Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial

Issaka Sagara, Stephen Rulisa, Wilfred Mbacham, Ishag Adam, Kourane Sissoko, Hamma Maiga, Oumar B Traore, Niawanlou Dara, Yahia T Dicko, Alassane Dicko, Abdoulaye Djimdé, F Herwig Jansen, Ogobara K Doumbo, Issaka Sagara, Stephen Rulisa, Wilfred Mbacham, Ishag Adam, Kourane Sissoko, Hamma Maiga, Oumar B Traore, Niawanlou Dara, Yahia T Dicko, Alassane Dicko, Abdoulaye Djimdé, F Herwig Jansen, Ogobara K Doumbo

Abstract

Background: The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance.

Methods: Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP) three-day (once daily for 3 days) regimen (N = 476) or AS-SMP 24-hour (0 h, 12 h, 24 h) regimen (N = 458) or artemether-lumefantrine (AL), the regular 6 doses regimen (N = 450). The primary objective was to demonstrate non-inferiority (using a margin of -6%) of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate.

Results: The PCR corrected 28-day cure rate on the intention to treat (ITT) analysis population were: 96.0%(457/476) in the AS-SMP three-day group, 93.7%(429/458) in the AS-SMP 24-hour group and 92.0%(414/450) in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437) in the AS-SMP three-day group, 99.5%(416/419) in the AS-SMP 24-hour group and 99.7(391/394)% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea) which were slightly higher in the AS-SMP 24-hour group.

Conclusion: AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated.

Trial registration: NCT00484900 http://www.clinicaltrials.gov.

Figures

Figure 1
Figure 1
The trial profile.
Figure 2
Figure 2
Proportion of participants with parasite during the first 3 days after treatment.

References

    1. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2:209–218. doi: 10.1016/S1473-3099(02)00239-6.
    1. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature. 2005;434:214–217. doi: 10.1038/nature03342.
    1. Greenwood BM, Bojang K, Whitty CJ, Targett GA. Malaria. Lancet. 2005;365:1487–1498. doi: 10.1016/S0140-6736(05)66420-3.
    1. World Health Organization Guidelines for the treatment of malaria Geneva.
    1. Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, Cisse M, Cobelens F, Diallo S, Faucher JF, Garner P, Gikunda S, Kremsner PG, Krishna S, Lell B, Loolpapit M, Matsiegui PB, Missinou MA, Mwanza J, Ntoumi F, Olliaro P, Osimbo P, Rezbach P, Some E, Taylor WR. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial. Lancet. 2002;20:1365–1372. doi: 10.1016/S0140-6736(02)08348-4.
    1. Omari AA, Gamble C, Garner P. Artemether-lumefantrine for uncomplicated malaria: a systematic review. Trop Med Int Health. 2004;9:192–199. doi: 10.1046/j.1365-3156.2003.01186.x.
    1. Falade C, Makanga M, Premji Z, Ortmann CE, Stockmeyer M, de Palacios PI. Efficacy and safety of artemether-lumefantrine (Coartem®) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg. 2005;99:459–467. doi: 10.1016/j.trstmh.2004.09.013.
    1. Jansen FH, Lesaffre E, Penali LK, Zattera MJ, Die-Kakou H, Bissagnene E. Assessment of the relative advantage of various artesunate-based combination therapies by a multi-treatment bayesian random-effects meta-analysis. Am J Trop Med Hyg. 2007;77:1005–1009.
    1. Mendis K. WHO guidelines for the treatment of malaria: Implication for the next generation of antimalarial medicines. Press release Global Malaria Programme, Washington. 2005.
    1. Sagara I, Dicko A, Djimde A, Guindo O, Kone M, Tolo Y, Thera MA, Sogoba M, Fofana M, Ouattara A, Sissoko M, Jansen HF, Doumbo OK. A randomized trial of artesunate-sulfamethoxypyrazine-pyrimethamine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali. Am J Trop Med Hyg. 2006;75:630–636.
    1. Rulisa S, Gatarayiha JP, Kabarisa T, Ndayisaba G. Comparison of different artemisinin-based combinations for the treatment of Plasmodium falciparum malaria in children in Kigali, Rwanda, an area of resistance to sulfadoxine-pyrimethamine: artesunate plus sulfadoxine/pyrimethamine versus artesunate plus sulfamethoxypyrazine/pyrimethamine. Am J Trop Med Hyg. 2007;77:612–616.
    1. Penali LK, Jansen FH. Single day, three dose treatment with fixed dose combination artesunate/sulfamethoxypyrazine/pyrimethamine to cure P. falciparum malaria. Int J Infect Dis. 2008;12:430–437. doi: 10.1016/j.ijid.2007.12.006.
    1. Adam I, Magzoub M, Osman ME, Khalil IF, Alifrangis M, Elmardi KA. A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. Ann Clin Microbiol Antimicrob. 2006;5:18. doi: 10.1186/1476-0711-5-18.
    1. Basco LK, Same-Ekobo A, Ngane VF, Ndounga M, Metoh T, Ringwald P, Soula G. Therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine and the sulfadoxine-pyrimethamine-amodiaquine combination against uncomplicated Plasmodium falciparum malaria in young children in Cameroon. Bull World Health Organ. 2002;80:538–545.
    1. Tahar R, Basco LK. Molecular epidemiology of malaria in Cameroon. XXVII: Clinical and parasitological response to sulfadoxine-pyrimethamine treatment and Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase alleles in Cameroonian children. Acta Trop. 2007;103:81–89. doi: 10.1016/j.actatropica.2007.04.008.
    1. Djimdé AA, Dolo A, Ouattara A, Diakité S, Plowe CV, Doumbo OK. Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones. J Infect Dis. 2004;190:853–855. doi: 10.1086/422758.
    1. Djimdé AA, Doumbo OK, Traore O, Guindo AB, Kayentao K, Diourte Y, Niare-Doumbo S, Coulibaly D, Kone AK, Cissoko Y, Tekete M, Fofana B, Dicko A, Diallo DA, Wellems TE, Kwiatkowski D, Plowe CV. Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria. Am J Trop Med Hyg. 2003;69:558–563.
    1. East African Network for Monitoring Antimalarial Treatment (EANMAT) The efficacy of antimalarial monotherapies, sulphadoxine-pyrimethamine and amodiaquine in East Africa: implications for sub-regional policy. Trop Med Int Health. 2003;8:860–867. doi: 10.1046/j.1360-2276.2003.01114.x.
    1. Elamin SB, Malik el-FM, Ahmed el-DS, Elabadil EK, Mohamad TA. Efficacy of chloroquine and sulfadoxine/pyrimethamine mono- and combined therapy against falciparum malaria in Sudan. East Mediterr Health J. 2007;13:25–34.
    1. Elbasit IE, Elbashir MI, Khalil IF, Alifrangis M, Giha HA. The efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine for malaria treatment in rural Eastern Sudan: the interrelation between resistance, age and gametocytogenesis. Trop Med Int Health. 2006;11:604–612. doi: 10.1111/j.1365-3156.2006.01616.x.
    1. World Health Organization Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94:S1–90. doi: 10.1016/S0035-9203(00)90300-6.
    1. World Health Organization Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria Geneva. pp. 1–68.
    1. Sagara I, Diallo A, Kone M, Coulibaly M, Diawara SI, Guindo O, Maiga H, Niambele MB, Sissoko M, Dicko A, Djimde A, Doumbo OK. A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Am J Trop Med Hyg. 2008;79:655–661.
    1. Gallup JL, Sachs JD. The economic burden of malaria. Am J Trop Med Hyg. 2001;64:85–96.
    1. Mukhtar EA, Gadalla NB, El-Zaki SE, Mukhtar I, Mansour FA, Babiker A, El-Sayed BB. A comparative study on the efficacy of artesunate plus sulphadoxine/pyrimethamine versus artemether-lumefantrine in eastern Sudan. Malar J. 2007;6:92. doi: 10.1186/1475-2875-6-92.
    1. Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, Talisuna AO, Greenhouse B, Nosten F, Rosenthal PJ, Wabwire-Mangen F, Dorsey G. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials. 2007;2:e20. doi: 10.1371/journal.pctr.0020020.
    1. Haynes RK, Chan HW, Lung CM, Ng NC, Wong HN, Shek LY, Williams ID, Cartwright A, Gomes MF. Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. Chem Med Chem. 2007;2:1448–1463.
    1. Jansen FH, Soomro SA. Chemical instability determines the biological action of the artemisinins. Curr Med Chem. 2007;14:3243–3259. doi: 10.2174/092986707782793844.
    1. Kremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004;364:285–94. doi: 10.1016/S0140-6736(04)16680-4.
    1. Priotto G, Kabakyenga J, Pinoges L, Ruiz A, Eriksson T, Coussement F, Ngambe T, Taylor WR, Perea W, Guthmann JP, Olliaro P, Legros D. Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial. Trans R Soc Trop Med Hyg. 2003;97:325–330. doi: 10.1016/S0035-9203(03)90161-1.
    1. Nahum A, Erhart A, Gazard D, Agbowai C, Van Overmeir C, van Loen H, Menten J, Akogbeto M, Coosemans M, Massougbodji A, D'Alessandro U. Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa. Malar J. 2007;6:170. doi: 10.1186/1475-2875-6-170.
    1. Mockenhaupt FP, Ehrhardt S, Dzisi SY, Teun Bousema J, Wassilew N, Schreiber J, Anemana SD, Cramer JP, Otchwemah RN, Sauerwein RW, Eggelte TA, Bienzle U. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health. 2005;10:512–520. doi: 10.1111/j.1365-3156.2005.01427.x.
    1. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet. 1992;339:821–824. doi: 10.1016/0140-6736(92)90276-9.

Source: PubMed

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