Evaluation of Artesunate-mefloquine as a Novel Alternative Treatment for Schistosomiasis in African Children

Study Overview
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Brief Summary
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The SchistoSAM study is an open label, two-arm, individually-randomized controlled trial with a non-inferiority design, conducted in northern Senegal. The study aims at determining if the efficacy of one and of repeated courses of artesunate-mefloquine (AM) is respectively similar to or higher than that of a standard praziquantel (PZQ) treatment. Secondly, the study will assess if novel DNA- and antigen-based diagnostics are more accurate than microscopy in assessing antischistosomal treatment response.

Detailed Description
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The SchistoSAM study is an open label, two-arm, individually-randomized controlled trial with a non-inferiority design, conducted in northern Senegal. The study aims at determining if the efficacy of one and of repeated courses of artesunate-mefloquine (AM) is respectively similar to or higher than that of a standard praziquantel (PZQ) treatment. Secondly, the study will assess if novel DNA- and antigen-based diagnostics are more accurate than microscopy in assessing antischistosomal treatment response. For this purpose, 726 school children, aged 6-14 years old and infected with Schistosoma (as demonstrated by presence of eggs in stool and/or urine) will be randomized in one of the following arms: AM, available in fixed dose tablets of 25/50 mg and 100/200 mg will be administered once daily for three days in a dose closest to 4 mg/kg artesunate and 8 mg/kg mefloquine. This treatment course will be repeated 2 times at 6-week intervals. PZQ, available in tablets of 600 mg, will be administered as a single dose of 40 mg/kg. Trial participants will be regularly followed-up: At each dose administration At day 7 after each dose for follow-up of safety At week 4, 10 and 16 for parasitological assessment and follow-up of safety At week 6 and 12 for clinical assessment before the second and third drug administration (only in the AM arm) At week 24 and 48 for assessment of Schistosoma spp. and malaria infection and associated morbidity (compared to baseline)

Official Title
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A Proof-of-concept Trial to Evaluate Artesunate-mefloquine as a Novel Alternative Treatment for Schistosomiasis in African Children

Conditions
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Schistosoma Haematobium, Schistosoma Mansoni

Intervention / Treatment
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* Drug: Praziquantel
* Drug: Artesunate + Mefloquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children ≥6 and ≤14 years of age Enrolled in one of the selected primary schools in the region Infected with schistosomiasis (i.e. Schistosoma spp. eggs in urine and/or stool) Informed consent from parents/guardians signed Exclusion Criteria: History of, or ongoing, epilepsy or psychiatric illness (I.e. recent history of depression, generalized anxiety disorder; history of psychosis, schizophrenia or other major psychiatric disorders) or known hypersensitivity to one of the three study drugs Chronic medication for any reason Any severe underlying illness, including severe malnutrition or severe chronic schistosomiasis, based on clinical judgement Any febrile illness Exposure to PZQ or ACT within the three previous months.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Praziquantel<br>Participants in this arm will receive one dose of PZQ at baseline at 40 mg/kg. | Drug: Praziquantel<br>* 40 mg/kg at baseline<br>|
| Experimental: Artesunate-Mefloquine<br>Participants in this arm will receive the Artesunate-Mefloquine (fixed-drug)combination at 4 mg/kg artesunate and 8 mg/kg mefloquine at 3 consecutive days. This will be repeated twice; at week 6 and week 12. | Drug: Artesunate + Mefloquine<br>* 4mg/kg artesunate and 8 mg/kg mefloquine at baseline (3 consecutive days) and repeated at Week 6 and Week 12<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of a single course of artesunate-mefloquine for the treatment of schistosomiasis, compared to the standard PZQ regimen: Parasitological cure rate | Parasitological cure rate, as assessed by microscopy, after administration of PZQ and after one AM course | Week 4 | 
| Number of safety events of a single course of artesunate-mefloquine for the treatment of schistosomiasis, compared to the standard PZQ regimen | Frequency of drug-related adverse events and serious adverse events | Week 4 | 
| Number of safety events of a single course of artesunate-mefloquine for the treatment of schistosomiasis, compared to the standard PZQ regimen | Pattern of drug-related adverse events and serious adverse events | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the cumulative efficacy of two additional courses of AM (at 6-week intervals each) for the treatment of schistosomiasis, compared to a single course of AM, and compared to the standard regimen: Cure rate | Cure rate, as assessed by microscopy, after the second and after the third AM administration | Week 48 | 
| Number of safety events of two additional courses of AM (at 6-week intervals each) for the treatment of schistosomiasis, compared to a single course of AM, and compared to the standard regimen. | Frequency of adverse events and serious adverse events up to 4 weeks after the second and third AM administration. | Week 16 | 
| Determine the egg reduction rate obtained after single and repeated courses of AM compared to the standard PZQ regimen. | Egg reduction rate after administration of PZQ and after each AM course | Week 48 | 
| Determine the parasitological efficacy of single and repeated courses of AM by Schistosoma species and by infection intensity. | Cure rate and egg reduction rate by Schistosoma species (S. haematobium and S. mansoni) and by initial Schistosoma infection intensity after PZQ administration and single and repeated courses of AM | Week 16 | 
| Assess the impact of repeated AM courses on schistosomiasis-related morbidity | Prevalence and severity of general and organ-specific schistosomiasis morbidity (as assessed by clinical evaluation, ultrasound, point-of-care morbidity markers and hemoglobin level) compared to baseline and compared to the control arm. | Week 48 | 
| Determine the diagnostic accuracy of novel schistosomiasis antigen- and DNA-based diagnostic assays to monitor antischistosomal treatment response | Diagnostic accuracy of the different conventional and novel diagnostic tests (antigen- and DNA-based) at baseline and at defined time points after treatment compared to conventional stool/urine microscopy, and to composite reference standards (any positive test would be considered as infection). | Week 48 | 
| Determine the effect of repeated AM courses on prevalence of P. falciparum infection as well as on incidence and morbidity of clinical malaria in school-age children with schistosomiasis | Prevalence of malaria infection, as assessed by molecular testing of dried blood spots. Incidence of clinical malaria, as assessed by the number of incident malaria cases diagnosed through passive case detection during the study period (by standard malaria rapid tests and molecular diagnostics on dried blood spots). Frequency and severity of anemia, as assessed by determination of hemoglobin levels. | Week 48 | 
| Monitor the prevalence of Pf molecular markers associated with mefloquine resistance and the potential emergence of reduced artesunate susceptibility | Prevalence and patterns of mutations in the K13 gene (for artemisinin susceptibility) and increased copy number of the Pfmdr1 gene or other relevant mutations (for mefloquine resistance) observed in the molecular surveys Presence and patterns of mutations observed in incident malaria cases. | Week 48 | 
| Number of safety events of two additional courses of AM (at 6-week intervals each) for the treatment of schistosomiasis, compared to a single course of AM, and compared to the standard regimen. | Pattern of adverse events and serious adverse events up to 4 weeks after the second and third AM administration. | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schistosoma, Schistosomiasis, Senegal, Praziquantel, Artesunate, Mefloquine