hours) or three doses of artesunate/amodiaquine (AS + AQ) (daily doses over 48 hours). Efficacy and safety of the two drugs were assessed using a 28-day follow-up and the primary outcome was PCR- corrected parasitological cure rate and clinical response. RESULTS: There were two (0.4%) early treatment failures, one in each treatment arm. The PCR corrected cure rates for day 28 was 97.9% in the AS + AQ arm and 95.6% in the AS + SMP arm (p = 0.15). The re-infection rate was 1.7% in the AS + AQ arm and 5.7% in the AS + SMP arm (p = 0.021). The fever clearance time was similar in the two treatment groups: 1 - 2 days for both AS + SMP and AS + AQ (p = 0.271). The parasite clearance time was also similar in the two treatment groups with 1 - 7 days for AS + SMP and 1 - 4 days for AS + AQ (p = 0.941). The proportion of children with gametocytes over the follow-up period was similar in both treatment groups. Serious Adverse Events were not reported in any of the patients and in all children, laboratory values (packed cell volume, liver enzymes, bilirubin) remained within normal levels during the follow-up period but the packed cell volume was significantly lower in the AS + SMP group. CONCLUSIONS: This study demonstrates that AS + SMP FDC given as three doses over 24 hours (12-hour intervals) has similar efficacy as AS + AQ FDC given as three doses over 48 hours (24-hour interval) for the treatment of uncomplicated Plasmodium falciparum malaria in children in Nigeria. Both drugs also proved to be safe. Therefore, AS + SMP could be an alternative to currently recommended first-line ACT with continuous resistance surveillance.",21194422,"Africa","Nigeria","http://www.malariajournal.com/content/9/1/378","Yes","Not Available","Not Available"]
["Clark-2010","Clark, T. D.;Njama-Meya, D.;Nzarubara, B.;Maiteki-Sebuguzi, C.;Greenhouse, B.;Staedke, S. G.;Kamya, M. R.;Dorsey, G.;Rosenthal, P. J.",2010,"Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children","PloS one",5,7,"e11759","BACKGROUND: Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen. CONCLUSIONS/SIGNIFICANCE: With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time. TRIAL REGISTRATION: isrctn.org ISRCTN37517549.",20689585,"Africa","Uganda","http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0011759","Yes","Available","Excluded","Subset of Dorsey-2007"]
["Faye-2010","Faye, B.;Offianan, A. T.;Ndiaye, J. L.;Tine, R. C.;Toure, W.;Djoman, K.;Sylla, K.;Ndiaye, P. S.;Penali, L.;Gaye, O.",2010,"Efficacy and tolerability of artesunate-amodiaquine (Camoquin plus) versus artemether-lumefantrine (Coartem) against uncomplicated Plasmodium falciparum malaria: multisite trial in Senegal and Ivory Coast","Tropical medicine & international health",15,5,"608-13","OBJECTIVE: To compare, in a phase IV trial, the efficacy and tolerability of artesunate-amodiaquine (Camoquin plus) dosed at 300 and 600 mg of amodiaquine per tablet to artemether-lumefantrine (Coartem) for the treatment of Plasmodium falciparum uncomplicated malaria in Ivory Coast and Senegal. METHOD: Multisite, randomised, open-labelled study in patients over the age of 7 years. The primary endpoint for efficacy was adequate clinical and parasitological response (ACPR) at day 28. The secondary endpoints were fever and parasite clearance and gametocyte carriage in each treatment group. Drug tolerability was assessed comparing adverse events and modification of biological parameters between D0 and D7. Data were analysed on an intention-to-treat and per protocol basis. RESULTS: We included 322 patients; 316 patients completed the monitoring to D28 (155 in AS + AQ group and 161 in AL group). In ITT analysis, an ACPR corrected rate of 97.4% was observed in AS + AQ group versus 97% in AL group (P = 0.99). No parasite recrudescence was observed in AS + AQ arm. All patients in both groups had a fever and parasite clearance at D2. Gametocytes had disappeared by D14 in the AL group and by D21 in the AS + AQ group. No serious adverse events were observed. Minor adverse events were significantly more frequent in the AS + AQ arm. Biological parameters between D0 and D7 did not show any significant statistical variations except for anaemia. CONCLUSION: This study demonstrates the efficacy and tolerability of AS + AQ for uncomplicated Plasmodium falciparum malaria treatment in African patients over the age of 7 years.",20214761,"Africa","Multicentred","http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2010.02487.x/full","Yes","Available","Included"]
["Jullien-2010","Jullien, V; Ogutu, B; Juma, E; Carn, G; Obonyo, C; Kiechel, JR",2010,"Population pharmacokinetics and pharmacodynamic considerations of amodiaquine and desethylamodiaquine in Kenyan adults with uncomplicated malaria receiving artesunate-amodiaquine combination therapy.","Antimicrob Agents Chemother.",54,6,"2611-7","Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to Plasmodium falciparum and is now available as a fixed-dose combination. Despite its widespread use, the simultaneous pharmacokinetics in patients of AQ and its active metabolite, desethylamodiaquine (DAQ), were not characterized to date. The pharmacokinetics of AQ and DAQ in 54 adult patients receiving the AS/AQ combination were therefore investigated by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination, as well as a first-order and irreversible transformation into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. The mean AQ apparent clearance and distribution volume were 3,410 liters/h and 39,200 liters, respectively. The mean terminal elimination half-life of DAQ was 211 h. Body weight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting of a fixed-dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.",20368402,"Africa","Kenya","http://aac.asm.org/content/54/6/2611.long","Yes","Available","Included"]
["Michael-2010","Michael, O. S.;Gbotosho, G. O.;Folarin, O. A.;Okuboyejo, T.;Sowunmi, A.;Oduola, A. M.;Happi, C. T.",2010,"Early variations in plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance","Malaria journal",9,335,"doi: 10.1186/1475-2875-9-335","BACKGROUND: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) are efficacious regimens that have been widely adopted in sub-Saharan Africa. However, most study designs ignore the effects of these regimens on peripheral parasitaemia in the first 24 hours of therapy. The study protocol was designed to evaluate more closely the early effects and the standard measures of efficacies of these two regimens. METHODS: In an open label, randomized controlled clinical trial, children aged 12 months to 132 months were randomized to receive AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily) or artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) for three days. Peripheral blood smears were made hourly in the first 4 hours, 8 h, 16 h, 24 h, and daily on days 2-7, and on days 7, 14, 21, 28, 35, and 42 for microscopic identification and quantification of Plasmodium falciparum. RESULTS: A total of 193 children were randomized to receive either AL (97) or AA (96). In children that received both medications, early response of peripheral parasitaemia showed that 42% of children who received AL and 36.7% of those who received AA had an immediate rise in peripheral parasitaemia (0-4 h after treatment) followed by a rapid fall. The rise in parasitaemia was significant and seems to suggest a mobilization of asexual parasites from the deep tissues to the periphery. Days 3, 7, 14, 28, and 42 cure rates in the per protocol (PP) population were > 90% in both groups of children. Both drug combinations were well tolerated with minimal side effects. CONCLUSION: The study showed the high efficacy of AL and AA in Nigerian children. In addition the study demonstrated the mobilisation of asexual parasites from the deep to the periphery in the early hours of commencing ACT treatment in a subset of patients in both study groups. It is unclear whether the early parasite dynamics discovered in this study play any role in the development of drug resistance and thus it is important to further evaluate this discovery. It may be useful for studies investigating delay in parasite clearance of artemisinin derivatives as a way of monitoring the development of resistance to artemisinin to assess the early effects of the drugs on the parasites.",21092220,"Africa","Nigeria","http://www.malariajournal.com/content/9/1/335","Yes","Not Available","Not Available"]
["Mwesigwa-2010","Mwesigwa J, Parikh S, McGee B, German P, Drysdale T, Kalyango JN, Clark TD, Dorsey G, Lindegardh N, Annerberg A, Rosenthal PJ, Kamya MR, Aweeka F",2010,"Pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in children in Kampala, Uganda.","ANTIMICROBIAL AGENTS AND CHEMOTHERAPY",54,1,"52-29","The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n = 20) or AQ-AS (n = 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (C(max)) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of 113 ng.h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C(max) of 473 ng/ml and an AUC(0-infinity) of 1,404 ng.h/ml. AR-DHA exhibited a C(max) of 34/119 ng/ml and an AUC(0-infinity) of 168/382 ng.h/ml, respectively. For LR, C(max) and AUC(0-infinity) were 6,757 ng/ml and 210 microg.h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the C(max)s were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC(0-infinity)s were 39.3 ng.h/ml and 148 microg.h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens",19841149,"Africa","Uganda",null,"Yes","Available","Excluded","Subset of Dorsey-2007 [PK Patients]"]
["Smithuis-2010","Smithuis, F.;Kyaw, M. K.;Phe, O.;Win, T.;Aung, P. P.;Oo, A. P.;Naing, A. L.;Nyo, M. Y.;Myint, N. Z.;Imwong, M.;Ashley, E.;Lee, S. J.;White, N. J.",2010,"Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial","The Lancet infectious diseases",10,10,"673-81","BACKGROUND: Artemisinin-combination therapy (ACT) is recommended as first-line treatment of falciparum malaria throughout the world, and fixed-dose combinations are preferred by WHO; whether a single gametocytocidal dose of primaquine should be added is unknown. We aimed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine, and assess the addition of a single gametocytocidal dose of primaquine. METHODS: In an open-label randomised trial in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 30, 2008, and March 20, 2009, we compared the effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate-mefloquine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artemether-lumefantrine) and loose artesunate-mefloquine in Burmese adults and children. Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection, who were older than 6 months, and who weighed more than 5 kg. Treatments were randomised in equal numbers within blocks of 50 and allocation was in sealed envelopes. All patients were also randomly assigned to receive either a single dose of primaquine 0.75 mg base/kg or not. Patients were followed up for 63 days. Treatment groups were compared by analysis of variance and multiple logistic regression. The primary outcome was the 63 day recrudescence rate. This study is registered with clinicaltrials.gov, number NCT00902811. FINDINGS: 155 patients received artesunate-amodiaquine, 162 artemether-lumefantrine, 169 artesunate-mefloquine, 161 loose artesunate-mefloquine, and 161 dihydroartemisinin-piperaquine. By day 63 of follow-up, 14 patients (9.4%; 95% CI 5.7-15.3%) on artesunate-amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether-lumefantrine (two patients; 1.4%; 0.3-5.3; p=0.0013), fixed-dose artesunate-mefloquine (0 patients; 0-2.3; p<0.0001), loose artesunate-mefloquine (two patients; 1.3%; 0.3-5.3; p=0.0018), and dihydroartemisinin-piperaquine (two patients 1.3%; 0.3-5.2%; p=0.0012). Hazard ratios for re-infection (95% CI) after artesunate-amodiaquine were 3.2 (1.3-8.0) compared with the two artesunate-mefloquine groups (p=0.01), 2.6 (1.0-6-0) compared with artemether-lumefantrine (p=0.04), and 2.3 (0.9-6.0) compared with dihydroartemisinin-piperaquine (p=0.08). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0.75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11.9 (95% CI 7.4-20.5). All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment. INTERPRETATION: Artesunate-amodiaquine should not be used in Myanmar, because the other ACTs are substantially more effective. Artesunate-mefloquine provided the greatest post-treatment suppression of malaria. Adding a single dose of primaquine would substantially reduce transmission potential. Vivax malaria, not recurrent falciparum malaria, is the main complication after treatment of P falciparum infections in this region. FUNDING: Medecins sans Frontieres (Holland) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme.",20832366,"Asia","Myanmar","http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(10)70187-0/abstract","Yes","Available","Included"]
["Whegang-2010","Whegang, S. Y.;Tahar, R.;Foumane, V. N.;Soula, G.;Gwet, H.;Thalabard, J. C.;Basco, L. K.",2010,"Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon","Malaria journal",9,56,"doi: 10.1186/1475-2875-9-56","BACKGROUND: The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT), is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. METHODS: Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28) were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis. FINDINGS: The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ) is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]). AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP. CONCLUSION: Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.",20170477,"Africa","Cameroon","http://www.malariajournal.com/content/9/1/56","Yes","Not Available","Not Available"]
["4ABC Study Group-2011","4ABC Study Group,The Four Artemisinin-Based Combinations Study Group",2011,"A Head-to-Head Comparison of Four Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children: A Randomized Trial","PLoS medicine",8,11,"e1001119","BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce. METHODS AND FINDINGS: Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28. CONCLUSIONS: This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750 Please see later in the article for the Editors' Summary.",22087077,"Africa","Multicentred","http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001119","Yes","Available","Included"]
