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

Margarida Mendes Jorge, Lucienne Ouermi, Peter Meissner, Guillaume Compaoré, Boubacar Coulibaly, Eric Nebie, Johannes Krisam, Christina Klose, Meinhard Kieser, Albrecht Jahn, Guangyu Lu, Umberto D Alessandro, Ali Sié, Frank Peter Mockenhaupt, Olaf Müller, Margarida Mendes Jorge, Lucienne Ouermi, Peter Meissner, Guillaume Compaoré, Boubacar Coulibaly, Eric Nebie, Johannes Krisam, Christina Klose, Meinhard Kieser, Albrecht Jahn, Guangyu Lu, Umberto D Alessandro, Ali Sié, Frank Peter Mockenhaupt, Olaf Müller

Abstract

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: ClinicalTrials.gov NCT02851108.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Consort flow chart.
Fig 1. Consort flow chart.
Fig 2. Boxplots of haemoglobin values by…
Fig 2. Boxplots of haemoglobin values by study group over time (ITT analysis).
Fig 3. Gametocyte prevalence during follow up…
Fig 3. Gametocyte prevalence during follow up by group.

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