Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children

Badara Cisse, Matthew Cairns, Ernest Faye, Ousmane NDiaye, Babacar Faye, Cecile Cames, Yue Cheng, Maguette NDiaye, Aminata Collé Lô, Kirsten Simondon, Jean-Francois Trape, Oumar Faye, Jean Louis NDiaye, Oumar Gaye, Brian Greenwood, Paul Milligan, Badara Cisse, Matthew Cairns, Ernest Faye, Ousmane NDiaye, Babacar Faye, Cecile Cames, Yue Cheng, Maguette NDiaye, Aminata Collé Lô, Kirsten Simondon, Jean-Francois Trape, Oumar Faye, Jean Louis NDiaye, Oumar Gaye, Brian Greenwood, Paul Milligan

Abstract

Background: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal.

Methods: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events.

Results: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season.

Conclusions: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites.

Trial registration: ClinicalTrials.gov NCT00529620.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Trial Profile.
Figure 1. Trial Profile.
Figure 2. Malaria incidence during the study…
Figure 2. Malaria incidence during the study period.
Incidence of first episode malaria associated with parasitaemia at any parasite density in the study area between September-December 2007. Single red lines indicate median date of the IPT rounds in September, October and November. Double red line indicates the median date of the December morbidity survey. One child had a second malaria episode in mid-November and 13 children had a second malaria episode detected at the survey in December (not shown).