["Gbotosho-2011a","Gbotosho, G. O.;Sowunmi, A.;Okuboyejo, T. M.;Happi, C. T.;Folarin, O. A.;Michael, O. S.;Adewoye, E. O.",2011,"Therapeutic efficacy and effects of artemether-lumefantrine and artesunate-amodiaquine coformulated or copackaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in Southwest Nigeria","The American journal of tropical medicine and hygiene",84,5,"813-9","The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine co-formulated (AAcf) or co-packaged (AAcp) on malaria-associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post-initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children.",21540395,"Africa","Nigeria","http://www.ajtmh.org/content/84/5/813.short","Yes","Not Available","Not Available"]
["Gbotosho-2011b","Gbotosho, G. O.;Sowunmi, A.;Happi, C. T.;Okuboyejo, T. M.",2011,"Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments","The American journal of tropical medicine and hygiene",84,6,"936-43","The therapeutic efficacies of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine during 5 years of adoption as first-line treatments were evaluated in 811 </= 12-year-old malarious children. Compared with artemether-lumefantrine, amodiaquine-artesunate significantly reduced the proportion of children with fever and parasitemia 1 day after treatment (day 1; P < 0.008 for both). The proportion of parasitemic children on day 2 and gametocytemia on presentation and carriage reduced significantly over the years (P < 0.000001 and P < 0.03, respectively; test for trend). Overall efficacy was 96.5% (95% confidence interval [CI] = 94.5-98.6) and remained unchanged over the years (P = 0.87; test for trend). Kinetics of parasitemias after treatments were estimated by a non-compartmental model. Declines of parasitemias were monoexponential, with a mean elimination half-life of 1.09 hours (95% CI = 1.0-1.16). Parasitemia half-lives and efficacy were similar for both regimens and in all ages. Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated falciparum malaria in Nigerian children 5 years after adoption.",21633031,"Africa","Nigeria","http://www.ajtmh.org/content/84/6/936.abstract","Yes","Not Available","Not targetted","Pooled analysis"]
["Ndiaye-2011","Ndiaye, JL; Faye, B; Gueye, A; Tine, R; Ndiaye, D; Tchania, C; Ndiaye, I; Barry, A; Cissé, B; Lameyre, V; Gaye, O",2011,"Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial","Malaria journal",10,237,"doi: 10.1186/1475-2875-10-237","BACKGROUND: The use of artemisinin-based combination therapy (ACT) is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT--artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--in subsequent episodes of Plasmodium falciparum malaria. METHODS: A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥ 12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR) after polymerase chain reaction (PCR) correction on day 28 for the first episode. RESULTS: A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182) and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182), PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03). No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during treatment with no clinical consequence.\nCONCLUSIONS: Study results confirmed the satisfactory efficacy and safety profile of ASAQ and AL. Moreover, in patients who were treated at least twice, repeated administration of ASAQ or AL did not identify any major safety issues.",21838909,"Africa","Senegal","http://www.malariajournal.com/content/10/1/237","Yes","Available","Included"]
["Offianan-2011","Andre T Offianan, Serge B Assi, Aristide MA Coulibaly, Landry T N'guessan, Aristide A Ako, Florence K Kadjo, Moïse K San, Louis K Penali2",2011,"Assessment of the efficacy of first-line antimalarial drugs after 5 years of deployment by the National Malaria Control Programme in Côte d'Ivoire","Open Access Journal of Clinical Trials",3,"NA","67-76","Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. Artesunate + amodiaquine (ASAQ) and artemether-lumefantrine (AL) are respectively the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. A comparison of the efficacy and safety of these two drug combinations was necessary to make evidence-based drug treatment policies. Methods: In an open-label, non inferiority, randomized, controlled clinical trial, children aged 6–59 months were randomized to receive ASAQ or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rates and was defined as proportion of patients with polymerase chain reaction (PCR)-corrected cure rate after 28 days of follow-up. Findings: A total of 251 patients who were attending the Ayame and Dabakala hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive ASAQ (128) and AL (123). The intention-to-treat analysis showed effectiveness rates of 94.5% and 93.5% for ASAQ and AL, respectively on day 28. After adjustment for PCR results, these rates were 96.1% and 96.8%, respectively. On day 28, the per-protocol analysis showed effectiveness rates of 98.4% and 96.6% for ASAQ and AL, respectively. After adjustment by PCR for reinfection, these rates were 100% for each drug, and both regimens were well tolerated. Conclusion: ASAQ and AL remain efficacious treatments of uncomplicated falciparum malaria in Ivorian children 5 years after adoption. The efficacy of ASAQ and AL in Côte d'Ivoire requires, therefore, continuous monitoring and evaluation.","Not of Pubmed","Africa","Cote d'Ivoire",null,"Yes","Available","Excluded","Missing PCR Results"]
["Anvikar-2012","Anvikar, A.R.; Sharma, B.; Shahi, B.H.; Tyagi, P.K.; Bose, T.K.; Sharma, S.K.; Srivastava, P.; Srivastava, B.; Kiechel, J.R.; Dash, A.P.; Valecha, N.",2012,"Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India.","Malaria journal",11,97,"doi: 10.1186/1475-2875-11-97","Background Artemisinin-based combination therapy (ACT) has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ) and amodiaquine (AQ) for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas. Methods This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate. Results Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1%) in ASAQ and 88.65% (81.3-93.9%) in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2%) and 88.30% (80-94%) in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs) were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel. Conclusion The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT.",22458860,"Asia","India","http://www.malariajournal.com/content/11/1/97","Yes","Available","Included"]
["De la Hoz Restrepo-2012","De la Hoz Restrepo, F; Porras Ramírez, A; Rico Mendoza, A; Córdoba, F; Rojas DP",2012,"Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a noninferiority trial.","Rev Soc Bras Med Trop.",45,6,"732-8","INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28-day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. Safety: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.",23295878,"S.America","Colombia","http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0037-86822012000600015&lng=en&nrm=iso&tlng=en","Yes","Not Available","Not Available"]
["Dorkenoo-2012","Dorkenoo, M. A.;Barrette, A.;Agbo, Y. M.;Bogreau, H.;Kutoati, S.;Sodahlon, Y. K.;Morgah, K.",2012,"Surveillance of the efficacy of artemetherlumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum among children under five in Togo, 2005-2009","Malaria journal",11,338,"doi: 10.1186/1475-2875-11-338","ABSTRACT: BACKGROUND: Malaria remains a major public health problem in Togo. The national malaria control programme in Togo changed the anti-malarial treatment policy from monotherapy to artemisinin combination therapy in 2004. This study reports the results of therapeutic efficacy studies conducted on artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Togo, between 2005 and 2009. METHODS: Children between 6 and 59 months of age, who were symptomatically infected with P. falciparum, were treated with either artemether-lumefantrine or artesunate-amodiaquine. The primary end-point was the 28-day cure rate, PCR-corrected for reinfection and recrudescence. Studies were conducted according to the standardized WHO protocol for the assessment of the efficacy of anti-malarial treatment. Differences between categorical data were compared using the chi-square test or the Fisher's exact test where cell counts were [less than or equal to] 5. Differences in continuous data were compared using a t-test. RESULTS: A total of 16 studies were conducted in five sentinel sites, with 459, 505 and 332 children included in 2005, 2007 and 2009, respectively. The PCR-corrected 28-day cure rates using the per-protocol analysis were between 96%-100% for artemether-lumefantrine and 94%- 100% for artesunate-amodiaquine. CONCLUSIONS: Both formulations of artemisinin-based combination therapy were effective over time and no severe adverse events related to the treatment were reported during the studies.",23043495,"Africa","Togo","http://www.malariajournal.com/content/11/1/338","Yes","Not Available","Not Available"]
["Espie-2012","Espie, E.;Lima, A.;Atua, B.;Dorba, M.;Flevaud, L.;Sompwe, E. M.;Palma, U. P. P.;Guerin, P. J.",2012,"Efficacy of fixed-dose combination artesunateamodiaquine versus artemether-lumefantrine for uncomplicated childhood plasmodium falciparum malaria in democratic republic of congo: a randomized non-inferiority trial","Malaria journal",11,174,"doi: 10.1186/1475-2875-11-174","ABSTRACT: BACKGROUND: In 2005, the Democratic Republic of Congo (DRC) adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment. In order to compare the efficacy of the fixeddose formulation ASAQ versus artemether-lumefantrine (AL), a randomized, non-inferiority open-label trial was conducted in Katanga. METHODS: Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were enrolled and randomly allocated into one of the two regimens. The risk of recurrent parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish recrudescence from new infection, was analysed. RESULTS: Between April 2008 and March 2009, 301 children were included: 156 with ASAQ and 145 with AL. No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32 patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI, 94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference 0.7%, one sided 95% CI 3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment regimens were generally well tolerated. CONCLUSION: Both ASAQ and AL are highly effective and currently adequate as he first-line treatment of uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large country, such as DRC, and because of possible emergence of resistance from other endemic regions, surveillance of efficacy of artemisinin-based combination treatments, including other evaluations of the resistance of ASAQ, need to be done in other provinces. Trial registration The protocol was registered with the clinicaltrials.gov, open clinical trial registry under the identifier number NCT01567423.",22631564,"Africa","Democratic Republic of Congo","http://www.malariajournal.com/content/11/1/174/abstract","Yes","Available","Included"]
["Faye-2012","Faye, B;Kuété, T; Kiki-Barro, CP; Tine, RC; Nkoa T, Ndiaye JL, Kakpo CA, Sylla K, Menan HE, Gaye O, Faye O, Same-Ekobo A, Moussa K",2012,"Multicentre study evaluating the non-inferiority of the new paediatric formulation of artesunate/amodiaquine versus artemether/lumefantrine for the management of uncomplicated Plasmodium falciparum malaria in children in Cameroon, Ivory Coast and Senegal.","Malaria journal",11,433,"doi: 10.1186/1475-2875-11-433","BACKGROUND: This multicentre study was carried out in Cameroon, Ivory Coast and Senegal to evaluate the non-inferiority of the new paediatric formulation of artesunate/amodiaquine (AS+AQ)(Camoquin-Plus Paediatric(R)) in suspension form versus artemether/lumefantrine (AL)(Coartem(R)) in the management  of African children with uncomplicated falciparum malaria. METHODS: It was an  open randomized trial including children aged between 7 months and 7 years. The endpoints were Adequate Clinical and Parasitological Response (ACPR) at day 28,  the clinical and biological tolerability. Statistical analyses were done in Intention To Treat (ITT) and in Per protocol (PP). RESULTS: At the end of the  study 481 patients were enrolled in the three countries (249 in the AS+AQ arm and  232 in the AL arm). ACRP in ITT after PCR correction did not show any statistical  difference between the two groups with 97.6% for AS+AQ versus 94.8% for AL. In  the PP analysis, the corrected ACRP were respectively 98.7% and 96.9% for the two  regimens. The clinical tolerance was good without significant difference. Anaemia   was significantly higher at D7 in the two groups compared to D0. CONCLUSION: This   study demonstrates the non-inferiority of AS+AQ versus AL, its efficacy and   tolerance in the management of uncomplicated Plasmodium falciparum malaria in African children.",23270636,"Africa","Multicentred","http://www.malariajournal.com/content/11/1/433/abstract","Yes","Not Available","Not Available"]
["Gbotosho-2012a","Gbotosho, G. O.;Sowunmi, A.;Okuboyejo, T. M.;Happi, C. T.;Folarin, O. O.;Adewoye, E. O.",2012,"A Simple Dose Regimen of Artesunate and Amodiaquine Based on Age or Body Weight Range for Uncomplicated Falciparum Malaria in Children: Comparison of Therapeutic Efficacy With Standard Dose Regimen of Artesunate and Amodiaquine and Artemether-Lumefantrine","American journal of therapeutics",19,4,"e122-31","A new dose regimen of artesunate and amodiaquine (NDRAA) based on age or body weight range was compared with standard dose regimen of artesunate and amodiaquine (SDRAA) calculated according to body weight and with fixed-dose artesunate-amodiaquine (FDAA) and artemether-lumefantrine (AL) in 304 children afflicted by malaria aged 15 years or younger. In initial comparison (n = 208), children on NDRAA received 1-3 times amodiaquine per kilogram of body weight and 1-1.5 times of artesunate per kilogram of body weight compared with those receiving SDRAA. Parasite but not fever clearance was significantly faster in children who received NDRAA (19.4 +/- 8.4 hours vs. 24.6 +/- 15.5 hours, P = 0.003). Polymerase chain reaction-uncorrected cure rates on days 28-42 were also significantly higher in children who received NDRAA (P < 0.02 in all cases). Therapeutic responses in children younger than 5 years (n = 96) treated with NDRAA, FDAA, and AL were similar. Changes in hematocrit values and reported adverse events after commencing therapy were similar in those who received NDRAA and SDRAA. All drug regimens were well tolerated. NDRAA based on age or body weight range is simple, is therapeutically superior to SDRAA calculated according to body weight, and is as efficacious as AL in children younger than 5 years.",21519221,"Africa","Nigeria","http://journals.lww.com/americantherapeutics/pages/results.aspx?txtKeywords=doi:%2010.1097/MJT.0b013e318209e031","Yes","Not Available","Not Available"]
