Dataset Information

Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.

ABSTRACT:

Background

Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies.

Methodology

We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d'Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel.

Principal findings

128 adolescents (age: 12-17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel).

Conclusion/significance

Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni.

SUBMITTER: Barda B

PROVIDER: S-EPMC5026339 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Publications

Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.

Barda Beatrice B Coulibaly Jean T JT Puchkov Maxim M Huwyler Jörg J Hattendorf Jan J Keiser Jennifer J

PLoS neglected tropical diseases 20160916 9

<h4>Background</h4>Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies.<h4>Methodology</h4>We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d'Ivoire. Our primary endpoints were cure ...[more]

PMID: 27636542

Similar Datasets

Project description:BackgroundIn sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup) is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied.MethodologyWe assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (<6 years) in the Azaguié district, south Côte d'Ivoire, where Schistosoma mansoni and S. haematobium coexist. Using a cross-sectional design, children provided two stool and two urine samples before and 3 weeks after treatment. Crushed praziquantel tablets, mixed with water, were administered at a dose of 40 mg/kg. Adverse events were assessed and graded 4 and 24 hours posttreatment by interviewing mothers/guardians.Principal findingsOverall, 160 preschool-aged children had at least one stool and one urine sample examined with duplicate Kato-Katz thick smears and a point-of-care circulating cathodic antigen (POC-CCA) cassette for S. mansoni, and urine filtration for S. haematobium diagnosis before and 3 weeks after praziquantel administration. According to the Kato-Katz and urine filtration results, we found high efficacy against S. mansoni (cure rate (CR), 88.6%; egg reduction rate (ERR), 96.7%) and S. haematobium (CR, 88.9%; ERR, 98.0%). POC-CCA revealed considerably lower efficacy against S. mansoni (CR, 53.8%). Treatment was generally well tolerated, but moderately severe adverse events (i.e., body and face inflammation), were observed in four Schistosoma egg-negative children.Conclusions/significanceCrushed praziquantel administered to preschool-aged children at a dose of 40 mg/kg is efficacious against S. mansoni and S. haematobium in a co-endemic setting of Côte d'Ivoire. Further research is required with highly sensitive diagnostic tools and safety must be investigated in more depth.Trial registrationControlled-Trials.com ISRCTN53172722.

Project description:BackgroundTreatment and morbidity control of schistosomiasis relies on a single drug, praziquantel. Hence, there is a pressing need to develop additional therapeutics against schistosomiasis. The antimalarial drug mefloquine shows antischistosomal activity in animal models and clinical trials, which calls for further investigations.MethodologyWe comparatively assessed the efficacy and tolerability of the following treatments against Schistosoma haematobium in school-aged children in Côte d'Ivoire: (i) praziquantel (40 mg/kg; standard treatment); (ii) mefloquine (25 mg/kg) combined with praziquantel (40 mg/kg); and (iii) mefloquine-artesunate (3× (100 mg artesunate +250 mg mefloquine)) combined with praziquantel (40 mg/kg) (treatments administered on subsequent days). Two urine samples were collected before, and on days 21-22 and 78-79 after the first dosing.Principal findingsSixty-one children were present on all examination time points and had complete datasets. No difference in efficacy was observed between the three treatment groups on either follow-up. On the 21-22 day posttreatment follow-up, based on available case analysis, cure rates of 33% (95% confidence interval (CI) 11-55%), 29% (95% CI 8-50%), and 26% (95% CI 5-48%) were observed for praziquantel, mefloquine-artesunate-praziquantel, and mefloquine-praziquantel, respectively. The corresponding egg reduction rates were 94% and above. On the second follow-up, observed cure rates ranged from 19% (praziquantel) to 33% (mefloquine-artesunate-praziquantel), and egg reduction rates were above 90%. Praziquantel monotherapy was the best tolerated treatment. In the mefloquine-artesunate-praziquantel group, adverse events were reported by 91% of the participants, and in the mefloquine-praziquantel group, 95% experienced adverse events. With the exception of abdominal pain at moderate severity, adverse events were mild.Conclusions/significanceThe addition of mefloquine or mefloquine-artesunate does not increase the efficacy of praziquantel against chronic S. haematobium infection. Additional studies are necessary to elucidate the effect of the combinations against acute schistosomiasis.

Project description:BackgroundUndernutrition and schistosomiasis are public health problems and often occur in low and middle-income countries. Protein undernutrition can alter the host-parasite environment system and aggravate the course of schistosomiasis. This study aimed to assess the impact of a low-protein diet on the efficacy of praziquantel.Methodology/principal findingsThirty-day-old mice were fed with a low-protein diet, and 40 days later, they were individually infected with fifty Schistosoma mansoni cercariae. A 28-day-treatment with praziquantel at 100 mg/kg for five consecutive days followed by distilled water begins on the 36th day post-infection. Mice were sacrificed on the 64th day post-infection. We determined the parasitological burden, liver and intestine histomorphometry, liver injury, and immunomodulation parameters. Praziquantel treatment of infected mice fed with a standard diet (IN-PZQ) resulted in a significant reduction of worm and egg burdens and a normalization of iron and calcium levels. The therapy also improved schistosomiasis-induced hepatopathy and oxidative stress. The anti-inflammatory and immunomodulatory activities of praziquantel were also significant in these mice. When infected mice receiving the low-protein diet were treated with praziquantel (ILP-PZQ), the body weight loss and hepatomegaly were not alleviated, and the worm and liver egg burdens were significantly higher than those of IN-PZQ mice (P < 0.001). The treatment did not reduce the increased activities of ALT and γ-GGT, the high malondialdehyde concentration, and the liver granuloma volume. The iron and calcium levels were not ameliorated and differed from those of IN-PZQ mice (P < 0.001 and P < 0.05). Moreover, in these mice, praziquantel treatment did not reverse the high level of IL-5 and the low mRNA expression of CCL3/MIP-1α and CXCL-10/IP-10 induced by S. mansoni infection.Conclusion/significanceThese results demonstrated that a low-protein diet reduced the schistosomicidal, antioxidant, anti-inflammatory, and immunomodulatory activities of praziquantel.

Project description:BackgroundMost studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods.MethodologyA sub-analysis was performed based on a previously published trial conducted in children from Côte d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA).Principal findingsIndividuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32-59%) in the standard and 78% (95% CI 66-87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52-75%) and 88%, 95% CI 78-93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11-24%) and 18% (95% CI 12-26%), even lower than observed by POC-CCA (31%, 95% CI 17-35% and 36%, 95% CI 26-47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups.Conclusion/significanceThe efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics (i.e. KK and PCR). Quantitative worm-based diagnostics (i.e. POC-CCA and UCP-LF CAA) revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis.Clinical trial registrationwww.clinicaltrials.gov, NCT02868385.

Dataset Information

Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.

Background

Methodology

Principal findings

Conclusion/significance

Publications

Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.

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