Safety and efficacy of artesunate-amodiaquine combined with either methylene blue or primaquine in children with falciparum malaria in Burkina Faso: A randomized controlled trial

Autoři: Margarida Mendes Jorge aff001;  Lucienne Ouermi aff002;  Peter Meissner aff003;  Guillaume Compaoré aff002;  Boubacar Coulibaly aff002;  Eric Nebie aff002;  Johannes Krisam aff004;  Christina Klose aff004;  Meinhard Kieser aff004;  Albrecht Jahn aff001;  Guangyu Lu aff005;  Umberto D`Alessandro aff006;  Ali Sié aff002;  Frank Peter Mockenhaupt aff007;  Olaf Müller aff001
Působiště autorů: Heidelberg Institute of Global Health, University Hospital, Heidelberg, Baden-Württemberg, Germany aff001;  Centre de Recherche en Santé de Nouna, Nouna, Kossi, Burkina Faso aff002;  Department of Paediatrics, University Hospital, Ulm, Germany aff003;  Institut of Medical Biometry and Informatics, University Hospital, Heidelberg, Baden-Württemberg, Germany aff004;  Medical College, Yangzhou University, Yangzhou, Jiangsu, China aff005;  MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, London, United Kingdom aff006;  Institute of Tropical Medicine and International Health, Charité-Universitätsmedizin Berlin, Berlin, Germany aff007
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Artemisinin resistance is threatening global efforts for malaria control and elimination. Primaquine (PQ) and methylene blue (MB) are gametocytocidal drugs that can be combined with artemisinin-based combination therapy (ACT) to reduce malaria transmission, including resistant strains. Children (6–59 months) with uncomplicated falciparum malaria in Burkina Faso were treated with artesunate-amodiaquine (AS-AQ) and randomized to MB (15 mg/kg/day for 3 days) or PQ (0.25 mg/kg at day 2) with the aim to show non-inferiority of the MB regimen with regard to haematological recovery at day 7 (primary endpoint). MB-AS-AQ could not be shown to be non-inferior to PQ-AS-AQ (mean Hb difference between treatment groups on day 7 was -0.352, 95% CI -0.832–0.128, p = 0.0767), however, haemoglobin recovery following treatment was alike in the two study arms (day 7: mean 0.2±1.4 g/dl vs. 0.5±0.9 g/dl, p = 0.446). Occurrence of adverse events was similar in both groups, except for vomiting, which was more frequent in the MB than in the PQ arm (20/50 vs 7/50, p = 0.003). Adequate clinical and parasitological response was above 95% in both groups, but significantly more asexual parasites were cleared in the MB arm compared to the PQ arm already on day 1 (48/50, 96%, vs 40/50, 80%, p = 0.014). Moreover, P. falciparum gametocyte prevalence and density were lower in the MB arm than in the PQ arm, which reached statistical significance on day 2 (prevalence: 2/50, 4%, vs 15/49, 31%, p<0.001; density: 9.6 vs 41.1/μl, p = 0.024). However, it should be considered that PQ was given only on day 2. MB-ACT appears to be an interesting alternative to PQ-ACT for the treatment of falciparum malaria. While there is a need to further improve MB formulations, MB-ACT may already be considered useful to reduce falciparum malaria transmission intensity, to increase treatment efficacy, and to reduce the risk for resistance development and spread.

Trial registration: NCT02851108.

Klíčová slova:

Antimalarials – Gametocytes – Malaria – Malarial parasites – Plasmodium – Methylene blue – Vomiting – Artemisinin


1. Greenwood BM, Bojang K, Whitty CJ, Targett GA. Malaria. Lancet. 2005;365(9469):1487–98. doi: 10.1016/S0140-6736(05)66420-3 15850634

2. WHO. World Malaria report 2017. 2017.

3. Müller O. Malaria in Africa: Challenges for control and elimination in the 21st Century: Peter Lang Verlag, Frankfurt; 2011.

4. Müller O, Traore C, Kouyate B. Clinical efficacy of chloroquine in young children with uncomplicated falciparum malaria—a community-based study in rural Burkina Faso. Tropical Medicine & International Health. 2003;8(3):202–3.

5. Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. The Lancet. 2018;391(10130):1608–21.

6. Müller O, Sie A, Meissner P, Schirmer RH, Kouyate B. Artemisinin resistance on the Thai-Cambodian border. Lancet. 2009;374(9699):1419.

7. Shanks GD, Edstein MD, Jacobus D. Evolution from double to triple-antimalarial drug combinations. Trans R Soc Trop Med Hyg. 2015;109(3):182–8. doi: 10.1093/trstmh/tru199 25549631

8. Dicko A, Roh ME, Diawara H, Mahamar A, Soumare HM, Lanke K, et al. Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. The Lancet Infectious Diseases. 2018.