["Gbotosho-2012b","Gbotosho, G. O.;Sowunmi, A.;Okuboyejo, T. M.;Happi, C. T.",2012,"Oral Artesunate-Amodiaquine and Artemether-Lumefantrine in the Treatment of Uncomplicated Hyperparasitaemic Plasmodium falciparum Malaria in Children","Journal of tropical pediatrics",58,2,"151-3","The therapeutic efficacy, changes in haematocrit and declines in parasitaemias were evaluated in 56 children with uncomplicated falciparum hyperparasitaemia after oral artesunate-amodiaquine or artemether-lumefantrine. All children recovered clinically within 2 days and without progression to severe malaria. Falls in haematocrit in the first 3 days after treatment began were similar and <5%. Declines in parasitaemias were monoexponential with both treatments with an estimated half-life of 1 h.",21622538,"Africa","Nigeria","http://tropej.oxfordjournals.org/content/early/2011/05/26/tropej.fmr045.abstract","Yes","Not Available","Not targetted","Hyperparasitaemic population; no PCR"]
["Ratsimbasoa-2012","Ratsimbasoa, A.;Ravony, H.;Vonimpaisomihanta, J.A.;Raherinjafy, R.;Jahevitra, M.;Rapelanoro, R.;Rakotomanga, J.D.;Malvy, D.;Millet, P.;Ménard, D.",2012,"Compliance, Safety, and Effectiveness of Fixed-Dose Artesunate-Amodiaquine for Presumptive Treatment of Non-Severe Malaria in the Context of Home Management of Malaria in Madagascar.","Am J Trop Med Hyg",86,2,"203-210","Home management of malaria is recommended for prompt, effective antimalarial treatment in children less than five years of age. Compliance, safety, and effectiveness of the new fixed-dose artesunate-amodiaquine regimen used to treat suspected malaria were assessed in febrile children enrolled in a 24-month cohort study in two settings in Madagascar. Children with fever were asked to visit community health workers. Presumptive antimalarial treatment was given and further visits were scheduled for follow-up. The primary endpoint was the risk of clinical/parasitologic treatment failure. Secondary outcomes included fever/parasite clearance, change in hemoglobin levels, and frequency of adverse events. The global clinical cure rate was 98.4% by day 28 and 97.9% by day 42. Reported compliance was 83.4%. No severe adverse effects were observed. This study provides comprehensive data concerning the clinical cure rate obtained with artesunate-amodiaquine and evidence supporting the scaling up of home management of malaria.",22302849,"Africa","Madagascar","http://www.ajtmh.org/content/86/2/203.long","Yes","Not Available","Not targetted","Effectiveness study: no follow-up between d3 and d28"]
["Sagara-2012","Sagara, I.;Fofana, B.;Gaudart, J.;Sidibe, B.;Togo, A.;Toure, S.;Sanogo, K.;Dembele, D.;Dicko, A.;Giorgi, R.;Doumbo, O. K.;Djimde, A. A.",2012,"Repeated artemisinin-based combination therapies in a malaria hyperendemic area of mali: efficacy, safety, and public health impact","The American journal of tropical medicine and hygiene",87,1,"50-56","Abstract. Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria.",22764291,"Africa","Mali","http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391057/","Yes","Available","Included"]
["Sowunmi-2012","Sowunmi, A.;Akinrinola, I. A.;Gbotosho, G. O.;Okuboyejo, T. M.;Happi, C. T.",2012,"A Simple Dose Regimen of Artesunate and Amodiaquine Based on Arm Span- or Age Range for Childhood Falciparum Malaria: A Preliminary Evaluation","Journal of tropical pediatrics",58,4,"263-8","A dose regimen of artesunate and amodiaquine based on arm span- or age range (DRAAAS), derived from a study of 1674 children, was compared with standard dose regimen of the same drugs calculated according to body weight (SDRAA) in 68 malarious children. Children on DRAAAS received 0.8-1.0 of artesunate/kg and 0.9-1.2 times amodiaquine/kg compared with those receiving SDRAA. Parasite and fever clearance and fall in hematocrit in the first 3 days were similar; both regimens were well tolerated. DRAAAS is simple and is efficacious.",22052702,"Africa","Nigeria","http://tropej.oxfordjournals.org/content/early/2011/11/02/tropej.fmr091.full","Yes","Not Available","Not Available"]
["Thanh-2012","Thanh, N.;Trung, T.;Phong, N.;Quang, H.;Dai, B.;Shanks, G.;Chavchich, M.;Edstein, M.D.",2012,"The efficacy and tolerability of artemisinin-piperaquine (Artequick(R)) versus artesunate-amodiaquine (CoarsucamTM) for the treatment of uncomplicated Plasmodium falciparum malaria in south-central Vietnam","Malaria journal",11,217,"doi: 10.1186/1475-2875-11-217","ABSTRACT: BACKGROUND: In Vietnam, the artemisinin-based combination therapy (ACT) of dihydroartemisinin-piperaquine is currently used for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT in Vietnam in case there is a reduction in the susceptibility of dihydroartemisinin-piperaquine. A study was conducted to compare the efficacy and tolerability of two fixed-dosed formulations of ACT, artemisinin-piperaquine (Artequick(R), ARPQ) and artesunate-amodiaquine (CoarsucamTM, ASAQ) for the treatment of P. falciparum malaria in south-central Vietnam. METHODS: A randomized, open-label trial was conducted comparing the efficacy of a two-day regimen of ARPQ (~2.8 mg/kg artemisinin plus ~16.9 mg/kg of piperaquine per day) and a three-day regimen of ASAQ (~4.5 mg/kg of artesunate plus ~12.3 mg/kg of amodiaquine per day) for the treatment of children and adults with uncomplicated falciparum malaria. Primary efficacy endpoint was day 42, PCR-corrected, parasitological cure rate. Secondary endpoints were parasite and fever clearance times and tolerability. RESULTS: Of 128 patients enrolled, 63 were administered ARPQ and 65 ASAQ. Of the patients who completed the 42 days follow-up period or had a recurrence of malaria, 55 were on ARPQ (30 children, 25 adults) and 59 were on ASAQ (31 children, 28 adults). Recrudescent parasitaemia was PCR-confirmed for one patient in each treatment group, with cure rates at day 42 of 98% (95% CI: 88-100) for both forms of ACT. The median parasite clearance time was significantly slower in the ARPQ group compared with the ASAQ group (48 h vs. 36 h, P < 0.001) and fever clearance times were shorter in the ASAQ group (12 h vs. 24 h, P = 0.07. The two forms of ACT were well-tolerated with no serious adverse events. CONCLUSION: Both forms of ACT were highly efficacious in the treatment of uncomplicated P. falciparum malaria. Although the two-day course of ARPQ was equally as effective as the three-day course of ASAQ, parasite and fever clearance times were shorter with ASAQ. Further studies are warranted in different regions of Vietnam to determine the nationwide efficacy of ASAQ.",22741618,"Asia","Vietnam","http://www.malariajournal.com/content/pdf/1475-2875-11-217.pdf","Yes","Available","Excluded","Missing PCR Results"]
["Ali-2013","Ali, I.M.; Netongo, P.M.; Atogho-Tiedeu, B.; Ngongang, E.O.; Ajua, A.; Achidi, E.A.; Mbacham, W.F.",2013,"Amodiaquine-Artesunate versus Artemether-Lumefantrine against Uncomplicated Malaria in Children Less Than 14 Years in Ngaoundere, North Cameroon: Efficacy, Safety, and Baseline Drug Resistant Mutations in pfcrt, pfmdr1, and pfdhfr Genes.","Malar Res Treat",2013,234683,"doi: 10.1155/2013/234683","Background. In Cameroon, both Artesunate-amodiaquine (AS/AQ) and artemether-lumefantrine (AL) are used as first-line treatment against uncomplicated malaria in line with the WHO recommendations. We compared the efficacy and safety of both therapeutic combinations and determined the prevalence of drug resistance conferring mutations in three parasite genes. Methods. One hundred and fifty acute malaria patients between six months and 14 years of age were randomized to receive standard doses of either AS/AQ (73) or AL (77) and followedup for 28 days. Outcome of treatment was according to the standard WHO classification. DNA samples from pretreatment parasite isolates were used to determine the prevalence of resistant mutations in the pfcrt, pfmdr1, and dhfr genes. Results. Both drug combinations induced rapid clearance of parasites and malaria symptoms. PCR-corrected cure rates were 100% and 96.4% for AL. The combinations were well tolerated. Major haplotypes included CVIET (71%), CVMNT (25%) for the pfcrt; SND (100%) for the pfmdr1; IRN (79, 8%), NCS (8.8%), and mixed haplotype (11, 8%) for the dhfr. Conclusion. Both AS/AQ and AL were highly effective and well tolerated for the treatment of uncomplicated falciparum malaria in Ngaoundere, Cameroon. High prevalence of mutant pfcrt alleles confirms earlier observations. Long-term monitoring of safety and efficacy and molecular markers is highly solicited.",24455414,"Africa","Cameroon","http://www.hindawi.com/journals/mrt/2013/234683/","Yes","Not Available","Not Available"]
["Charle-2013","Charle, P.;Berzosa, P.;de, L. A.;Raso, J.;Nseng, N. G.;Benito, A.",2013,"Artesunate/Amodiaquine Malaria Treatment for Equatorial Guinea (Central Africa)","The American journal of tropical medicine and hygiene",88,6,"1087-92","ABSRTACT The objectives of this study were: 1) to evaluate the safety and efficacy of combination artesunate (AS)/amodiaquine (AQ) therapy, and 2) to determine the difference between recrudescence and resistance. An in vivo efficacy study was conducted in Equatorial Guinea. A total of 122 children 6-59 months of age from two regional hospitals were randomized and subjected to a 28-day clinical and parasitological follow-up. A blood sample on Whatman paper was taken on Days 0, 7, 14, 21, and 28 or on any day in cases of treatment failure, with the parasite DNA then being extracted for molecular analysis purposes. A total of 4 children were excluded, and 9 cases were lost to follow-up. There were 17 cases of late parasitological failure, 3 cases of late clinical failure, and 89 cases of adequate clinical and parasitological response. The parasitological failure rate was 18.3% (20 of 109) and the success rate 81.70% (95% confidence interval [72.5-87.9%]). After molecular correction, real treatment efficacy stood at 97.3%. Our study showed the good efficacy of combination AS/AQ therapy. This finding enabled this treatment to be recommended to Equatorial Guinea's National Malaria Control Program to change the official treatment policy as of March 2008.",23530078,"Africa","Equatorial Guinea","http://www.ajtmh.org/content/early/2013/03/21/ajtmh.12-0290.long","Yes","Not Available","Not Available"]
["Lopera-Mesa-2013","Lopera-Mesa, T. M.;Doumbia, S.;Chiang, S.;Zeituni, A. E.;Konate, D. S.;Doumbouya, M.;Keita, A. S.;Stepniewska, K.;Traore, K.;Diakite, S. A.;Ndiaye, D.;Sa, J. M.;Anderson, J. M.;Fay, M. P.;Long, C. A.;Diakite, M.;Fairhurst, R. M.",2013,"Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity","The Journal of infectious diseases",7,11,"1655-63","Background. Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced.Methods. We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring 6-hourly parasite density until undetectable, and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half-life. We quantified the proportion of parasitized RBCs recognized by autologous IgG.Results. The geometric mean half-life was 1.9 hours (95% CI 1.8-2.0) and did not correlate with parasite ex-vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half-life (r=-0.475, p=0.0006).Conclusions. Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity, and correlates of parasite-clearing immunity have not been identified.Trial registration. Clinicaltrials.gov (NCT00669084).",23448727,"Africa","Mali","http://jid.oxfordjournals.org/content/207/11/1655.long","Yes","Not Available","Not targetted","PCT Study"]
["Nambei-2013","Nambei, WS; Lango, Yaya E; Pounguinza, S; Achonduh, O; Bogon, A; Lengande, R; Evehe, MS; Ekollo, Mbange AH; Mbacham, W.",2013,"Efficacy and safety of antimalarial combinations for treatment of uncomplicated malaria in children in Bangui, Central African Republic","Med Sante Trop.",23,3,"313-9","Abstract  Objective. The aim of this study was to evaluate the efficacy and safety of three anti-malarial combinations - artemether-lumefantrine (A-L), amodiaquine-sulfadoxine-pyrimethamine (AQ-SP), and artesunate-amodiaquine (AQ-AS) - in the treatment of uncomplicated malaria in children younger than 5 years in Bangui, Central African Republic. Methodology. This study included 186 children aged 6-59 months with uncomplicated falciparum malaria who were treated at the Bédé Combattant Hospital from July through October 2010: 63 randomized to receive A-L, 63 AQ-SP, and 60 AQ-AS. Clinical outcome was classified according to WHO criteria as early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF), or adequate clinical and parasitological response (ACPR). The occurrence of mutations in the pfcrt, pfmdr-1, dhfr and dhps genes was studied by PCR-RFLP. Results. After PCR correction, ACPR at D28 was 100% for A-L, 96.55% for AQ-SP, and 100% for AQ-AS, with no significant difference between the three combinations (p = 0.36). The 2 cases of treatment failure for AQ-SP were associated with mutations at the following resistance markers: Pfcrt 76T, PfmdrI 86Y, Dhfr 108N, and Dhps A437. There was no significant difference in the reduction of anemia, fever (p = 0.87), or parasitemia (p = 0.63) between the three combinations. Conclusion. This study demonstrates that artemisinin-based combinations are still effective and tolerated in the treatment of uncomplicated malaria in children younger than 5 years in Bangui. Treatment failures were due to new infections and mutations in resistance markers.",24122669,"Africa","Central Republic of Africa","http://www.jle.com/fr/revues/medecine/mst/e-docs/00/04/8D/D8/resume.phtml","Yes","Not Available","Not Available"]