References

    1. Greenwood B, Bojang K, Chandramohan D, Cisse B, Kweku M, et al. Reply: Intermittent preventive anti-malarial treatment to children (IPTc): firebreak or fire trap? Trends in Parasitology. 2008;24(11):485–6. doi: .
    1. Cisse B, Faye S, Dial Y, Faye O, Gaye O, et al. Pilot study of the implementation of seasonal intermittent treatment in children (IPTc) with community participation in Senegal. Abstract 025-40. 5th European Congress Tropical Medicine and International Health May 2007. Trop Med Intl Hlth. 2007;12(suppl 1):46.
    1. Cisse B, Sokhna C, Boulanger D, Milet J, Ba EH, et al. Seasonal intermittent preventive treatment with artesunate and sulphadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double blind trial. Lancet. 2006;367:659–667.
    1. Sokhna C, Cisse B, Ba EH, Milligan P, Hallett R, et al. A trial of the efficacy, safety and impact on drug resistance of four drug regimens for seasonal intermittent preventive treatment in Senegalese children. PLoS One. 2008;3:e1471.
    1. Benazet F. Plasmodium berghei et antimalariques a action de longue duree. 1965. WHO/Mal/501.65.
    1. WHO Chemotherapy of malaria. 1967. Report of a WHO Scientific group. WHO Technical Report Series No 375.
    1. Lafaix C, Rey M, Diop Mar I, Nouhouayi A. Essai de traitement curative du paludisme pour un nouvel antipaludique de synthese, le 16,126 RP. Bull Soc Med Afr Noire Langue Fr. 1967;22:546–551.
    1. Vidal L, Fall AS, Gadou D. Les Professionnels de Sante en Afrique de l'Ouest: Entre savoirs et pratiques. L'Harmattan, Paris. 2005.
    1. Working Group on Malaria Prevention in China. Summary of field verification of antimalarial piperaquine, piperaquine-sulfadoxine and hydroxypiperaquine (in Chinese). Acad J Second Mil Med College. 1980;1:30–36.
    1. Lv HY. Summary on research progress of the long-acting antimalarial: ‘Preventive 3’ (in Chinese). Acad J First Mil Med College. 1988;8(Suppl):460–463.
    1. Changxiong L, Lin X, Huang ZS, Chen YS, Guo RN. In vivo sensitivity of Plasmodium falciparum to piperaquine phosphate assayed in Linshui and Baisha counties, Hainan Province. Chin J Parasitol Parasitic Dis. 1989;7:163–165.
    1. Senqi H. The present status of malaria control in the People's Republic of China. Japan J Trop Med Hyg. 1980;8(3,4):159–172.
    1. Chen L, Qu FY, Zhou Y. Field observations on the antimalarial piperaquine. Chin Med J (Engl) 1982;95:281–6.
    1. Ahmed T, Sharma P, Gautam A, Varshney B, Kothari M, et al. Safety, Tolerability, and Single- and Multiple-Dose Pharmacokinetics of Piperaquine Phosphate in Healthy Subjects. J Clin Pharmacol. 2008;48:166.
    1. Tarning J, Lindegardh N, Annerberg A, Singtoroj T, Day NP, et al. Pitfalls in estimating piperaquine elimination. Antimicrob Agents Chemother. 2005;49:5127–5128.
    1. Myint HY, Ashley EA, Daya NPJ, Nosten F, White NJ. Efficacy and safety of dihydroartemisinin-piperaquine. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2007;101:858–866.
    1. European Medicines Agency. ICH Topic Q3B(R2) Impurities in New Drug Products. Note for guidance on impurities in new drug products (CPMP/ICH/2738/99). EMA, London. 2006. ( downloaded April 3 2009)
    1. Plowe CV, Djimde A, Bouare M, Doumbo O, Wellems TE. Pyrimethamine and proguanil resistance–conferring mutations in Plasmodium falciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. Am J Trop Med Hyg. 1995;52:565–8.
    1. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, et al. Mutations in Plasmodium falciparum Dihydrofolate Reductase and Dihydropteroate Synthase and Epidemiologic Patterns of Pyrimethamine-Sulfadoxine Use and Resistance. J Infect Dis. 1997;176(6):1590–6.
    1. Wang P, Brooks DR, Sims PF, Hyde JE. A mutation-specific PCR system to detect sequence variation in the dihydropteroate synthetase gene of Plasmodium falciparum. Mol Biochem Parasitol. 2005;71:115–25.
    1. Donner A, Klar N. London: Arnold; 2000. Design and analysis of cluster randomization trials in health research.
    1. European Medicines Agency. Guideline on the choice of the non-inferiority margin. 2005. .
    1. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. Jama. 2006;295:1152–1160.
    1. Hayes R, Moulton L. London: Chapman & Hall/CRC; 2009. Cluster Randomised Trials.
    1. Bennett S, Parpia T, Hayes R, Cousens S. Methods for the analysis of incidence rates in cluster randomized trials. Int J Epidemiol. 2002;31:839–846.
    1. Cheung YB, Jeffries D, Thomson A, Milligan P. A simple approach to test for interaction between intervention and an individual-level variable in community randomized trials. Trop Med Int Health. 2008;13:247–255.
    1. WHO. The use of artemisinin & its derivatives as anti-malarial drugs. 1998. Report of a Joint CTD/DMP/TDR Informal Consultation Geneva, 10–12 June 1998. WHO, Geneva.
    1. Zhao HJ, Xia YY, Zheng Z. Pre-clinical toxicity study of new antimalarial agents. IV. Liver ultrastructure changes affected by antimalarial agent, compound tablet of piperaquine phosphate and sulfadoxine. Acad J Second Mil Med College. 1981;1:47–8.
    1. Sheng N, Jiang W, Tang HL. Pre-clinical toxicological study of new antimalarial agents: II. Piperaquine phosphate and its compound “Preventive No. 3.”. Ti Erh Chun i Ta Hsueh Hsueh Pao. 1981;1:40–46.
    1. Qu FY. The antimalarial effects of piperaquine phosphate and sulphadoxine composite as tested in Hainan Island (article in Chinese). Zhonghua Yi Xue Za Zhi. 1981;61(7):388–91.
    1. Marbiah NT, Petersen E, David K, Magbity E, Lines J, Bradley DJ. A controlled trial of lambda-cyhalothrin-impregnated bed nets and/or dapsone/pyrimethamine for malaria control in Sierra Leone. Am J Trop Med Hyg. 1998;58(1):1–6.
    1. Pagnoni F. Malaria treatment: no place like home. Trends in Parasitology. 2009;25:115–119.

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