Evaluation of Artesunate-mefloquine as a Novel Alternative Treatment for Schistosomiasis in African Children (SchistoSAM): protocol of a proof-of-concept, open-label, two-arm, individually-randomised controlled trial

Abstract

IntroductionAlternative drugs and diagnostics are needed for the treatment and control of schistosomiasis. The exclusive use of praziquantel (PZQ) in mass drug administration programmes may result in the emergence of drug resistance. PZQ has little activity against Schistosoma larvae, thus reinfection remains a problem in high-risk communities. Furthermore, the insufficient sensitivity of conventional microscopy hinders therapeutic response assessment. Evaluation of artesunate-mefloquine (AM) as a Novel Alternative Treatment for Schistosomiasis in African Children (SchistoSAM) aims to evaluate the safety and efficacy of the antimalarial combination artesunate-mefloquine, re-purposed for the treatment of schistosomiasis, and to assess the performance of highly sensitive novel antigen-based and DNA-based assays as tools for monitoring treatment response.Methods and analysisThe SchistoSAM study is an open-label, two-arm, individually randomised controlled non-inferiority trial, with a follow-up of 48 weeks. Primary school-aged children from the Richard Toll district in northern Senegal, an area endemic for Schistosoma mansoni and Schistosoma haematobium, are allocated to the AM intervention arm (3-day courses at 6-week intervals) or the PZQ control arm (single dose of 40 mg/kg). The trial’s primary endpoints are the efficacy (cure rate (CR), assessed by microscopy) and safety (frequency and pattern of drug-related adverse events) of one AM course versus PZQ at 4 weeks after treatment. Secondary endpoints include (1) cumulative CR, egg reduction rate and safety after each additional course of AM, and at weeks 24 and 48, (2) prevalence and severity of schistosomiasis-related morbidity and (3) malaria prevalence, incidence and morbidity, both after 24 and 48 weeks. CRs and intensity reduction rates are also assessed by antigen-based and DNA-based diagnostic assays, for which performance for treatment monitoring is evaluated.Ethics and disseminationEthics approval was obtained both in Belgium and Senegal. Oral assent from the children and signed informed consent from their legal representatives was obtained, prior to enrolment. The results will be disseminated in peer-reviewed journals and at international conferences.Trial registration numberNCT03893097; pre-results.

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

“…However, microscopy is considered an insensitive method that tends to overestimate treatment efficacy. Concurrently with microscopic examinations, we therefore evaluated a set of highly sensitive antigen-based (that is, circulating cathodic and anodic antigens) and DNA-based detection assays as alternative tests of cure 22 ; due to space limitations, comparative results on the performance of those diagnostics will be published elsewhere. The use of the egg reduction rate as measure for the efficacy outcome would have substantially inflated the required sample size, beyond the scope of a proof-of-concept trial.…”

“…Baseline assessment included parasitological confirmation and quantification of Schistosoma infection (both with microscopy and novel diagnostics, see below), as well as a medical and laboratory evaluation. Detailed descriptions were published elsewhere 22 . For the parasitological baseline assessment, two urine and two stool samples were collected on consecutive days.…”

“…In case of discordant results (this occurred in less than 2% of the revised slides), those assessed by the most experienced microscopist were entered in the database. In accordance with the SchisoSAM protocol 22 , in parallel to conventional microscopy, DNA- and antigen-based assays (both the point-of-care circulating cathodic antigen and circulating anodic antigen) were also systematically run either in the study hospital or in reference laboratories (methods and results to be reported in a second manuscript). The medical evaluation was performed in the study schools and included the measurement of body weight and height, a clinical examination focused on schistosomiasis-related complications, the determination of the hemoglobin level via a finger prick (with HemoCue Hb 301, HemoCue), and an abdominal ultrasound exploration of urinary or hepatic abnormalities 39 by an experienced radiologist with a portable machine (Samsung Medison SonoAce R3).…”

“…The follow-up sampling was organized within the primary schools in close collaboration with community health workers and teachers. All samples were cryopreserved to perform additional molecular and antigenic diagnostic investigations as detailed in the published study protocol 22 .…”

“…In this Article, we present the results of SchistoSAM, whose primary objectives were to compare the parasitological cure rate and safety of a 3-day course of the artesunate–mefloquine combination at antimalarial dosage versus the standard-care single-dose praziquantel for the treatment of schistosomiasis in African primary school-aged children 22 . The secondary objectives were (1) to determine the egg reduction rates by Schistosoma species, (2) to assess the cumulative antischistosomal efficacy and toxicity of one and two additional courses of artesunate–mefloquine, and (3) to monitor the incidence of clinical malaria and explore the frequency of Plasmodium falciparum infection and possible emergence of resistant markers.…”