["Ndounga-2013","Ndounga, M.;Mayengue, P. I.;Casimiro, P. N.;Loumouamou, D.;Basco, L. K.;Ntoumi, F.;Brasseur, P.",2013,"Artesunate-amodiaquine efficacy in Congolese children with acute uncomplicated falciparum malaria in Brazzaville","Malaria journal",12,53,"doi: 10.1186/1475-2875-12-53","BACKGROUND: Congo-Brazzaville adopted artemisinin-based combination therapy (ACT) in 2006. Artesunate-amodiaquine (AS + AQ) and artemether-lumefantrine are the first-line and second-line anti-malarial drugs to treat uncomplicated Plasmodium falciparum malaria, respectively. The baseline efficacy of AS + AQ was evaluated from February to August 2005 in patients living in Brazzaville, the capital city of the Republic of Congo. METHODS: One hundred and ninety-seven patients (96 </= 5 years old and 101 >5 years old, including adults) were recruited in a non-randomized study, treated under supervision with AS + AQ, and were followed up for 28 days in accordance with the 2003 World Health Organization protocol. Plasmodium falciparum recrudescent isolates from day 7 to day 28 were compared to pretreatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. RESULTS: The overall efficacy of AS + AQ after PCR correction on day 28 was 94.4%. An adequate clinical and parasitological response was observed in 94.3% and 94.4% of children aged </= 5 years old and those aged >5 years old (including adults), respectively. The main reported adverse events were dizziness, vomiting, diarrhoea, pruritus, headache, anorexia, and abdominal pain. CONCLUSION: This study has shown the high efficacy of AS + AQ in Congolese patients of all ages with acute uncomplicated falciparum malaria and serves as the baseline efficacy and tolerance of this ACT in Brazzaville.",23384005,"Africa","Republic of Congo","http://www.malariajournal.com/content/12/1/53","Yes","Not Available","Not Available"]
["Ojurongbe O-2013","Ojurongbe O, Lawal OA, Abiodun OO, Okeniyi JA, Oyeniyi AJ, Oyelami OA.",2013,"Efficacy of artemisinin combination therapy for the treatment of uncomplicated falciparum malaria in Nigerian children.","J Infect Dev Ctries",7,12,"975-82","INTRODUCTION: The development and spread of Plasmodium falciparum resistance to most commonly used antimalarials remain a major challenge in the control of malaria. Constant monitoring of drug efficacy is an important tool in establishing rational antimalarial drug policies. METHODOLOGY: A randomized comparative study was conducted at the Wesley Guild Hospital, Ilesa, Nigeria between February 2010 and September 2011 comparing the efficacy and safety of artemether-lumefantrine (Coartem) and fixed dose of artesunate plus amodiaquine (Larimal) in the treatment of uncomplicated P. falciparum malaria in children betweem 6 and 144 months of age. P. falciparum malaria parasitemia was assessed by microscopy and rapid diagnostic test. Drugs were administered according to age for three days under supervision. The primary efficacy endpoint was a day 28 PCR-corrected parasitological cure. RESULTS: A total of 182 patients were enrolled in the two treatment groups, Coartem (n = 101) and Larimal (n = 81), and tested after 28 days. In the intention-to-treat population, Coartem (n = 101) and Larimal (n = 81) had a PCR-corrected cure rate of 98% and 100% respectively, while in the per-protocol population, Coartem (n = 89) and Larimal (n = 71) both had a PCR-corrected cure rate of 100% at day 28. Although parasite and fever clearance time was faster in the Larimal group, no significant difference was observed between the two drugs. No serious adverse effects  were reported. CONCLUSION: Five years after being introduced in Nigeria, both Coartem and Larimal have been shown to be safe and highly effective in the treatment of uncomplicated P. falciparum malaria in children.",24334945,"Africa","Nigeria","http://www.jidc.org/index.php/journal/article/view/24334945","Yes","Not Available","Not Available"]
["Pasaribu-2013","Pasaribu, AP; Chokejindachai, W; Sirivichayakul, C; Tanomsing, N; Chavez, I; Tjitra, E; Pasaribu, S; Imwong, M; White, NJ; Dondorp, AM",2013,"A Randomized Comparison of Dihydroartemisinin-Piperaquine and Artesunate-Amodiaquine Combined with Primaquine for Radical Treatment of Vivax Malaria in Sumatera, Indonesia","The Journal of infectious diseases",208,11,"1906-13","Abstract Background. High prevalence of chloroquine resistant P. vivax in Indonesia, has shifted first-line treatment to artemisinin-based combination therapies (ACTs), combined with primaquine for radical cure. Which combination is most effective and safe, needs to be established.Methods. We conducted a prospective open-label randomized comparison of 14 days primaquine (0.25 mg base/kg) plus either artesunate-amodiaquine (AAQ+PQ) or dihydroartemisinin-piperaquine (DHP+PQ) for the treatment of uncomplicated mono-infection P. vivax malaria in North Sumatera, Indonesia. Patients were randomized and treatments were given without prior testing for G6PD-status. The primary outcome was parasitological failure at day-42. Patients were followed up to one year.Results. Between December 2010 and April 2012, 331 patients were included. After AAQ+PQ, recurrent infection occurred in 0/167 patients within 42 days and in 15/130 (11.5%, 95%CI 6.6%-18.3%) within a year. With DHP+PQ this was 1/164 (0.6%, 95%CI 0.01%-3.4%) and 13/143 (9.1%, 95%CI 4.9%-15.0%), respectively (p>0.2). Intravascular hemolysis occurred in 5 patients, of which 3 males were hemizygous for G6PD-Mahidol. Minor adverse events were more frequent with AAQ+PQ.Conclusions. In North Sumatera, Indonesia, AAQ and DHP, both combined with primaquine, were effective for blood stage parasite clearance of uncomplicated P.vivax malaria. Both treatments were safe, but DHP+PQ was better tolerated. Registration: NCT01288820.",23926329,"Asia","Indonesia","http://jid.oxfordjournals.org/content/early/2013/08/06/infdis.jit407.long","Yes","Not Available","Not targetted","P Vivax study"]
["Sahr-2013","Sahr, F; Smith, S. J; Kamara, A; Warsame, M; Sillah, J; Swarray A",2013,"ASSESSMENT OF THE THERAPEUTIC EFFICACY OF TWO ARTEMISININ-BASED COMBINATIONS IN THE TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA AMONG CHILDREN UNDER 5 YEARS IN FOUR DISTRICT HOSPITALS IN SIERRA LEONE","Sierra Leone J Biomed Res",5,1,"4-8","Plasmodium falciparum has developed resistance to almost every class of antimalarial compounds. As\na result of this, the World Health Organization has recommended artemisinin-based combination\ntherapy as first line treatment for P. falciparum malaria. There is however need for the continuous\nmonitoring of the efficacy of these antimalarials in order to provide timely information on trends of\nthe emergence of resistant strains. We assessed the therapeutic efficacy of oral artesunate –\namodiaquine and artemether-lumefantrine combinations in the treatment of uncomplicated P.\nfalciparum malaria in four District Hospitals in Sierra Leone. A total of 320 children under five years\npartiiccipated in the study sites (Kenema, Rokupa, Bo and Makeni). Oral Artesunate-amodiaquine\ncombination was administered to participants in Kenema and Rokupa whilst Artemetherlumefantrine\ncombination was administered to participants in Bo and Makeni. The new WHO\nProtocol for recruitment of participants in therapeutic efficacy trials in high transmission zones was\nadopted for the study with filter paper blood samples taken from each participant on days 0 and 28 to\ndistinguish between treatment failure and new infection. When uncorrected for PCR analysis, 96%\n(95% CI: 902 – 989) and 100% (95% CI:63.1 – 100) responses were obtained in Kenema and Bo\nrespectively with Artesunate-amodiaquine combination whilst 94.3% (CI 95 : 88.1 – 979) and 100%\n(95% CI: 96.5 – 100) were obtained with Artemether-lumefantrine combination in Bo and Makeni\nrespectively. When corrected for PCR on the other hand, a 100% (95% CI) Adequate Clinical and\nParasitological Response was obtained for the two drugs in all four study sites. Results from this\nstudy indicate that both Artesunate-amodiaquine and Artemether-lumefantrine combinations remain\nhighly efficacious in Sierra Leone with presently no observed emergence of resistant strains to both\ndrugs.","NA","Africa","Sierra Leone","http://www.ajol.info/index.php/sljbr/article/view/97997","Yes","Not Available","Not Available"]
["Schramm-2013a","Schramm, B; Valeh, P; Baudin, E; Mazinda, CS; Smith, R; Pinoges, L; Sundaygar, T; Zolia, YM; Jones, JJ; Comte, E; Bruneel, A; Branger, M; Jullien, V; Carn, G; Kiechel, JR; Ashley, EA; Guérin, PJ",2013,"Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia","Malaria journal",12,250,"doi:10.1186/1475-2875-12-250","Background Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal.\nMethods Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop(R)) or artemether-lumefantrine (AL, Coartem(R)), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28.\nResults Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p & 0.001), vomiting (7.1% vs 1.6%, p & 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis).\nConclusion Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.\nTrial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713 (http://www.controlled-trials.com). ",23866736,"Africa","Liberia","http://www.malariajournal.com/content/12/1/250/abstract","Yes","Available","Not targetted","Subset of Schramm-2013b; Safety data"]
["Schramm-2013b","Schramm, B; Valeh, P; Baudin, E; Mazinda, CS; Smith, R; Pinoges, L; Dhorda, M; Boum, Y 2nd; Sundaygar, T; Zolia, YM; Jones, JJ; Comte, E; Houzé, P; Jullien, V; Carn, G; Kiechel, JR; Ashley, EA; Guérin, PJ",2013,"Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non inferiority trial","Malaria journal",12,251,"doi:10.1186/1475-2875-12-251","Background Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce.\nMethods\n\nAn open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop?) to AL (Coartem?) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured.\nResults\n\nThe day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was ?3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p?=?0.017).\nConclusions\n\nBoth ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended. Trial registration The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713 , ISRCTN40020296 . ",23866774,"Africa","Liberia","http://www.malariajournal.com/content/12/1/251/abstract","Yes","Available","Included"]
["Sowunmi-2013","Sowunmi, A; Gbotosho, GO; Happi, CT; Okuboyejo, TM; Sijuade, AO; Michael, OS; Adewoye, EO; Folarin, O.",2013,"Therapeutic efficacy of artesunate-amodiaquine combinations and the plasma and saliva concentrations of desethylamodiaquine in children with acute uncomplicated Plasmodium falciparum malaria","American Journal of Therapeutics",20,1,"48-56","Abstract: The treatment efficacy of artesunate-amodiaquine (AQ) coformulated or copackaged, and the plasma and saliva concentrations of desethylamodiaquine (DEAQ), the active metabolite of AQ, were evaluated in 120 and 7 children, respectively, with uncomplicated Plasmodium falciparum malaria treated with oral daily doses of the 2 formulations for 3 days. All children recovered clinically. Fever clearance (1.1 +/- 0.2 vs 1.0 +/- 0 days) and parasite clearance times (21.1 +/- 10.2 vs 19.0 +/- 7.0 hours) in artesunate-AQ coformulated and artesunate-AQ copackaged treated children, respectively, were similar. All children remained aparasitemic for at least 28 days. Blood and saliva samples were collected over 35 days and DEAQ in plasma and saliva was determined by high-performance liquid chromatography. DEAQ was detectable in plasma and saliva within 40 minutes of oral administration of artesunate-AQ. DEAQ concentrations 7 days after the start of therapy were 247.8 and 125.1 ng/mL in plasma and saliva, respectively. The concentration-time curves of plasma and saliva in declining phases were approximately parallel giving a similar half-life of 169.1 +/- 16.4 and 142.8 +/- 6.5 hours in plasma and saliva, respectively. Clearance from plasma and saliva was also similar (335.6 and 443.4 mL.h.kg, respectively). Area under concentration-time curves (AUC0-35d) for plasma and saliva were 94,744.9 and 74,004.2 ng.mL.h, respectively. In general, Saliva-plasma concentration ratio was 0.25-0.4. DEAQ concentrations in saliva may be useful for monitoring therapy and for the evaluation of the disposition of AQ in children with falciparum malaria treated with AQ-based combination.",21192244,"Africa","Nigeria","http://journals.lww.com/americantherapeutics/Abstract/2013/01000/Therapeutic_Efficacy_of_Artesunate_Amodiaquine.9.aspx","Yes","Not Available","Not Available"]
["Sylla K-2013","Sylla K, Abiola A, Tine RC, Faye B, Sow D, Ndiaye JL, Ndiaye M, Lo AC, Folly K, Ndiaye LA, Gaye O.",2013,"Monitoring the efficacy and safety of three artemisinin based-combinations therapies in Senegal: results from two years surveillance","BMC Infect Dis",13,598,"doi: 10.1186/1471-2334-13-598","BACKGROUND: Malaria remains a major public health problem in developing countries. Then in these countries prompt access to effective antimalarial treatment such as Artemisinin based-Combination Therapies (ACT) proves to be an essential tool for controlling the disease. In Senegal, since 2006 a nationwide scaling up program of ACT is being implemented. In this context it has become relevant to monitor ACT efficacy and provide recommendations for the Senegalese national malaria control program. METHODS: An open randomized trial was conducted during two malaria transmission seasons (2011 and 2012) to assess the efficacy and safety of three combinations: dihydro-artemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ). The primary end point of the study was represented by a PCR adjusted adequate clinical and parasitological response (ACPR) at day 28. Secondary end points included: (i) a ACPR at days 35 and 42, (ii) a parasite and fever clearance time, (iii) ACTs safety and tolerability. The 2003 WHO's protocol for antimalarial drug evaluation was used to assess each outcome. RESULTS: Overall, 534 patients were randomized selected to receive, either ASAQ (n = 180), AL (n = 178) or DHAPQ (n = 176). The PCR adjusted ACPR at day 28 was 99.41% for the group ASAQ, while that was 100% in the AL and DHAPQ groups (p = 0.37). The therapeutic efficacy was evaluated at 99.37% in the ASAQ arm versus 100% in AL and DHAPQ arm at day 35 (p = 0.37). At day 42, the ACPR was 99.27% in the ASAQ group versus 100% for both AL and DHAPQ groups, (p = 0.36). No serious adverse event was noted during the study period. Also a similar safety profile was noted in the 3 study groups. CONCLUSION: In the context of scaling up of ACTs in Senegal, ASAQ, AL and DHAPQ are highly effective and safe antimalarial drugs. However, it's remains important to continue to monitor their efficacy.",24354627,"Africa","Senegal","http://www.biomedcentral.com/1471-2334/13/598","Yes","Not Available","Not Available"]