9. Coulibaly B, Zoungrana A, Mockenhaupt FP, Schirmer RH, Klose C, Mansmann U, et al. Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomised controlled trial. PLoS One. 2009;4(5):e5318. doi: 10.1371/journal.pone.0005318 19415120

10. Coulibaly B, Pritsch M, Bountogo M, Meissner PE, Nebie E, Klose C, et al. Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: a randomized controlled trial in Burkina Faso. J Infect Dis. 2015;211(5):689–97. doi: 10.1093/infdis/jiu540 25267980

11. Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. The Lancet Infectious diseases. 2010;10(10):673–81. doi: 10.1016/S1473-3099(10)70187-0 20832366

12. Recht J, Ashley E, White N. Safety of 8-aminoquinoline antimalarial medicines: WHO; 2014.

13. Bastiaens GJH, Tiono AB, Okebe J, Pett HE, Coulibaly SA, Gonçalves BP, et al. Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials. PLOS ONE. 2018;13(1):e0190272. doi: 10.1371/journal.pone.0190272 29324864

14. Shekalaghe SA, ter Braak R, Daou M, Kavishe R, van den Bijllaardt W, van den Bosch S, et al. In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. Antimicrob Agents Chemother. 2010;54(5):1762–8. doi: 10.1128/AAC.01135-09 20194698

15. Guttmann P, Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. Berliner Klinische Wochenschrift 1891; 28: 935–56.

16. Lu G, Nagbanshi M, Goldau N, Mendes Jorge M, Meissner P, Jahn A, et al. Efficacy and safety of methylene blue in the treatment of malaria: a systematic review. BMC Medicine. 2018;16(1):59. doi: 10.1186/s12916-018-1045-3 29690878

17. Sie A, Louis VR, Gbangou A, Muller O, Niamba L, Stieglbauer G, et al. The Health and Demographic Surveillance System (HDSS) in Nouna, Burkina Faso, 1993–2007. Glob Health Action. 2010;3(0).

18. Muller O, Becher H, van Zweeden AB, Ye Y, Diallo DA, Konate AT, et al. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomised double blind placebo controlled trial. BMJ. 2001;322(7302):1567. doi: 10.1136/bmj.322.7302.1567 11431296

19. WHO. Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7–131.

20. Bloland, Peter B, Ringwald, Pascal, Snow, Robert W & Global Partnership to Roll Back Malaria. (‎2003)‎. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparium malaria. Geneva: World Health Organization.

21. ICH Harmonised Tripartite Guideline. (1999) Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group. Stat Med. 18(15):1905–42. 10532877

22. Snapinn SM. (2000) Noninferiority trials. Current controlled trials in cardiovascular medicine. 1(1):19–21. doi: 10.1186/cvm-1-1-019 11714400

23. Van Buuren S. (2012) Flexible Imputation of Missing Data. Boca Raton: Chapman & Hall/CRC

24. Meissner P, Mandi G, Witte S, Coulibaly B, Mansmann U, Rengelshausen J, et al. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso. Malaria Journal 4: 46 (2005) doi: 10.1186/1475-2875-4-46

25. Meissner P, Mandi G, Coulibaly B, Witte S, Tapsoba T, Mansmann U, et al. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malaria Journal, 5: 84 (2006) doi: 10.1186/1475-2875-5-84 17026773

26. Zoungrana A, Coulibaly B, Sié A, Walter-Sack I, Mockenhaupt FP, Kouyaté B, et al. 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 (2008) doi: 10.1371/journal.pone.0001630 18286187

27. Coulibaly B, Pritsch M, Bountogo M, Meissner PE, Nebié E, Klose C, et al. Efficacy and safety of triple combination therapy with artesunate-amodiaquine-methylene blue for falciparum malaria in children: a randomised controlled trial in Burkina Faso. Journal of Infectious Diseases 211 (5): 689–697 (2015) doi: 10.1093/infdis/jiu540 25267980

28. Dicko A, Roh ME, Diawara H, Mahamar A, Soumare H, Lanke K, et al. Phase 2, single-blind randomised controlled trial of the efficacy and safety of primaquine and methylene blue for preventing Plasmodium falciparum transmission in Mali. Lancet Infectious Diseases 18, 6: 627–639 (2018) doi: 10.1016/S1473-3099(17)30536-4

29. Bountogo M, Zoungrana A, Coulibaly B, Klose C, Mansmann U, Mockenhaupt F, et al. Short communication: Efficacy of methylene blue monotherapy in semi-immune adults with uncomplicated falciparum malaria: a controlled trial in Burkina Faso. Tropical Medicine & International Health 15: 713–17 (2010)

30. Müller O, Mockenhaupt FP, Marks B, Meissner P, Coulibaly B, Kuhnert R, et al. Haemolysis risk in methylene blue treatment of G6PD sufficient and G6PD deficient West-African children with uncomplicated falciparum malaria: a synopsis of four RCTs. Pharmacoepidemiology and Drug Safety 22 (4): 376–85 (2013) doi: 10.1002/pds.3370 23135803

31. Akoachere M, Buchholz K, Fischer E, Burhenne J, Haefeli WE, Schirmer RH, et al. In vitro assessment of methylene blue on chloroquine-sensitive and -resistant Plasmodium falciparum strains reveals synergistic action with artemisinins. Antimicrob Agents Chemother. 2005;49(11):4592–7. doi: 10.1128/AAC.49.11.4592-4597.2005 16251300

32. Adjalley SH, Johnston GL, Li T, Eastman RT, Ekland EH, Eappen AG, et al. Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc Natl Acad Sci U S A. 2011;108(47):E1214–23. doi: 10.1073/pnas.1112037108 22042867

33. Coulibaly B, Zoungrana A, Mockenhaupt F, Schirmer H, Klose C, Mansmann U, et al. Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomised controlled trial. PLoS One 4 (5): e5318 (2009) doi: 10.1371/journal.pone.0005318 19415120

34. Marsh K. Malaria disaster in Africa. The Lancet 352: 924 (1998)

35. Müller O, Sié A, Meissner P, Schirmer RH, Kouyaté B. Artemisinin resistance on the Thai-Cambodian border. The Lancet (communication) 374: 1418–19 (2009)

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden