Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

Catherine Maiteki-Sebuguzi, Prasanna Jagannathan, Vincent M Yau, Tamara D Clark, Denise Njama-Meya, Bridget Nzarubara, Ambrose O Talisuna, Moses R Kamya, Philip J Rosenthal, Grant Dorsey, Sarah G Staedke, Catherine Maiteki-Sebuguzi, Prasanna Jagannathan, Vincent M Yau, Tamara D Clark, Denise Njama-Meya, Bridget Nzarubara, Ambrose O Talisuna, Moses R Kamya, Philip J Rosenthal, Grant Dorsey, Sarah G Staedke

Abstract

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.

Figures

Figure 1
Figure 1
Trial Profile.

References

    1. Attaran A, Barnes KI, Curtis C, d'Alessandro U, Fanello CI, Galinski MR, Kokwaro G, Looareesuwan S, Makanga M, Mutabingwa TK, Talisuna A, Trape JF, Watkins WM. WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet. 2004;363:237–240. doi: 10.1016/S0140-6736(03)15330-5.
    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. 2006.
    1. Faye B, Ndiaye JL, Ndiaye D, Dieng Y, Faye O, Gaye O. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal. Malar J. 2007;6:80. doi: 10.1186/1475-2875-6-80.
    1. Zongo I, Dorsey G, Rouamba N, Dokomajilar C, Lankoande M, Ouedraogo JB, Rosenthal PJ. Amodiaquine, sulfadoxine-pyrimethamine, and combination therapy for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso. Am J Trop Med Hyg. 2005;73:826–832.
    1. Zongo I, Dorsey G, Rouamba N, Tinto H, Dokomajilar C, Guiguemde RT, Rosenthal PJ, Ouedraogo JB. Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial. Lancet. 2007;369:491–498. doi: 10.1016/S0140-6736(07)60236-0.
    1. Simooya O. The WHO 'Roll Back Malaria Project': planning for adverse event monitoring in Africa. Drug Saf. 2005;28:277–286. doi: 10.2165/00002018-200528040-00001.
    1. Phillips-Howard PA, West LJ. Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. Journal of the Royal Society of Medicine. 1990;83:82–85.
    1. Gimnig JE, MacArthur JR, M'Bang'ombe M, Kramer MH, Chizani N, Stern RS, Mkandala C, Newman RD, Steketee RW, Campbell CH. Severe cutaneous reactions to sulfadoxine-pyrimethamine and trimethoprim-sulfamethoxazole in Blantyre District, Malawi. Am J Trop Med Hyg. 2006;74:738–743.
    1. Markham LN, Giostra E, Hadengue A, Rossier M, Rebsamen M, Desmeules J. Emergency liver transplantation in amodiaquine-induced fulminant hepatitis. Am J Trop Med Hyg. 2007;77:14–15.
    1. Sturchler D, Mittelholzer ML, Kerr L. How frequent are notified severe cutaneous adverse reactions to Fansidar? Drug Safety. 1993;8:160–168.
    1. Olliaro P, Mussano P. Amodiaquine for treating malaria. Cochrane Database Syst Rev. 2003:CD000016.
    1. Toovey S, Jamieson A. Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg. 2004;98:261–7; discussion 268-9. doi: 10.1016/j.trstmh.2003.11.001.
    1. Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara VI, Ashley E, Singhasivanon P, White NJ, Nosten F. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg. 2006;74:211–214.
    1. World Health Organization . Assessment of the safety of artemisinin compounds in pregnancy. Geneva ; 2003.
    1. van Vugt M, Ezzet F, Nosten F, Gathmann I, Wilairatana P, Looareesuwan S, White NJ. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. Am J Trop Med Hyg. 1999;61:964–967.
    1. Makanga M, Premji Z, Falade C, Karbwang J, Mueller EA, Andriano K, Hunt P, De Palacios PI. Efficacy and safety of the six-dose regimen of artemether-lumefantrine in pediatrics with uncomplicated Plasmodium falciparum malaria: a pooled analysis of individual patient data. Am J Trop Med Hyg. 2006;74:991–998.
    1. Omari AA, Gamble C, Garner P. Artemether-lumefantrine (six-dose regimen) for treating uncomplicated falciparum malaria. Cochrane Database Syst Rev. 2005:CD005564.
    1. Fanello CI, Karema C, van Doren W, Rwagacondo CE, D'Alessandro U. Tolerability of amodiaquine and sulphadoxine-pyrimethamine, alone or in combination for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan adults. Trop Med Int Health. 2006;11:589–596. doi: 10.1111/j.1365-3156.2006.01610.x.
    1. Karema C, Fanello CI, Van Overmeir C, Van Geertruyden JP, van Doren W, Ngamije D, D'Alessandro U. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin®) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–1111. doi: 10.1016/j.trstmh.2006.01.001.
    1. Bukirwa H, Yeka A, Kamya MR, Talisuna A, Banek K, Bakyaita N, Rwakimari JB, Rosenthal PJ, Wabwire-Mangen F, Dorsey G, Staedke SG. Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PLoS Clin Trials. 2006;1:e7. doi: 10.1371/journal.pctr.0010007.
    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. Olliaro P, Nevill C, LeBras J, Ringwald P, Mussano P, Garner P, Brausseur P. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet. 1996;348:1196–1201. doi: 10.1016/S0140-6736(96)06217-4.
    1. Talisuna AO, Staedke SG, D'Alessandro U. Pharmacovigilance of antimalarial treatment in Africa: is it possible? Malar J. 2006;5:50. doi: 10.1186/1475-2875-5-50.
    1. Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Dokomajilar C, Kamya MR, Rosenthal PJ. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. Jama. 2007;297:2210–2219. doi: 10.1001/jama.297.20.2210.
    1. Davis JC, Clark TD, Kemble SK, Talemwa N, Njama-Meya D, Staedke SG, Dorsey G. Longitudinal study of urban malaria in a cohort of Ugandan children: description of study site, census and recruitment. Malar J. 2006;5:18. doi: 10.1186/1475-2875-5-18.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidance for Industry: Good Clinical Practice: Consolidated Guidance (ICH-E6) Rockville, MD , U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER); 1996.
    1. Fanello CI, Karema C, van Doren W, Van Overmeir C, Ngamije D, D'Alessandro U. A randomised trial to assess the safety and efficacy of artemether-lumefantrine (Coartem) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwanda. Trans R Soc Trop Med Hyg. 2007;101:344–350. doi: 10.1016/j.trstmh.2006.06.010.
    1. Bindschedler M, Lefevre G, Degen P, Sioufi A. Comparison of the cardiac effects of the antimalarials co-artemether and halofantrine in healthy participants. Am J Trop Med Hyg. 2002;66:293–298.
    1. Novartis . Coartem monograph. Basel, Switzerland ; 2003.
    1. Bakshi R, Hermeling-Fritz I, Gathmann I, Alteri E. An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug. Trans R Soc Trop Med Hyg. 2000;94:419–424. doi: 10.1016/S0035-9203(00)90126-3.
    1. Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, Ruel T, Charlebois E, Staedke SG, Kekitiinwa A, Rosenthal PJ, Havlir D, Dorsey G. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis. 2008;46:985–991. doi: 10.1086/529192.
    1. Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, Greenwood BM, Whitty CJ. 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. 2005;365:1474–1480. doi: 10.1016/S0140-6736(05)66417-3.
    1. Morrow RH. Antimalarial drug combinations in vastly different settings. Lancet. 2007;369:444–445. doi: 10.1016/S0140-6736(07)60209-8.

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