["Djallé-2014","Djallé D, Njuimo SP, Manirakiza A, Laganier R, Le Faou A, Rogier C",2014,"Efficacy and safety of artemether + lumefantrine, artesunate + sulphamethoxypyrazine-pyrimethamine and artesunate + amodiaquine and sulphadoxine-pyrimethamine + amodiaquine in the treatment of uncomplicated falciparum malaria in Bangui, Central African Republic: a randomized trial.","Malaria journal",13,9,"doi: 10.1186/1475-2875-13-9.","BACKGROUND:The efficacy of artemisinin-based combination therapy (ACT) has been established. The objective of the present study was to compare the efficacy and safety in the Central African Republic (CAR) of three commercially available artemisinin-based combinations, artemether + lumefantrine (AL), artesunate + sulphamethoxypyrazine-pyrimethamine (AS-SMP) and artesunate + amodiaquine (AS-AQ), with those of sulphadoxine-pyrimethamine + amodiaquine (SP-AQ), which was the first-line reference treatment in the country from 2004, until it was replaced by ACT in 2006 in accordance with changes in international recommendations based on resistance identified in other regions. METHODS:Children aged six to 59 months with uncomplicated Plasmodium falciparum malaria were recruited in Bangui, the capital of the CAR. The 251 patients selected were randomly assigned to receive AL (n = 60), AS-SMP (n = 58), AS-AQ (n = 68) or SP-AQ (n = 65) and were followed up for 28 days. Clinical outcome was classified according to the standard 2003 World Health Organization protocol.RESULTS:At day 28, the cure rates in a per-protocol analysis were 92% (48/52) with AL, 93% (50/54) with AS-SMP, 93% (55/59) with AS-AQ and 100% (57/57) with SP-AQ, with no statistically significant difference between the four treatments. Defervescence was significantly faster with AS-AQ than with AL (p <0.035). Fatigue was reported significantly more frequently by patients receiving AQ than by those treated with AS-SMP or AL (p = 0.006). All the other adverse events reported were mild, and no significant difference was noted by treatment. CONCLUSION:The three artemisinin-bsed combinations show similar, satisfactory results, comparable to that with SP-AQ. This evaluation is the first conducted in CAR since the official introduction of ACT. It should guide the National Malaria Control Programme in choosing the appropriate ACT for treatment of uncomplicated P. falciparum malaria in the future.",24393479,"Africa","Central African Republic",null,"Yes","Available","Excluded","Missing Body Weight"]
["Lui-2014","Liu Y, Hu C, Liu G, Jia J, Yu C, Zhu J, Zheng Q, Zhang KE",2014,"A Replicate Designed Bioequivalence Study to Compare Two Fixed Dose Combination Products of Artesunate and Amodiaquine in Healthy Chinese Volunteers.","ANTIMICROBIAL AGENTS AND CHEMOTHERAPY","NA","NA","doi:10.1128/AAC.02617-14","Artesun-Plus® is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compared the pharmacokinetic and safety profiles between Artesun-Plus® and the WHO designated comparator product Artesunate Amodiaquine Winthrop®. To overcome the high intra-subject variability of artesunate, the study applied a two-sequence and four-period crossover (2 x 4), replicate study design, to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the geometric mean ratios of Cmax and AUC0-last for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and the corresponding 90% confidence intervals were 84.5-108.7% and 87.2-101.1%; while those for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7-104.1% and 93.5-107.0%. In conclusion, bioequivalence was demonstrated between the two artesunate and amodiaquine fixed-dose combination products for both components. The study also confirmed high intra-subject variability, especially for artesunate: CV% of Cmax values for the test and reference products were 39.2% and 43.7%, respectively; while those for amodiaquine were 30.6% and 30.2%, respectively.",25070094,"Asia","China",null,"Yes","Not Available","Not Targetted","Study in Healthy Volunteers"]
["Onyamboko-2014","Onyamboko AM, Fanello CI, Wongsaen K, Tarning J, Cheah PY, Tshefu KA, Dondorp AM, Nosten F, White NJ, Day NP.",2014,"A randomized comparison of the efficacy and tolerability of three artemisinin-based combination treatments for children with acute falciparum malaria in The Democratic Republic of Congo.","ANTIMICROBIAL AGENTS AND CHEMOTHERAPY","NA","NA","doi:10.1128/AAC.02682-14","An open label, randomized controlled trial was carried out in 2011-12 in the Democratic Republic of Congo to test the efficacy, safety and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate and artemether-lumefantrine. 684 children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm. Children were hospitalized for three days, given supervised treatment and followed-up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 hours and similar between arms (p=0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine and 86.3% for dihydroartemisinin-piperaquine (p=0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (p=0.78). The latter provided a longer post-treatment prophylactic effect compared with the other two treatments. The day 7 plasma concentration of piperaquine was below 30 ng/mL in 47% of the children treated with dihydroartemisinin-piperaquine and the day 7 lumefantrine concentration was below 280 ng/mL in 37.0% of children who received artemether-lumefantrine. Thus although cure rates were all satisfactory, they could be improved by increasing the dose (Trial Registration ISRCTN20984426)",25001306,"Africa","Democratic Republic of Congo",null,"Yes","Not Available","Not Available"]
["Tahar-2014","Tahar R, Almelli T, Debue C, Foumane Ngane V, Djaman Allico J, Whegang Youdom S, Basco LK5.",2014,"Randomized Trial of Artesunate-Amodiaquine, Atovaquone-Proguanil, and Artesunate-Atovaquone-Proguanil for the Treatment of Uncomplicated Falciparum Malaria in Children","Journal of Infectious Diseases","NA","NA","doi: 10.1093/infdis/jiu341","BACKGROUND: Artemisinin-based combination therapies (ACTs) are recommended for the treatment of acute uncomplicated falciparum malaria in many malaria-endemic countries. Despite the emergence of artemisinin resistance, few alternative non-ACTs, including atovaquone-proguanil, are currently available. METHODS:Plasmodium falciparum-infected Cameroonian children ≤5 years old (n = 338) were randomly assigned to artesunate-amodiaquine, atovaquone-proguanil, or artesunate-atovaquone-proguanil treatment groups and followed for 28 days, according to the standard World Health Organization protocol. In vitro response to atovaquone and cytochrome b sequence of clinical isolates were determined. RESULTS:Eight late failures and 16 failures (8 late and 8 early failures) were observed after artesunate-amodiaquine and atovaquone-proguanil therapies, respectively. Most late failures were due to reinfections. Artesunate-atovaquone-proguanil was not associated with any failure. After correction by genotyping, per-protocol analysis showed no difference in the efficacy of 3 drugs. However, the proportion of atovaquone-proguanil-treated patients with positive smears on day 3 was much higher (36.0%; P < .05) than that of the artesunate-amodiaquine (2.9%) and artesunate-atovaquone-proguanil (1.0%) groups. In vitro response and cytochrome b sequence did not indicate atovaquone resistance. CONCLUSIONS:Atovaquone-proguanil was characterized by a slow blood schizontocidal action and resulted in early treatment failure in a few patients. Artesunate-atovaquone-proguanil was a highly effective alternative treatment.",24943722,"Africa","Cameroon",null,"Yes","Not Available","Not Available"]
["Falade-2014","Falade CO, Dada-Adegbola HO, Ogunkunle OO, Oguike MC, Nash O, Ademowo OG",2014,"Evaluation of the comparative efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine and artesunate-amodiaquine-chlorpheniramine (Artemoclo™) for the treatment of acute uncomplicated malaria in Nigerian children.","Medical Principles and Practice","NA","NA","204–211","OBJECTIVE:To evaluate the comparative efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and artesunate-amodiaquine-chlorpheniramine (AQC) for the treatment of acute uncomplicated malaria among Southwest Nigerian children.SUBJECTS AND METHODS: One hundred and sixty children aged 6 months to 14 years with acute uncomplicated malaria were randomized to AL (n = 53), ASAQ (n = 53), or AQC (n = 54). Enrollees were seen daily on days 0-3 and then on days 7, 14, 21, 28 and 42 for clinical and parasitological evaluations. Paired samples of genomic DNA at enrolment and at the time of recurrent parasitaemia were genotyped using nested PCR to distinguish between reinfection and recrudescence. Detailed haematological and biochemical evaluations were carried out in a subset of enrollees on days 0, 7 and 28 as part of a safety evaluation.RESULTS:Of the 160 children, 144 (90%) completed the study. The mean fever clearance times and parasite clearance times for AL, ASAQ and AQC were comparable (p = 0.94 and p = 0.122, respectively). On day 14, the adequate clinical and parasitological response (ACPR) for AL and AQC was 100% and for ASAQ it was 90% (p = 0.39). The PCR-uncorrected results on days 28 and 42 and the ACPR-corrected results on day 42 were similar for all drugs (p = 0.62 and p = 0.56, respectively). AQC resulted in the best parasite clearance and haematological recovery on day 2 (p = 0.022 and p = 0.018, respectively). Biochemical parameters were not adversely affected by the three artemisinin-based combination therapies (ACTs) and these were well tolerated.CONCLUSION:The three ACTs were efficacious and safe, but AQC resulted in a better haematological recovery on day 2 and higher cure rates throughout the study period.",24732940,"Africa","Nigeria",null,"Yes","Not Available","Not Available"]
["Tinto-2014","Tinto H, Diallo S, Zongo I, Guiraud I, Valea I, Kazienga A, Kpoda H, Sorgho H, Ouédraogo JB, Guiguemdé TR, D'Alessandro U.",2014,"Effectiveness of artesunate-amodiaquine vs. artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Nanoro, Burkina Faso: a non-inferiority randomised trial.","Trop Med Int Health",19,4,"469-75","OBJECTIVES: Artemisinin-based combination therapies (ACTs) are essential for the effective control of falciparum malaria in endemic countries. However, in most countries, such choice has been carried out without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ).\nMETHODS: Between September 2008 and January 2010, 340 children were randomised to one of the two study arms and followed up for 42 days. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days.\nRESULTS: The results showed a significantly higher unadjusted adequate clinical and parasitological response in the ASAQ (58.4%) than in the AL arm (46.1%) at day 28 but these trends were similar after correction with PCR data (ASAQ (89.7%) and AL (89.8%)). New infections started to appear after day 14, first in the AL and then in the ASAQ arm but at day 42 day of follow-up we observed no difference in the occurrence of recrudescent infection.\nCONCLUSION: Despite a lower cure rate than those reported in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso.",24494602,"Africa","Burkina Faso",null,"Yes","Not Available","Not Available"]
["Scarsi-2014","Scarsi KK, Fehintola FA, Ma Q, Aweeka FT, Darin KM, Morse GD, Akinola IT, Adedeji WA, Lindegardh N, Tarning J, Ojengbede O, Adewole IF, Taiwo B, Murphy RL, Akinyinka OO, Parikh S.",2014,"Disposition of amodiaquine and desethylamodiaquine in HIV-infected Nigerian subjects on nevirapine-containing antiretroviral therapy.","Journal of Antimicrobial Chemotherapy","NA","NA","1370–1376","OBJECTIVES:Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ).METHODS:This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods.RESULTS:Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC₀₋₂₄ 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC₀₋₉₆ 14,571 versus 21,648 ng·h/mL, P < 0.01). The AUCDEAQ/AUC(amodiaquine) ratio was not different between groups (ART group 116 versus control group 102, P = 0.67).CONCLUSIONS:Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.",24446424,"Africa","Nigeria",null,"Yes","Not Available","Not Targetted","Study in HIV patients [PK study] followed for 7 days"]
["Gaye-2010*","Oumar Gaye,  Jean Louis Ndiaye, Babacar Faye, Roger Tine, Sylla Khadime, Mamadou Sarifou Ba, Mbaye Pene, Doudou Sow",2010,"Study on the efficacy of antimalarial drugs in the suburbs of Dakar in collaboration with the NMCP and the WHO","Unpublished","NA","NA","NA","NA","NA","Africa","Senegal","NA","No","Available","Included"]
["Grandesso-2003*","Francesco Grandesso,  Philippe Guerin, Birgit SCHRAMM, Loretxu PINOGES, Jean-Francois Etard",2003,"Efficacy of chloroquine + sulfadoxine-pyrimethamine,artesunate + amodiquine and artesunate + sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum in Amudat, Uganda","Unpublished","NA","NA","NA","NA","NA","Africa","Uganda","NA","No","Available","Included"]
["Juma-2005*","Elizabeth Juma",2005,"Efficacy of co-adminsitered amodiaquine plus artesunateand artemether/lumefantrine for the treatment of uncomplicated falciparum malaria in children less than five years in different epidemiological settings in Kenya","Unpublished","NA","NA","NA","NA","NA","Africa","Kenya","NA","No","Available","Included"]
["Laminou-2011*","Ibrahim Laminou",2011,"Etude comparative randomisee, a double bras aveugle, de l'efficacite therapeutique et d'innocuite de l'artemether-lumefantrine et de l'artesunate-amodiaquine au niveau de site sentinelle de Gaya-Niger","Unpublished","NA","NA","NA","NA","NA","Africa","Niger","NA","No","Available","Included"]
["Menan-2012*","Herve Menan",2012,"2012-Côte d’Ivoire-Multisite--H.Menan","Unpublished","NA","NA","NA","NA","NA","Africa","Cote d'Ivoire","NA","No","Available","Included"]
["Nikiema-2010*","Frederic Nikiema, Issaka Zongo, Fabrice Some, Jean-Bosco Ouedraogo",2012,"Evolution of therapeutic efficacies of artemisinin-based combination therapies (ASAQ and AL) for treatment of uncomplicated falciparum malaria in Burkina Faso during five years of adoption as first-line treatments","Unpublished","NA","NA","NA","NA","NA","Africa","Burkina Faso","NA","No","Available","Included"]
["Sanofi-2013*","Valerie Lameyre, François Bompart",2013,"Ugandan FDC study","Unpublished","NA","NA","NA","NA","NA","Africa","Uganda","NA","No","Available","Included"]
["Temu-2010*","Emmanuel Temu, Richard Allan",2010,"Monitoring Therapeutic Efficacy of Artesunate-Amodiaquine FDC for treatment of uncomplicated falciparum malaria in Liberia","Unpublished","NA","NA","NA","NA","NA","Africa","Liberia","NA","No","Available","Included"]

{"sheet":"Study Data","index":1,"n_rows":127,"n_cols":18,"rows_kept":127,"flags":["formulas_cached_only"]}
