Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial

Abstract

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate-mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6-14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg^-1 single dose; n = 364) or to artesunate-mefloquine (antimalarial dosage: artesunate 4 mg kg^-1 and mefloquine 8 mg kg^-1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate-mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate-mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of -2.5% (95% confidence interval (CI) -9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate-mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate-mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

Fig. 1. CONSORT flow diagram of the SchistoSAM trial and analysis population.

AM, artesunate–mefloquine; PZQ, praziquantel; ITT, intention to treat; PP, per protocol.

Fig. 2. Parasitological efficacy 4 weeks post treatment.

Efficacy results are shown as determined by microscopy for praziquantel (PZQ, white diamond) and artesunate–mefloquine (AM, black circle) in participants overall (pooled, n = 718) and infected by S. haematobium (Sh, n = 713) or S. mansoni (Sm, n = 109). a, Estimated cure rates (proportion of participants without any Schistosoma eggs at week 4) with 95% CI. b, Cure rate difference of artesunate–mefloquine compared with praziquantel with 95% CI. The dotted line represents the noninferiority margin for the difference in cure rates. c, Estimated egg reduction rates with 95% bootstrap CI. The striped line represents the efficacy threshold defined by WHO. AM, artesunate–mefloquine; PZQ, praziquantel.

Fig. 3. Parasitological efficacy of repeated administrations of artesunate–mefloquine.

a, Cure rates (proportion of participants without any Schistosoma eggs) with 95% CI are shown as determined by microscopy in the praziquantel (PZQ, white diamond) and artesunate–mefloquine (AM, black circle) arms in participants infected with any Schistosoma species (n = 718). b, Cure rate difference with 95% CI of repeated administrations of artesunate–mefloquine (as assessed at weeks 10, 16 and 24 post-initial treatment), compared with week 4 assessment. Detailed numbers are available in Supplementary Table 2.