["Accession Number","Reference","Country","Treatment arm","manufacturer","Supervision","Start year recruitment","End year recruitment","Number of patients   with Pf/Pf mixed                                                                           ","Number of patients with Pv","<5yrs","5-15yrs","Adults","Pregnant Women","Length of follow up (days)","Published","pooled analysis","Comments"]
[22087077,"4ABC Study Group-2011","Multicentred","ASAQ3","Sanofi-Aventis","full",2007,2009,1002,0,1,0,0,0,180,"Yes","Included"]
[15040556,"Abacassamo-2004","Mozambique","AS3 plus AQ3",null,"partial",2002,2002,61,0,0,0,0,0,21,"Yes","Not targetted","Two phase trial: First phase with 28 day follow up while second phase had 14 day follow up"]
[18620577,"Adjei-2008a","Ghana","AS3 plus AQ3","Mepha Ltd and Pfizer","full",2004,2006,116,0,1,1,0,0,28,"Yes","Excluded","Missing PCR and Dosing Information"]
[18779360,"Adjei-2008b","Ghana","ASAQ3","Mepha Ltd and Pfizer","full",2004,2006,116,0,1,1,0,0,28,"Yes","Excluded","Subset of Adjei-2008a (18620577): PK Patients"]
[11978332,"Adjuik-2002","Multicentred","AS3 plus AQ3","Sanofi-Synthélabo and Parke-Davis","full",1999,2000,470,0,1,1,0,0,28,"Yes","Included"]
[24455414,"Ali-2013","Cameroon","AS3 plus AQ3",null,"full",2007,2007,73,0,1,1,0,0,28,"Yes","Not Available"]
[22458860,"Anvikar-2012","India","ASAQ3","Sanofi-Aventis","full",2007,2008,201,0,1,1,1,0,28,"Yes","Included"]
[19478248,"Asih-2009","Indonesia","AS3 plus AQ3",null,"full",2006,2006,103,0,1,1,1,0,28,"Yes","Not Available"]
[21194422,"Ayede-2010","Nigeria","ASAQ3","Dafra Pharma ltd","full",null,null,250,0,1,1,0,0,28,"Yes","Not Available"]
[15078261,"Barennes-2004","Burkina Faso","AS3 plus AQ3","Hoechst Marion Roussel and Sanofi Winthrop Amo","full",2001,2001,33,0,0,0,0,0,28,"Yes","Included"]
[17477865,"Bonnet-2007","Guinea","AS3 plus AQ3","Guilin Pharmaceutical Works and Parke-Davis","full",2004,2005,110,0,1,0,0,0,28,"Yes","Included"]
[19664280,"Bonnet-2009","Democratic Republic of Congo","AS3 plus AQ3","Sanofi Winthrop AMO and Pfizer","full",2003,2004,148,0,1,1,0,0,28,"Yes","Excluded","Missing PCR Results"]
[18005408,"Brasseur-2007","Senegal","AS3 plus AQ3","Sanofi-Aventis","full",2000,2003,731,0,1,1,1,0,28,"Yes","Excluded","Subset of Brasseur-2009"]
[18005408,"Brasseur-2007","Senegal","AS3 plus AQ3","Sanofi-Aventis","full/partial",2004,2005,235,0,1,1,1,0,28,"Yes","Excluded","Subset of Brasseur-2009"]
[19021893,"Brasseur-2009","Senegal","ASAQ3","Sanofi-Aventis","full/partial",2000,2006,731,0,1,1,1,0,28,"Yes","Included"]
[19021893,"Brasseur-2009","Senegal","ASAQ3","Sanofi-Aventis","full/partial",2000,2006,235,0,1,1,1,0,28,"Yes","Included"]
[16871329,"Bukirwa-2006","Uganda","AS3 plus AQ3","Sanofi-Aventis and Parke-Davis, Pfizer","full",2004,2005,211,0,0,0,0,0,28,"Yes","Included"]
[23530078,"Charle-2013","Equatorial Guinea","AS3 plus AQ3","Action Medeor and Holden Medical","full",2006,2006,122,0,1,0,0,0,28,"Yes","Not Available"]
[20689585,"Clark-2010","Uganda","AS3 plus AQ3",null,"full",2004,2008,404,0,1,1,0,0,28,"Yes","Excluded","Subset of Dorsey-2007"]
[23295878,"De la Hoz Restrepo-2012","Colombia","ASAQ3","Sanofi-Aventis","full",2008,2009,105,0,0,0,1,0,28,"Yes","Not Available"]
[24393479,"Djallé-2014","Central African Republic","ASAQ3","Sanofi-Aventis","Full",2008,2009,68,0,1,0,0,0,28,"Yes","Excluded","Missing Body Weight"]
[18337343,"Djimde-2008","Mali","AS3 plus AQ3","Sanofi-Aventis","full",2002,2004,250,0,1,1,1,0,28,"Yes","Excluded","Missing Dosing Plan"]
[23043495,"Dorkenoo-2012","Togo","AS3 plus AQ3","Sanofi Synthélabo and Hoechst Marion Roussel","full",2005,2009,485,0,1,0,0,0,28,"Yes","Not Available"]
[23043495,"Dorkenoo-2012","Togo","AS3 plus AQ3","Sanofi-Aventis","full",2005,2009,166,0,1,0,0,0,28,"Yes","Not Available"]
[17519410,"Dorsey-2007","Uganda","AS3 plus AQ3",null,"full",2004,2006,113,0,1,1,0,0,28,"Yes","Included"]
[15941414,"Durrani-2005","Afghanistan","AS3 plus AQ3","Mepha and Parke Davis","full",2002,2003,79,0,1,1,1,0,42,"Yes","Not Targetted","PCR Not Carried Out"]
[22631564,"Espie-2012","Democratic Republic of Congo","ASAQ3","Sanofi-Aventis","full",2008,2009,156,0,1,0,0,0,42,"Yes","Included"]
[18346028,"Falade-2008","Nigeria","AS3 plus AQ3","Sanofi-Synthelabo and Pfizer Pharmaceuticals Limited","full",2004,2005,66,0,1,1,0,0,28,"Yes","Not Available"]
[19469703,"Faucher-2009","Benin","ASAQ3","Sanofi","partial",2007,2007,96,0,1,0,0,0,42,"Yes","Included"]
[17570848,"Faye-2007","Senegal","AS3 plus AQ3",null,"full",2002,2003,360,0,1,1,1,0,28,"Yes","Excluded","Missing Dosing Table and Missing PCR Results"]
[20214761,"Faye-2010","Multicentred","AS3 plus AQ3","Pfizer Pharma","full",2007,2008,159,0,0,1,1,0,28,"Yes","Included"]
[23270636,"Faye-2012","Multinational","AS3 plus AQ3","Pfizer Pharmaceutical Laboratories","full",2008,2009,249,0,1,1,0,0,28,"Yes","Not Available"]
[18574653,"Fehintola-2008","Nigeria","AS3 plus AQ3",null,"full",2006,2006,61,0,1,1,0,0,28,"Yes","Not Available"]
[21540395,"Gbotosho-2011a","Nigeria","ASAQ3","Sanofi-Aventis","full",2009,2010,100,0,1,1,0,0,42,"Yes","Not Available"]
[21540395,"Gbotosho-2011a","Nigeria","AS3 plus AQ3","Swiss Pharma","full",2009,2010,104,0,1,1,0,0,42,"Yes","Not Available"]
[21633031,"Gbotosho-2011b","Nigeria","ASAQ3","Sanofi-Aventis","full",2005,2010,158,0,1,1,0,0,42,"Yes","Not Targetted ","Pooled analysis with previously published data"]
[21633032,"Gbotosho-2011b","Nigeria","AS3 plus AQ3","Swiss Pharma","full",2006,2011,328,0,2,2,1,1,43,"Yes","Not Targetted ","Pooled analysis with previously published data"]
[21519221,"Gbotosho-2012a","Nigeria","AS3 plus AQ3",null,"NA",2010,2011,"NA",null,1,1,0,0,42,"Yes","Not Available"]
[21622538,"Gbotosho-2012b","Nigeria","ASAQ3","Sanofi-Aventis","full",2009,2011,12,0,1,1,0,0,42,"Yes","Not Targetted ","Hyperparasitaemic population; no PCR"]
[21622538,"Gbotosho-2012b","Nigeria","AS3 plus AQ3","Swiss Pharma","full",2009,2011,12,0,1,1,0,0,42,"Yes","Not Targetted ","Hyperparasitaemic population; no PCR"]
[16827702,"Grandesso-2006","Sierra Leone","AS3 plus AQ3","Sanofi Winthrop AMO and Pfizer","full",2004,2004,126,0,1,0,0,0,28,"Yes","Included"]
[15876443,"Guthmann-2005","Angola","AS3 plus AQ3","Sanofi Winthrop and Parke Davis","full",2003,2003,97,0,1,0,0,0,28,"Yes","Included"]
[16837721,"Guthmann-2006","Angola","AS3 plus AQ3","Sanofi and Park-Davis","full",2004,2004,69,0,1,0,0,0,28,"Yes","Included"]
[15869770,"Hamour-2005","Sudan","AS3 plus AQ3","Sanofi and Park-Davis","full",2003,2003,80,0,1,0,0,0,28,"Yes","Included"]
[17366451,"Hasugian-2007","Indonesia","AS3 plus AQ3","Guilin Pharmaceuticals and Aventis","full",2005,2005,0,166,1,1,1,0,42,"Yes","Included"]
[17244406,"Ibrahium-2007","Sudan","AS3 plus AQ3","Dafra","full",2005,2005,48,0,0,0,0,0,28,"Yes","Not Available"]
[20368402,"Jullien-2010","Kenya","ASAQ3","Sanofi-Aventis","full",2007,2009,26,0,0,0,1,0,28,"Yes","Included"]
[20368402,"Jullien-2010","Kenya","AS3 plus AQ3",null,"full",2007,2009,28,0,0,0,1,0,28,"Yes","Included"]
[17996121,"Kabanywanyi-2007","Tanzania","AS3 plus AQ3",null,"full",2004,2004,65,0,0,0,0,0,28,"Yes","Not Available"]
[16766006,"Karema-2006","Rwanda","AS3 plus AQ3","Sanofi","full",2003,2004,253,0,1,1,0,0,28,"Yes","Included"]
[19128455,"Kayentao-2009","Mali","AS3 plus AQ3",null,"full",2005,2006,133,0,1,0,0,0,28,"Yes","Included"]
[19099594,"Kobbe-2008","Ghana","AS3 plus AQ3","Sanofi-Aventis","partial",2006,2007,117,0,1,0,0,0,28,"Yes","Not Available"]
[16054584,"Koram-2005","Ghana","AS3 plus AQ3",null,"full",2003,2003,54,0,1,0,0,0,28,"Yes","Not Available"]
[19180204,"Koram-2008","Ghana","AS3 plus AQ3",null,"full",2005,2006,540,0,1,0,0,0,28,"Yes","Not Targetted ","PCR results not carried out for this priliminary report"]
[23448727,"Lopera-Mesa-2013","Mali","AS3 plus AQ3",null,"full",2010,2011,215,0,1,1,0,0,3,"Yes","Not Targetted ","<28 days follow up [ Patients followed up for 3 days, Parasite Clearance Study]"]
[18547415,"Maiteki-Sebuguzi-2008","Uganda","AS3 plus AQ3","Sanofi-Aventis and Parke-Davis","partial",2004,2007,133,0,1,1,0,0,42,"Yes","Not Targetted ","Active follow-up up to 14 days"]
[16163624,"Martensson-2005","Tanzania","AS3 plus AQ3","Mepha and Roussel","full",2002,2003,207,0,1,0,0,0,42,"Yes","Included"]
[17519010,"Menard-2007","Madagascar","AS3 plus AQ3",null,"full",2006,2006,83,0,1,1,0,0,28,"Yes","Excluded","Subset of Menard-2008 Study"]
[18394169,"Menard-2008","Madagascar","AS3 plus AQ3",null,"full",2006,2007,346,0,1,1,0,0,28,"Yes","Included"]
[16704735,"Meremikwu-2006","Nigeria","AS3 plus AQ3",null,"full",2004,2004,59,0,1,0,0,0,14,"Yes","Not Targetted ","<28 days follow up [14 day follow up study]"]
[21092220,"Michael-2010","Nigeria","AS3 plus AQ3",null,"full",null,null,96,0,1,1,0,0,42,"Yes","Not Available"]
[15850631,"Mutabingwa-2005","Tanzania","AS3 plus AQ3","Sanofi","partial",2002,2004,515,0,1,0,0,0,28,"Yes","Excluded","Missing Dosing Plan"]
[19352498,"Mutabingwa-2009","Tanzania","AS3 plus AQ3",null,"full",2004,2006,83,0,0,0,1,1,28,"Yes","Not Targetted ","Study in pregnant women"]
[19841149,"Mwesigwa-2010","Uganda","ASAQ3","NA",null,2004,2008,21,0,1,1,0,0,"NA","Yes","Excluded","Subset of Dorsey-2007 [PK Patients]"]
[24122669,"Nambei-2013","Central Republic of Africa",{"$nulls":3},2010,2010,60,0,1,0,0,0,28,"Yes","Not Available"]
[15189457,"Ndayiragije-2004","Burundi","AS3 plus AQ3","Mepha and Sedapharm","full",2001,2002,153,0,1,0,0,0,14,"Yes","Not Targetted ","Patients followed up to 14 days (290/295 patients followed up only up to 14 days)"]
[18205945,"Ndiaye-2008","Multicentred","AS3 plus AQ3","Sanofi","full",2005,2005,161,0,0,0,0,0,14,"Yes","Not Targetted ","<28 days follow up [14 day follow up study]"]
[18205945,"Ndiaye-2008","Multicentred","AS3 plus AQ3","Sanofi","full",2005,2005,155,0,0,0,0,0,14,"Yes","Not Targetted ","<28 days follow up [14 day follow up study]"]
[19505304,"Ndiaye-2009","Multicentred","ASAQ3","Sanofi-Aventis","full",2006,2006,313,0,1,1,1,0,28,"Yes","Included"]
[19505304,"Ndiaye-2009","Multicentred","ASAQ3","Sanofi-Aventis","full",2006,2006,316,0,1,1,1,0,28,"Yes","Included"]
[21838909,"Ndiaye-2011","Senegal","ASAQ3 ","Sanofi-Aventis","full",2007,2009,184,0,1,1,1,0,28,"Yes","Included"]
[23384005,"Ndounga-2013","Republic of Congo","AS3 plus AQ3","Sanofi-Aventis","full",2005,2005,197,0,1,1,1,0,28,"Yes","Not Available"]
[18817597,"Oduro-2008","Ghana","AS3 plus AQ3","Ipca Laboratories","full",2005,2006,150,0,1,1,0,0,28,"Yes","Not Available"]
[18817597,"Oduro-2008","Ghana","AS3 plus AQ3","Ipca Laboratories","unsupervised",2005,2006,151,0,1,1,0,0,28,"Yes","Not Available"]
["Not of Pubmed","Offianan-2011","Cote d'Ivoire","ASAQ3","Sanofi-Aventis","Full",2008,2009,128,0,1,0,0,0,28,"Yes","Excluded","Missing PCR Results"]
[24334945,"Ojurongbe O-2013","Nigeria","ASAQ3","Ipca","full",2010,2011,81,0,1,1,0,0,28,"Yes","Not Available"]
[17328806,"Osorio-2007b","Colombia","AS3 plus AQ3","Sanofi","full",2000,2004,42,0,1,1,1,0,28,"Yes","Included"]
[18575626,"Owusu-Agyei-2008","Ghana","AS3 plus AQ3","Sanofi-Aventis","full",2005,2006,178,0,1,1,0,0,28,"Yes","Not Available"]
[17352806,"Oyakhirome-2007","Gabon","AS3 plus AQ3","Sanofi Synthélabo","full",2004,2005,48,0,1,0,0,0,28,"Yes","Not Targetted ","Patients followed up on day2 and day28 only"]
[17352806,"Oyakhirome-2007","Gabon","AS3 plus AQ3","Sanofi Synthélabo","unsupervised",2004,2005,41,0,1,0,0,0,28,"Yes","Not Targetted ","Patients followed up on day2 and day28 only"]
[23926329,"Pasaribu-2013","Indonesia","ASAQ3 + PQ","Guilin Pharmaceuticals","full",2010,2012,0,167,1,1,1,0,42,"Yes","Not Targetted ","P Vivax study"]
[22302849,"Ratsimbasoa-2012","Madagascar","ASAQ3","Sanofi-Aventis","partial",2008,2009,375,0,1,0,0,0,730,"Yes","Not Targetted ","Effectiveness study: no follow-up between d3 and d28"]
[15482401,"Rwagacondo-2004","Rwanda","AS3 plus AQ3","Dafra","full",2002,2002,158,0,1,0,0,0,28,"Yes","Included"]
[22764291,"Sagara-2012","Mali","AS3 plus AQ3","Sanofi-Aventis","full",2005,2007,260,0,1,1,1,0,28,"Yes","Included"]
["N/A","Sahr-2013","Sierra Leone",null,null,"full",null,null,109,0,1,0,0,0,28,"Yes","Not Available"]
[23866736,"Schramm-2013a","Liberia","ASAQ3","Sanofi-Aventis","full",2008,2009,498,0,1,1,1,0,42,"Yes","Not targetted","Subset of Schramm-2013b; Safety data"]
[23866774,"Schramm-2013b","Liberia","ASAQ3","Sanofi-Aventis","full",2008,2009,150,0,1,0,0,0,42,"Yes","Included"]
[20166428,"Sinou-2009","Democratic Republic of Congo","ASAQ3","TRIMALACT","full",2007,2007,13,0,0,0,1,0,28,"Yes","Included"]
[19291301,"Sirima-2009","Burkina Faso","AS3 plus AQ3","Sanofi-Aventis","full",2004,2006,375,0,1,0,0,0,28,"Yes","Included"]
[19291301,"Sirima-2009","Burkina Faso","ASAQ3","Sanofi-Aventis","full",2004,2006,375,0,1,0,0,0,28,"Yes","Included"]
[20832366,"Smithuis-2010","Myanmar","ASAQ3 + PQ","Sanofi-Aventis","partial",2008,2009,71,0,1,1,1,0,63,"Yes","Included"]
[20832366,"Smithuis-2010","Myanmar","ASAQ3","Sanofi-Aventis","partial",2008,2009,84,0,1,1,1,0,63,"Yes","Included"]
[16262741,"Sowunmi-2005","Nigeria","AS3 plus AQ3","Ipca Pharmaceutical","full",2004,2004,104,0,1,1,0,0,28,"Yes","Not Available"]
[17325222,"Sowunmi-2007","Nigeria","AS3 plus AQ3",null,"full",2005,2006,120,0,1,1,0,0,35,"Yes","Not Targetted ","PCR Not Carried Out"]
[22052702,"Sowunmi-2012","Nigeria","AS3 plus AQ3",null,"full",2010,2011,1674,0,1,1,0,0,42,"Yes","Not Available"]
[22052702,"Sowunmi-2012","Nigeria","AS3 plus AQ3",null,"full",2010,2011,68,0,1,1,0,0,42,"Yes","Not Available"]
[21192244,"Sowunmi-2013","Nigeria","AS3 plus AQ3",{"$nulls":4},7,0,{"$nulls":4},28,"Yes","Not Available"]
[21192244,"Sowunmi-2013","Nigeria","ASAQ3",{"$nulls":4},120,0,{"$nulls":4},28,"Yes","Not Available"]
[15567011,"Staedke-2004","Uganda","AS3 plus AQ3",null,"full",2002,2003,139,0,0,0,0,0,28,"Yes","Included"]
[17002724,"Swarthout-2006","Democratic Republic of Congo","AS3 plus AQ3",null,"full",2004,2004,90,0,1,0,0,0,28,"Yes","Included"]
[24354627,"Sylla K-2013","Senegal","ASAQ3","Sanofi-Aventis","full",2011,2012,180,0,1,1,1,0,28,"Yes","Not Available"]
[17568549,"Tall-2007","Comoros","AS3 plus AQ3",null,"full",2003,2003,56,0,0,0,0,0,14,"Yes","Not Targetted ","<28 days follow up [14 day follow up study]"]
[19320869,"Thanh-2009","Vietnam","AS3 plus AQ3","Namha Pharmaceutical Joint Stock Company and Sunward Pharmaceutical Pty Ltd","full",2006,2007,56,0,0,0,0,0,42,"Yes","Not Available"]
[22741618,"Thanh-2012","Vietnam","ASAQ3","Sanofi-Aventis","full",2008,2009,65,0,0,1,1,0,42,"Yes","Excluded","Missing PCR Results"]
[19187521,"Thwing-2009","Kenya","AS3 plus AQ3","Cosmos Pharmaceuticals Limited and Pfizer ","full",2007,2007,110,0,1,0,0,0,28,"Yes","Included"]
[15730557,"van den Broek-2005","Sudan","AS3 plus AQ3",null,"full",2003,2004,134,0,1,0,0,0,42,"Yes","Excluded","Missing dosing plan"]
[17125496,"van den Broek-2006","Republic of Congo","AS3 plus AQ3","Sanofi and Parkes Davis/Pfizer","full",2004,2004,101,0,1,0,0,0,28,"Yes","Included"]
[19026606,"Warsame-2009","Somalia","AS3 plus AQ3",null,"full",2003,2006,198,0,1,1,0,0,28,"Yes","Not Available"]
[20170477,"Whegang-2010","Cameroon","AS3 plus AQ3",null,"full",2003,2007,186,0,1,0,0,0,28,"Yes","Not Available"]
[16033307,"Yeka-2005","Uganda","AS3 plus AQ3",null,"full",2002,2004,731,0,0,0,0,0,28,"Yes","Included"]
[18286187,"Zoungrana-2008","Burkina Faso","AS3 plus AQ3","Guilin Pharmaceuticals Co., Ltd. And ??","full",2006,2006,61,0,0,1,0,0,28,"Yes","Not Targetted","Methylene Blue Study"]
[19698172,"Zwang-2009","Multicentred","ASAQ3","Various","full",1999,2006,"N/A",0,1,1,"NA",0,28,"Yes","Not Targetted ","Pooled Analysis"]
[25070094,"Lui-2014","China","ASAQ","Guilin Pharmaceutics & Sanofi-Aventis","Full","NA","NA",36,0,0,0,1,0,3,"Yes","Not Targetted","Study in Healthy Volunteers; PK study"]
[25001306,"Onyamboko-2014","Democratic Republic of Congo","ASAQ","Sanofi Aventis","Full",2011,2012,228,0,1,0,0,0,42,"Yes","Not Available"]
[24943722,"Tahar-2014","Cameroon","ASAQ","Dafra and Pfizer","Full",2008,2009,70,0,1,0,0,0,28,"Yes","Not Available"]
[24732940,"Falade-2014","Nigeria","ASAQ","Pfizer","Full","NA","NA",53,0,1,1,0,0,42,"Yes","Not Available"]
[24494602,"Tinto-2014","Burkina Faso","ASAQ","Sanofi Aventis","Partial",2008,2010,170,0,1,0,0,0,42,"Yes","Not Available"]
[24446424,"Scarsi-2014","Nigeria","ASAQ","Dart","NA",2009,2010,11,0,"NA","NA","NA",0,7,"Yes","Not Targetted","Study in HIV patients [PK study] followed for 7 days"]
["Unpublished","Gaye-2010*","Senegal","ASAQ3","Sanofi-Aventis","full",2010,2010,130,0,1,1,1,0,42,"No","Included"]
["Unpublished","Grandesso-2003*","Uganda","AS3 plus AQ3","Sanofi-Parke Davis","full",2003,2003,106,0,1,0,0,0,28,"No","Included"]
["unpublished","Juma-2005*","Kenya","AS3 plus AQ3","Sanofi and Hoechst M. Roussel","full",2004,2005,201,0,1,0,0,0,28,"No","Included"]
["Unpublished","Laminou-2011*","Niger","ASAQ3","Sanofi-Aventis","partial",2011,2011,80,0,1,1,0,0,28,"No","Included"]
["Unpublished","Menan-2012*","Cote d'Ivoire","ASAQ3","Sanofi-Aventis","full",2012,2012,146,0,1,1,1,0,28,"No","Included"]
["Unpublished","Nikiema-2010*","Burkina Faso","ASAQ3","Sanofi-Aventis","full",2006,2010,532,0,1,1,1,0,28,"No","Included"]
["Unpublished","Sanofi-2013*","Uganda","ASAQ3","Sanofi-Aventis","full",2008,2008,208,0,1,0,0,0,42,"No","Included"]
["Unpublished","Temu-2010*","Liberia","ASAQ3","Sanofi-Aventis","full",2010,2011,102,0,1,0,0,0,28,"No","Included"]

{"sheet":"Dosing schedule","index":2,"n_rows":48,"n_cols":11,"rows_kept":48,"flags":["formulas_cached_only"]}
["Reference","Formulation","Manufacturer","Adults Tablet Contents","Paediatric Tablet Contents","Calculation of Total Doses","Dosing Schedule","Schedule","Total target dose of AS over 3 days (mg/kg)","Total target dose of AQ over 3 days (mg/kg)","comments"]
["4ABC Study Group-2011","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,30]
["Adjuik-2002","Arsumax plus Camoquin","Sanofi-Synthélabo and Parke-Davis","50 mg AS and 200 mg AQ","-","Tablets","See Further Dosing Table","once daily for 3 days",12,30]
["Anvikar-2012","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg","Per Protocol","6 to 11 months: 1 PAED1 tablet; 1 to 5 years: 2 PAED1 tablets; 6 to 13 years: 1 adult tablet; ≥ 14 years: 2 adult tablets","once daily for 3 days",12,30]
["Barennes-2004","Arsumax and Flavoquine","Sanofi Winthrop Amo, Gentilly, France & Hoechst Marion Roussel","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Bonnet-2007","Arsumax and Camoquin","Guilin Pharmaceutical Works and Parke-Davis","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Brasseur-2011","Arsumax and Flavoquine","Sanofi-Aventis","50 mg AS and 153 mg AQ","-","Per Protocol","AQ dosing: <1y: 1/2 tablet; 1-<6y: 1 tablet and 6-<13y: 2 tablets. AS dosing: <1 y: 1/2 tablet; 1-<6y: 1 tablet; 6-<13y: 2 tablet, 13-<100y: 4 tablets","once daily for 3 days","N/A","N/A"]
["Bukirwa-2006","Arsumax and Camoquin","Sanofi-Aventis and Parke-Davis, Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,25]
["Dorsey-2007","Arsumax and Camoquin","Sanofi-Aventis and Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,25]
["Espie-2012","ASAQ Winthrop","Sanofi-Aventis","-","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Tablets","5 to 8.9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet","once daily for 3 days",12,30]
["Faucher-2009","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","5 to 9 kg: 1 PAED1 tablet; >9 to 18 kg: 1 PAED2 tablet; >18kg: 1 adult tablet","once daily for 3 days",12,30]
["Faye-2010","Camoquin Plus","Pfizer","100 mg AS/300 mg AQ","PAED1: 100 mg AS/300 mg AQ","Per Protocol","7 yo 14 yrs: 1 PEAD1 tablet; 14 to 100 years: 2* PEAD1 tablets","once daily for 3 days","N/A","N/A"]
["Gaye-2010b*","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,30]
["Grandesso-2003*","Arsumax plus Camoquin","Sanofi and Park-Davis","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Grandesso-2006","Arsumax and Camoquin","Sanofi Winthrop AMO and Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Guthmann-2005","Arsumax plus Camoquin","Sanofi Winthrop and Parke Davis","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Guthmann-2006","Arsumax and Camoquin","Sanofi Winthorp AMO and Pfizer","50 mg AS and 200 mg AQ",null,"Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Hamour-2005","Arsumax plus Camoquin","Sanofi and Park-Davis","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Hasugian-2007","Arsumax and Flavoquine","Guilin Pharmaceuticals and Aventis","50 mg AS and 200 mg AQ","-","Tablets","See Further Dosing Table","once daily for 3 days",12,30]
["Jullien-2010","arsucam","Sanofi-Aventis","50 mg AS and 153 mg AQ","-","Tablets","AQ dosing : 4 tablets/day for all weight ; AS dosing: 4 tablets/day for all weight","once daily for 3 days",12,30]
["Jullien-2010","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","-","Tablets","2 tablets/day foo all patients","once daily for 3 days","N/A","N/A"]
["Juma-2005*","Arsumax and Flavoquine","Sanofi and Hoechst Marion Roussel","50 mg AS and 200 mg AQ",null,"Tablets","See Further Dosing Table","once daily for 3 days",12,30]
["Karema-2006","Arsumax","Sanofi-Aventis","50 mg AS and 200 mg AQ","-","Tablets","AQ Dosing <15 kg: 3/4 tablets; 15-<120 kg: 1 tablet; 20-<25 kg: 1.25 tablets. AS Dosing: <15 kg: 1 tablet, 15-<20 kg: 1/5 tablet, 20-<25 kg: 2 tablets","once daily for 3 days",12,30]
["Kayentao-2009","-","-","50 mg AS and 153 mg AQ","-","Tablets","AQ Dosing: <10 kg: 100 mg/daily; 10-<15 kg: 150 mg/daily;15-<25 kg: 200 mg/daily. AS Dosing:  <7 kg: 25 mg/daily;  7-<13 kg: 50 mg/daily; 13-<20 kg: 75 mg/daily; 20-<25 kg: 100 mg/daily","once daily for 3 days",12,30]
["Laminou-2011*","-","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet; ≥ 36 kg: 2 adult tablets","once daily for 3 days",12,30]
["Martensson-2005","Plasmotrim and Flavoquin","Mepha and Roussel","100 mg AS  and 153 mg AQ","-","Per Protocol","AQ dosing: <10 kg; 1/2 tablet; 10-20 kg; 1 tablet. AS dosing:  <10 kg: 1/4 tablet, 10-20 kg; 1/2 tablets","once daily for 3 days",12,30]
["Menan-2012*","-","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet; ≥ 36 kg: 2 adult tablets","once daily for 3 days",12,30]
["Ménard-2008","-","-","50 mg AS and 200 mg AQ","-","Tablets","AS and AQ Dosing : 6-<10 kg: 1 tablet; 10-21 kg: 1.5 tablets; 21-<41 kg: 2 tablets: 41-5<54 kg: 4 tablets","once daily for 3 days",12,30]
["Ndiaye-2009 (once-daily arm)","Coarsucam","Sanofi-Aventis","-","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","10-<15 kg: 1 X 135 mg tablet/day,  15-<18 kg: 2 X67.5 mg tabelts/day; 18-<35kg: 2 X 135 mg tablets/day ; 36-<100 kg: 4 X 135 mg tablets/day","once daily for 3 days",12,30]
["Ndiaye-2009 (twice-daily arm)","Coarsucam","Sanofi-Aventis","-","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","10-<18 kg: 2 X 1 tablets of 67.5 mg tablet/day;  18- <35 kg: 2 X 2 tablets of 67.5 tablets/day; 36-<100 kg: 2 X 4 tablets of 67.5 tablets/day","twice daily for 3 days",12,30,"Daily doses given 8 hrs apart"]
["Ndiaye-2011","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Tablets","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,30]
["Ndiaye-2011","Coarsucam","Sanofi-Aventis","101 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Tablets","6 to <9 kg: 1 PAED1 tablet; 9 to <18 kg: 1 PAED2 tablet; >=18 kg: 1 adult tablet","once daily for 3 days",12,30]
["Nikiema-2010*","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,30]
["Osorio-2007b","Arsumax and Camoquin","Sanofi","200 mg of AQ","-","Tablets","See Further Dosing Table","once daily for 3 days",12,30]
["Rwagacondo-2004","-","Dafra","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Sagara-2012","Arsucam","Sanofi-Aventis","50 mg AS and 200 mg AQ","-","Per Protocol","AS and AQ Dosing : <10 kg: 1/2 tablet; 10-21 kg: 1 tablet; 21-<40 kg: 2 tablets: 40-<100 kg: 4 tablets","once daily for 3 days",12,30]
["Sanofi-2013*","Coarsucam","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,30]
["Schramm-2013b","ASAQ Winthrop","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","5 to <9 kg: 1 PAED1 tablet; 9 to <18 kg: 1 PAED2 tablet; 18 to 36 kg: 1 adult tablet; ≥ 36 kg: 2 adult tablets","once daily for 3 days",12,30]
["Sinou-2009","TRIMALACT (Fixed)","Saokim Pharmaceuticals Co","100 mg AS and 300 mg AQ","-","Per Protocol","2 tablets/day","once daily for 3 days","N/A","N/A"]
["Sirima-2009","Arsucam","Sanofi-Aventis","-","25 mg of AS/67.5 mg of AQ","Tablets","< 12 months: 1 tablet; 12 to 60 months: 2 tablets","once daily for 3 days",12,30]
["Sirima-2009","Arsumax and Flavoquine","Sanofi-Aventis","-","50 mg AS and 153 mg AQ","Tablets","AQ Dosing: < 1y:  1/2 tablet; 1-<5 y: 1 tablet. AS Dosing: <1 y: 1/2tablet, 1-<5 y: 1 tablet ","once daily for 3 days",12,30]
["Smithuis-2010"," Artesunate Amodiaquine Winthrop","Sanofi Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","<9 kg: 1 PAED1 tablet;  9 to 17.9 kg: 1 PAED2 tablet; 18 to 35.9 kg: 1 adult tablet","once daily for 3 days",12,32.4]
["Staedke-2004","-","Sanofi-Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,25]
["Swarthout-2006","-","Not Stated","50 mg AS and 200 mg AQ","-","Tablets","See Further Dosing Table","once daily for 3 days","N/A","N/A"]
["Temu-2010*"," Artesunate Amodiaquine Winthrop","Sanofi-Aventis","100 mg AS/270 mg AQ","PAED1: 25 mg AS/67.5 mg; PAED2: 50 mg AS/135 mg AQ","Per Protocol","5 to <9 kg: 1 PAED1 tablet; 9 to <18 kg: 1 PAED2 tablet; >=18 kg: 1 adult tablet","once daily for 3 days",12,30]
["Thwing-2009","-","Cosmos Pharmaceuticals Limited and Pfizer ","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,25]
["van den Broek-2006","Arsumax and Camoquin","Sanofi and Parkes Davis/Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,30]
["Yeka-2005","Arsumax and Camoquin","Sanofi-Pfizer","50 mg AS and 200 mg AQ","-","Per Protocol","See Further Dosing Table","once daily for 3 days",12,25]

{"sheet":"Further Dosing Table For AQ","index":3,"n_rows":96,"n_cols":32,"rows_kept":96,"merged":[[3,0,3,1],[3,2,3,4],[3,6,3,7],[3,14,3,16],[3,21,3,23],[15,19,15,20],[15,21,15,23],[17,0,17,1],[17,2,17,4],[22,6,22,7],[22,8,22,10],[29,14,29,16],[32,19,32,20],[32,21,32,23],[35,6,35,7],[35,8,35,10],[59,12,59,13],[59,14,59,16],[61,20,61,22]],"flags":["formulas_cached_only"]}
["Extracted from WWARN Chassis on 16/04/2014"]
[]
["Adjuik-2002 (Scheme derived from Raw Tablet counts)",{"$nulls":5},"Grandesso-2006",{"$nulls":5},"Hasugian-2007",{"$nulls":6},"Thwing-2009"]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":4},"Weight Band",null,"Number of Daily Tablets",{"$nulls":5},"Staedkae-2004"]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets"]
[5,5.99,0.25,0.25,0.25,null,4,4.99,0.25,0.25,0.25,null,6,9.99,0.5,0.5,0.5,null,null,5,7.99,0.25,0.25,0.25,{"$nulls":3},"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[6,9.99,0.5,0.5,0.5,null,5,5.99,0.5,0.25,0.25,null,10,17.99,1,1,1,null,null,8,9.99,0.5,0.25,0.25,{"$nulls":3},5,7.99,0.25,0.25,0.25]
[10,15.99,0.75,0.75,0.75,null,6,7.99,0.5,0.5,0.25,null,18,26.99,1.5,1.5,1.5,null,null,10,11.99,0.5,0.5,0.25,{"$nulls":3},8,9.99,0.5,0.25,0.25]
[16,20.99,1,1,1,null,8,9.99,0.5,0.5,0.5,null,27,35.99,2,2,2,null,null,12,13.99,0.5,0.5,0.5,{"$nulls":3},10,11.99,0.5,0.5,0.25]
[21,30.99,1.5,1.5,1.5,null,10,10.99,0.75,0.5,0.5,null,36,49.99,3,3,3,null,null,14,15.99,0.75,0.5,0.5,{"$nulls":3},12,13.99,0.5,0.5,0.5]
[31,35.99,1.75,1.75,1.75,null,11,12.99,0.75,0.75,0.5,null,">=50",null,4,4,4,null,null,16,17.99,0.75,0.75,0.5,{"$nulls":3},14,15.99,0.75,0.5,0.5]
[36,40.99,2,2,2,null,13,14.99,0.75,0.75,0.75,{"$nulls":8},18,19.99,1,0.75,0.5,{"$nulls":3},16,17.99,0.75,0.75,0.5]
[">=41",null,2.25,2.25,2.25,null,15,15.99,1,0.75,0.75,{"$nulls":16},18,19.99,1,0.75,0.5]
[{"$nulls":6},16,17.99,1,1,0.75,{"$nulls":16},20,21.99,1,1,0.5]
[{"$nulls":6},17,17.99,1,1,0.75,null,"Osorio-2007(Scheme derived from Raw Tablet counts)",{"$nulls":6},"van den Broek-2006",{"$nulls":7},22,23.99,1,1,0.5]
[{"$nulls":6},18,19.99,1,1,1,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":4},"Weight Band",null,"Number of Daily Tablets",{"$nulls":5},24,25.99,1.25,1.25,0.5]
["Bareness-2007",{"$nulls":5},20,20.99,1.25,1,1,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",{"$nulls":3},26,27.99,1.25,1,1]
["Weight Band",null,"Total Daily Dose AQ (mg)",{"$nulls":3},21,22.99,1.25,1.25,1,null,"-","<15",0.75,0.75,0.75,null,null,5,5.99,0.5,0.25,0.25,{"$nulls":3},28,31.99,1.25,1.25,1]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,23,24.99,1.25,1.25,1.25,null,24,24.99,1.25,1.25,1.25,null,null,6,7.99,0.5,0.5,0.25,{"$nulls":3},32,33.99,1.5,1.5,1]
[5,6.99,50,50,50,{"$nulls":7},26,29.99,1.5,1.5,1.5,null,null,8,9.99,0.5,0.5,0.5,{"$nulls":3},34,37.99,1.5,1.5,1.25]
[7,8.99,75,75,75,{"$nulls":7},33,34.99,1.75,1.75,1.75,null,null,10,10.99,0.75,0.5,0.5,{"$nulls":3},38,39.99,2,1.5,1.25]
[9,10.99,100,100,100,null,"Guthmann-2005 & Guthmann-2006",{"$nulls":5},43,45.99,2.25,2.25,2.25,null,null,11,12.99,0.75,0.75,0.5,{"$nulls":3},40,43.99,2,2,1]
[11,13.99,125,125,125,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},46,48.99,2.5,2.5,2.5,null,null,13,14.99,0.75,0.75,0.75,{"$nulls":3},44,47.99,2,2,1.5]
[14,16.99,150,150,150,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,51,54.99,2.75,2.75,2.75,null,null,15,15.99,1,0.75,0.75,{"$nulls":3},48,49.99,2,2,2]
[17,19.99,175,175,175,null,5,5.99,0.5,0.25,0.25,null,">=56",null,3,3,3,null,null,16,17.99,1,1,0.75,{"$nulls":3},50,59.99,2,2,2]
[20,22.99,200,200,200,null,6,7.99,0.5,0.5,0.25,{"$nulls":8},18,19.99,1,1,1]
[23,24.99,225,225,225,null,8,9.99,0.5,0.5,0.5,{"$nulls":8},20,20.99,1.25,1,1]
[25,26.99,250,250,250,null,10,10.99,0.75,0.5,0.5,{"$nulls":8},21,22.99,1.25,1.25,1]
[27,28.99,275,275,275,null,11,12.99,0.75,0.75,0.5,null,"Rwagacondo-2004",{"$nulls":6},23,24.99,1.25,1.25,1.25]
[29,31.99,300,300,300,null,13,14.99,0.75,0.75,0.75,null,"Weight Band",null,"Number of Daily Tablets"]
[32,34.99,325,325,325,null,15,15.99,1,0.75,0.75,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[35,36.99,350,350,350,null,16,17.99,1,1,0.75,null,5.01,6,0.25,0.25,0.25,null,null,"Yeka-2005"]
[37,39.99,375,375,375,{"$nulls":7},6.01,10,0.5,0.5,0.5,null,null,"Weight Band",null,"Number of Daily Tablets"]
[40,41.99,400,400,400,{"$nulls":7},10.1,15,0.75,0.75,0.75,null,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[42,44.99,425,425,425,null,"Grandesso-2003*",{"$nulls":5},15.01,20,1,1,1,null,null,5,7.99,0.25,0.25,0.25]
[45,46.99,450,450,450,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},20.01,25,1.25,1.25,1.25,null,null,8,9.99,0.5,0.25,0.25]
[47,48.99,475,475,475,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,25.01,30,1.5,1.5,1.5,null,null,10,11.99,0.5,0.5,0.25]
[49,51.99,500,500,500,null,5,6.99,0.25,0.25,0.25,null,30.01,35,1.75,1.75,1.75,null,null,12,13.99,0.5,0.5,0.5]
[{"$nulls":6},7,7.99,0.5,0.25,0.25,null,35.01,40,2,2,2,null,null,14,15.99,0.75,0.5,0.5]
[{"$nulls":6},8,8.99,0.5,0.5,0.25,null,40.01,45,2.25,2.25,2.25,null,null,16,17.99,0.75,0.75,0.5]
[{"$nulls":6},9,11.99,0.5,0.5,0.5,null,45.01,50,2.5,2.5,2.5,null,null,18,19.99,1,0.75,0.5]
[{"$nulls":6},12,12.99,0.75,0.5,0.5,null,50.01,55,2.75,2.75,2.75,null,null,20,21.99,1,1,0.5]
["Bonnet-2007",{"$nulls":5},13,14.99,0.75,0.75,0.5,null,55.01,60,3,3,3,null,null,22,23.99,1.25,1,0.5]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":3},15,15.99,0.75,0.75,0.75,null,60.01,65,3.25,3.25,3.25,null,null,24,25.99,1.25,1.25,0.5]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,16,17.99,1,0.75,0.75,null,65.01,70,3.5,3.5,3.5,null,null,26,27.99,1.25,1,1]
[5,5.99,0.5,0.25,0.25,null,18,19.99,1,1,0.75,null,70.01,75,3.75,3.75,3.75,null,null,28,31.99,1.25,1.25,1]
[6,7.99,0.5,0.5,0.25,null,20,21.99,1,1,1,null,75.01,80,4,4,4,null,null,32,33.99,1.5,1.5,1]
[8,9.99,0.5,0.5,0.5,null,22,22.99,1.5,1,1,null,80.01,85,4.25,4.25,4.25,null,null,34,37.99,1.5,1.5,1.25]
[10,10.99,0.75,0.5,0.5,null,23,23.99,1.5,1.5,1,null,85.01,90,4.5,4.5,4.5,null,null,38,38.99,2,1.5,1.25]
[11,12.99,0.75,0.75,0.5,null,24,24.99,1.5,1.5,1,null,90.01,95,4.75,4.75,4.75,null,null,39,39.99,2,1.5,1.25]
[13,14.99,0.75,0.75,0.75,null,25,25.99,1.5,1.5,1.25,null,95.01,100,5,5,5,null,null,40,43.99,2,2,1]
[15,15.99,1,0.75,0.75,{"$nulls":7},100.01,105,5.25,5.25,5.25,null,null,44,47.99,2,2,1.5]
[16,17.99,1,1,0.75,null,"Hamour-2005",{"$nulls":5},105.01,110,5.5,5.5,5.5,null,null,48,49.99,2,2,2]
[18,19.99,1,1,1,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},110.01,115,5.75,5.75,5.75,null,null,50,59.99,2.5,2,2]
[20,20.99,1.25,1,1,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,115.01,120,6,6,6,null,null,60,100.99,3,3,1.5]
[21,21.99,1.25,1.25,1,null,5,5.99,0.25,0.25,0.25]
[23,24.99,1.25,1.25,1,null,6,6.99,0.5,0.25,0.25]
[{"$nulls":6},7,7.99,0.5,0.5,0.25]
[{"$nulls":6},8,8.99,0.5,0.5,0.25,null,"Swarthout-2006 (Scheme derived from Raw Tablet counts)"]
[{"$nulls":6},9,10.99,0.5,0.5,0.5,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":4},"Juma-2005"]
["Bukirwa-2006",{"$nulls":5},11,11.99,0.75,0.5,0.5,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":3},12,13.99,0.75,0.75,0.5,null,5,5.99,0.5,0.25,0.25,null,null,"Weight of Subject (kg)","Number of daily tablets (200mg base) "]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,14,15.99,0.75,0.75,0.75,null,6,7.99,0.5,0.5,0.25]
[10,11.99,0.5,0.5,0.25,null,16,16.99,1,1,0.5,null,8,9.99,0.5,0.5,0.5,{"$nulls":3},"Day 0","Day 1","Day 2"]
[12,13.99,0.5,0.5,0.5,null,17,18.99,1,1,0.75,null,10,10.99,0.75,0.5,0.5]
[14,15.99,0.75,0.5,0.5,null,19,20.99,1,1,1,null,11,12.99,0.75,0.75,0.5,null,null,5,"¼","¼","¼"]
[16,17.99,0.75,0.75,0.5,null,21,21.99,1.25,1,1,null,13,14.99,0.75,0.75,0.75,null,null,6,"¼","¼","¼"]
[18,19.99,1,0.75,0.5,null,22,23.99,1.25,1.25,1,null,15,15.99,1,0.75,0.75,null,null,7,"¼","¼","¼"]
[20,21.99,1,1,0.5,null,24,25.99,1.25,1.25,1.25,{"$nulls":8},8,"½","½","¼"]
[22,23.99,1.25,1,0.5,{"$nulls":14},9,"½","½","¼"]
[24,25.99,1.25,1.25,0.5,{"$nulls":14},10,"½","½","¼"]
[26,27.99,1,1,1,{"$nulls":14},11,"½","½","¼"]
[28,31.99,1.25,1.25,1,{"$nulls":14},12,"½","½","¼"]
[{"$nulls":19},13,"¾","¾","¼"]
[{"$nulls":19},14,"¾","¾","¼"]
["Dorsey-2007",{"$nulls":18},15,"¾","¾","½"]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":16},16,"¾","¾","½"]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",{"$nulls":14},17,"¾","¾","½"]
[10,11.99,0.5,0.5,0.25,{"$nulls":14},18,1,1,"½"]
[12,13.99,0.5,0.5,0.5,{"$nulls":14},19,1,1,"½"]
[14,15.99,0.75,0.5,0.5,{"$nulls":14},20,1,1,"½"]
[16,17.99,0.75,0.75,0.5,{"$nulls":14},21,1,1,"½"]
[18,19.99,1,0.75,0.5,{"$nulls":14},22,1,1,"½"]
[20,21.99,1,1,0.5,{"$nulls":14},23,"1¼","1¼","½"]
[22,23.99,1.25,1,0.5,{"$nulls":14},24,"1¼","1¼","½"]
[24,25.99,1.25,1.25,0.5,{"$nulls":14},25,"1¼","1¼","¾"]
[26,27.99,1.25,1,1,{"$nulls":14},"26-27","1¼","1¼","¾"]
[28,31.99,1.25,1.25,1,{"$nulls":14},28,"1½","1½","¾"]
[32,33.99,1.5,1.5,1,{"$nulls":14},"29-31","1½","1½","¾"]
[34,37.99,1.5,1.5,1.25,{"$nulls":14},32,"1½","1½","¾"]
[38,39.99,2,1.5,1.25,{"$nulls":14},33,"1¾","1¾",1]
[40,43.99,2,2,1,{"$nulls":14},"34-35","1¾","1¾",1]
[44,47.99,2,2,1.5,{"$nulls":14},"36-37","1¾","1¾",1]
[48,49.99,2,2,2]
[50,59.99,2.5,2,2]
[60,100,3,3,1.5]

{"sheet":"Further Dosing Table For AS","index":4,"n_rows":73,"n_cols":36,"rows_kept":73,"merged":[[4,0,4,1],[4,2,4,4],[4,6,4,7],[4,8,4,10],[4,12,4,13],[4,14,4,16],[4,18,4,19],[4,20,4,22],[4,24,4,25],[4,26,4,28],[14,18,14,19],[14,20,14,22],[16,0,16,1],[16,2,16,4],[26,25,26,27],[29,6,29,7],[29,8,29,10],[29,12,29,13],[29,14,29,16],[38,18,38,19],[38,20,38,22],[45,6,45,7],[45,8,45,10],[45,12,45,13],[45,14,45,16],[63,0,63,1],[63,2,63,4]],"flags":["formulas_cached_only"]}
["Extracted from WWARN Chassis on 16/04/2014"]
[]
[]
["Adjuik-2002 (Scheme derived from Raw Tablet counts)",{"$nulls":5},"Grandesso-2006",{"$nulls":5},"Hamour-2005",{"$nulls":5},"Thwing-2009",{"$nulls":5},"Yeka-2005",{"$nulls":6},"Stadekae-2004"]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":4},"Weight Band",null,"Number of Daily Tablets"]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[5,7.99,0.5,0.5,0.5,null,4,4.99,0.5,0.5,0.25,null,5,5.99,0.5,0.5,0.25,null,5,7.99,0.5,0.5,0.5,null,5,7.99,0.5,0.5,0.5,null,null,5,7.99,0.5,0.5,0.5]
[8,16.99,1,1,1,null,5,5.99,0.5,0.5,0.5,null,6,6.99,0.5,0.5,0.5,null,8,10.99,0.75,0.75,0.75,null,8,10.99,0.75,0.75,0.75,null,null,8,10.99,0.75,0.75,0.75]
[17,20.99,1.5,1.5,1.5,null,6,6.99,0.75,0.5,0.5,null,7,7.99,0.75,0.5,0.5,null,11,13.999,1,1,1,null,11,13.99,1,1,1,null,null,11,13.99,1,1,1]
[21,29.99,2,2,2,null,7,7.99,0.75,0.75,0.5,null,8,8.99,0.75,0.75,0.5,null,14,16.99,1.25,1.25,1.25,null,14,16.99,1.25,1.25,1.25,null,null,14,16.99,1.25,1.25,1.25]
[30,33.99,2.5,2.5,2.5,null,8,8.99,0.75,0.75,0.75,null,9,9.99,0.75,0.75,0.75,null,17,19.99,1.5,1.5,1.5,null,17,19.99,1.5,1.5,1.5,null,null,17,19.99,1.5,1.5,1.5]
[">=34",null,3,3,3,null,9,9.99,1,0.75,0.75,null,10,10.99,1,0.75,0.75,null,20,22.99,1.75,1.75,1.75,null,20,22.99,1.75,1.75,1.75,null,null,20,22.99,1.75,1.75,1.75]
[{"$nulls":6},10,10.99,1,1,0.75,null,11,11.99,1,1,0.75,{"$nulls":7},23,25.99,2,2,2,null,null,23,25.99,2,2,2]
[{"$nulls":6},11,11.99,1,1,1,null,12,12.99,1,1,1,null,"van den Broek-2006",{"$nulls":5},26,28.99,2.25,2.25,2.25,null,null,26,28.99,2.25,2.25,2.25]
[{"$nulls":6},12,12.99,1.25,1,1,null,13,13.99,1.25,1,1,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},29,32.99,2.5,2.5,2.5,null,null,29,32.99,2.5,2.5,2.5]
["Bareness-2007",{"$nulls":5},13,13.99,1.25,1.25,1,null,14,14.99,1.25,1.25,1,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,33,35.99,2.75,2.75,2.75,null,null,33,35.99,2.75,2.75,2.75]
["Weight Band",null,"Total Daily Dose AS (mg)",{"$nulls":3},14,14.99,1.25,1.25,1.25,null,15,15.99,1.25,1.25,1.25,null,5,5.99,0.5,0.5,0.5,null,36,38.99,3,3,3,null,null,36,38.99,3,3,3]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,15,15.99,1.5,1.25,1.25,null,16,16.99,1.5,1.25,1.25,null,6,6.99,0.75,0.5,0.5,null,39,43.99,3.25,3.25,3.25,null,null,39,43.99,3.25,3.25,3.25]
[5,7.99,25,12.5,12.5,null,16,16.99,1.5,1.5,1.25,null,17,17.99,1.5,1.5,1.25,null,7,7.99,0.75,0.75,0.5,null,44,47.99,3.5,3.5,3.5,null,null,44,47.99,3.5,3.5,3.5]
[8,11.99,37.5,18.75,18.75,null,17,17.99,1.5,1.5,1.5,null,18,18.99,1.5,1.5,1.5,null,8,8.99,0.75,0.75,0.75,null,48,49.99,3.75,3.75,3.75,null,null,48,49.99,3.75,3.75,3.75]
[12,14.99,50,25,25,null,18,18.99,1.75,1.5,1.5,null,19,19.99,1.75,1.5,1.5,null,9,9.99,1,0.75,0.75,null,50,59.99,4,4,4,null,null,50,59.99,4,4,4]
[15,17.99,62.5,31.25,31.25,null,19,19.99,1.75,1.75,1.5,null,20,20.99,1.75,1.75,1.5,null,10,10.99,1,1,0.75,null,60,100.99,5,5,5]
[18,20.99,75,37.5,37.5,null,20,20.99,1.75,1.75,1.75,null,21,21.99,1.75,1.75,1.75,null,11,11.99,1,1,1]
[21,23.99,87.5,43.75,43.75,null,21,21.99,2,1.75,1.75,null,22,22.99,2,1.75,1.75,null,12,12.99,1.25,1,1]
[24,26.99,100,50,50,null,22,22.99,2,2,1.75,null,23,23.99,2,2,1.75,null,13,13.99,1.25,1.25,1,null,"Juma-2005"]
[27,29.99,112.5,56.25,56.25,null,23,23.99,2,2,2,null,24,25.99,2,2,2,null,14,14.99,1.25,1.25,1.25]
[30,32.99,125,62.5,62.5,null,24,24.99,2,2,2,{"$nulls":7},15,15.99,1.5,1.25,1.25,null,"Weight of Subject (kg)","Number of daily tablets (50 mg)",{"$nulls":5},"Dorsey-2007"]
[33,35.99,137.5,68.75,68.75,{"$nulls":13},17,17.99,1.5,1.5,1.5,null,null,"Day 0","Day 1","Day 2",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets"]
[36,39.99,150,75,75,null,"Guthmann-2005 & Guthmann-2006",{"$nulls":5},"Hasugian-2007",{"$nulls":5},18,18.99,1.75,1.5,1.5,{"$nulls":8},"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[40,42.99,162.5,81.25,81.25,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},19,19.99,1.75,1.75,1.5,null,5,"½","½","½",{"$nulls":3},10,10.99,0.75,0.75,0.75]
[43,45.99,175,87.5,87.5,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,20,20.99,1.75,1.75,1.75,null,6,"½","½","½",{"$nulls":3},11,13.99,1,1,1]
[46,48.99,187.5,93.75,93.75,null,5,5.99,0.5,0.5,0.5,null,6,8.99,0.5,0.5,0.5,null,21,21.99,2,1.75,1.75,null,7,"½","½","½",{"$nulls":3},14,16.99,1.25,1.25,1.25]
[49,51.99,200,100,100,null,6,6.99,0.75,0.5,0.5,null,9,15.99,1,1,1,null,22,22.99,2,2,1.75,null,8,"¾","¾","¾",{"$nulls":3},17,19.99,1.5,1.5,1.5]
[{"$nulls":6},7,7.99,0.75,0.75,0.5,null,16,22.99,1.5,1.5,1.5,null,23,23.99,2,2,2,null,9,"¾","¾","¾",{"$nulls":3},20,22.99,1.75,1.75,1.75]
[{"$nulls":6},8,8.99,0.75,0.75,0.75,null,23,28.99,2,2,2,null,24,24.99,2.25,2,2,null,10,"¾","¾","¾",{"$nulls":3},23,25.99,2,2,2]
[{"$nulls":6},9,9.99,1,0.75,0.75,null,32,34.99,2.5,2.5,2.5,{"$nulls":7},11,1,1,1,{"$nulls":3},26,28.99,2.25,2.25,2.25]
["Bonnet-2007",{"$nulls":5},10,10.99,1,1,0.75,null,36,40.99,3,3,3,{"$nulls":7},12,1,1,1,{"$nulls":3},29,32.99,2.5,2.5,2.5]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":3},11,11.99,1,1,1,null,42,48.99,3.5,3.5,3.5,null,"Grandesso-2003*",{"$nulls":5},13,1,1,1,{"$nulls":3},33,35.99,2.75,2.75,2.75]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,12,12.99,1.25,1,1,null,49,53.99,4,4,4,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},14,"1¼","1¼","1¼",{"$nulls":3},36,38.99,3,3,3]
[5,5.99,0.5,0.5,0.5,null,13,13.99,1.25,1.25,1,null,54,59.99,4.5,4.5,4.5,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,15,"1¼","1¼","1¼",{"$nulls":3},39,43.99,3.25,3.25,3.25]
[6,6.99,0.75,0.5,0.5,null,14,14.99,1.25,1.25,1.25,null,60,66.99,5,5,5,null,5,5.99,0.5,0.5,0.25,null,16,"1¼","1¼","1¼",{"$nulls":3},44,47.99,3.5,3.5,3.5]
[7,7.99,0.75,0.75,0.5,null,15,15.99,1.5,1.25,1.25,null,68,72.99,5.5,5.5,5.5,null,6,6.99,0.5,0.5,0.5,null,17,"1½","1½","1½",{"$nulls":3},48,49.99,3.75,3.75,3.75]
[8,8.99,0.75,0.75,0.75,null,16,16.99,1.5,1.5,1.25,{"$nulls":7},7,7.99,0.75,0.5,0.5,null,18,"1½","1½","1½",{"$nulls":3},50,59.99,4,4,4]
[9,9.99,1,0.75,0.75,{"$nulls":13},8,8.99,0.75,0.75,0.5,null,19,"1½","1½","1½",{"$nulls":3},60,100,5,5,5]
[10,10.99,1,1,0.75,null,"Osorio-2007(Scheme derived from Raw Tablet counts)",{"$nulls":5},"Rwagacondo-2004",{"$nulls":5},9,9.99,0.5,0.5,0.75,null,20,"1¾","1¾","1¾"]
[11,11.99,1,1,1,null,"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},"Weight Band",null,"Number of Daily Tablets",{"$nulls":3},10,10.99,1,0.75,0.75,null,21,"1¾","1¾","1¾"]
[12,12.99,1.25,1,1,null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,"Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2",null,11,11.99,1,1,0.75,null,22,"1¾","1¾","1¾"]
[13,13.99,1.25,1.25,1,null,"-","<15",1,1,1,null,5,8.33,0.5,0.5,0.5,null,12,13.99,1,1,1,null,23,2,2,2]
[14,14.99,1.25,1.25,1.25,null,24,29.99,2,2,2,null,8.34,16.67,1,1,1,null,14,14.99,1.25,1,1,null,24,2,2,2]
[16,16.99,1.5,1.5,1.25,null,33,33.99,2.5,2.5,2.5,null,16.68,20.82,1.5,1.5,1.5,null,15,15.99,1.25,1.25,1,null,25,2,2,2]
[17,17.99,1.5,1.5,1.5,null,34,34.99,3,3,3,null,20.83,29.17,2,2,2,null,16,16.99,1.25,1.25,1.25,null,"26-27","2¼","2¼","2¼"]
[18,18.99,1.75,1.5,1.5,null,43,46.99,3.5,3.5,3.5,null,29.18,33.32,2.5,2.5,2.5,null,17,17.99,1.5,1.25,1.25,null,28,"2¼","2¼","2¼"]
[19,19.99,1.75,1.75,1.5,null,47,54.99,4,4,4,null,33.33,41.67,3,3,3,null,18,18.99,1.5,1.5,1.25,null,"29-31","2½","2½","2½"]
[20,20.99,1.75,1.75,1.75,null,56,57.99,4.5,4.5,4.5,null,41.68,45.82,3.5,3.5,3.5,null,19,19.99,1.5,1.5,1.5,null,32,"2½","2½","2½"]
[21,21.99,2,1.75,1.75,null,59,65.99,5,5,5,null,45.83,54.17,4,4,4,null,20,20.99,1.75,1.5,1.5,null,33,"2¾","2¾","2¾"]
[22,22.99,2,2,1.75,null,68,70.99,5.5,5.5,5.5,null,54.18,58.32,4.5,4.5,4.5,null,21,21.99,1.75,1.75,1.5,null,"34-35","2¾","2¾","2¾"]
[23,23.99,2,2,2,null,77,80.99,6,6,6,null,58.33,66.67,5,5,5,null,22,22.99,1.75,1.75,1.75,null,"36-37",3,3,3]
[24,24.99,2.25,2,2,{"$nulls":7},66.68,70.82,5.5,5.5,5.5,null,23,23.99,2,1.75,1.75]
[{"$nulls":12},70.83,79.17,6,6,6,null,24,24.99,2,2,1.75]
[{"$nulls":12},79.18,83.32,6.5,6.5,6.5,null,35,25.99,2,2,2]
[{"$nulls":12},83.33,91.67,7,7,7]
[{"$nulls":12},91.68,95.82,7.5,7.5,7.5]
["Bukirwa-2006",{"$nulls":11},95.83,104.17,8,8,8]
["Weight Band",null,"Number of Daily Tablets",{"$nulls":9},104.18,108.32,8.5,8.5,8.5]
["Min Weight (kg)","Max Weight(kg)","Day0","Day1","Day2"]
[10,10.99,0.75,0.75,0.75]
[11,13.99,1,1,1]
[14,16.99,1.25,1.25,1.25]
[17,19.99,1.5,1.5,1.5]
[20,22.99,1.75,1.75,1.75]
[23,25.99,2,2,2]
[26,28.99,2.25,2.25,2.25]
[29,32.99,2.5,2.5,2.5]