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Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of ascending doses of Moxidectin against strongyloides stercoralis infections in adults a randomised parallel group single blinded placebo controlled dose ranging phase 2a trial
Lancet Infectious Diseases, 2021Co-Authors: Jennifer Keiser, Jan Hattendorf, Daniela Hofmann, Somphou Sayasone, Khanpaseuth Sengngam, Bounthunh ChongvilayAbstract:Summary Background Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that Moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of Moxidectin in Strongyloides stercoralis-infected patients. Methods We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18–65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of Moxidectin, 4 mg of Moxidectin, 6 mg of Moxidectin, 8 mg of Moxidectin, 10 mg of Moxidectin, 12 mg of Moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of Moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato–Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic Emax models. Safety was evaluated in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT04056325 , and is complete. Findings Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of Moxidectin had a predicted cure rate of 75% (95% CI 59–87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5–31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76–88; 26 [90%] of 29 cured) at 4 mg to 86% (79–90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80–92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80–93; 29 [97%] of 30 cured) at 10 mg and 88% (80–93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild. Interpretation 4–12 mg of Moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of Moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy. Funding Fondazione Adiuvare.
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development and validation of an lc ms ms method for the quantification of the anthelmintic drug Moxidectin in a volumetric absorptive microsample blood and plasma application to a pharmacokinetic study of adults infected with strongyloides stercoral
Journal of Chromatography B, 2021Co-Authors: Daniela Hofmann, Jennifer Keiser, Somphou SayasoneAbstract:Abstract Moxidectin is a promising candidate for addition to the lean repertoire of drugs against neglected tropical diseases (NTD) including strongyloidiasis. Pharmacokinetic (PK) and -dynamic studies are required to support its clinical development. Microsampling approaches enable PK studies in the challenging environments where NTDs are most prevalent, due to simplified collection and processing. We developed a liquid chromatography tandem mass spectrometry method for the sensitive quantification of Moxidectin in human blood obtained by capillary sampling with the microsampling device Mitra® compared to blood and plasma obtained by venous sampling. Sample preparation consisted of protein precipitation, evaporation and reconstitution and also included phospholipid filtration for blood and plasma. Moxidectin was detected by multiple reaction monitoring (640.4 → 528.5 m/z) using a Luna C8(2) (30 × 2.0 mm, 3 µm particle size, 100 A) analytical column with a gradient program of 6 min duration. Validation was performed with respect to accuracy, precision, sensitivity, selectivity, linearity, stability, recovery, and haematocrit influence with a limit of quantification of 0.5 and 2.5 ng/mL, for venous and capillary blood respectively. Moxidectin was stable up to 2 months at storage condition (blood and plasma: −20 °C, microsamples: room temperature), 3 cycles of temperature shift, for at least 4 h on the bench-top and 24 h in the autosampler (4 °C). Deviations of inter- and intra-assay accuracy and precision were smaller than 12.6% and recoveries were in the range of 80.7–111.2%. The method was applied to samples obtained from nine Strongyloides stercoralis-infected adults from northern Laos. A good agreement in the time-concentration profiles of Moxidectin and a high consistency in PK parameters was found between the different matrixes and sampling strategies: e.g. identical time to reach maximal concentration of 4.0 h and a similar maximal concentration of 83.9–88.5 ng/mL of Moxidectin. The simple and practical capillary procedure using Mitra® microsampling has been demonstrated to be suitable for PK studies of Moxidectin and will pave the way for future PK studies.
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characterization of Moxidectin against strongyloides ratti in vitro and in vivo activity and pharmacokinetics in the rat model
ACS Infectious Diseases, 2020Co-Authors: Jennifer Keiser, Valentin Buchter, Daniela Hofmann, Cecile HaberliAbstract:Strongyloides stercoralis is a soil-transmitted helminth affecting an estimated 30-100 million people. Since the infection may be severe and life-threatening, accessible and effective treatment is pivotal. Currently, ivermectin is the drug of choice but has limitations. Moxidectin, a veterinary anthelminthic approved for use in human onchocerciasis, is a promising drug alternative against strongyloidiasis. In this study, we evaluated the in vitro activity of Moxidectin on Strongyloides ratti larvae (L3) and adult females and the activity as well as the pharmacokinetics of Moxidectin in S. ratti infected rats. In vitro, Moxidectin had an activity that was similar to that of ivermectin, with median lethal concentration values for L3 and adults in the range of 0.08-1.44 μM, after 72 h of exposure. In vivo, doses of 250, 500, and 750 μg/kg of Moxidectin resulted in a reduction of the worm burden ranging from 48.5 to 75%. At the highest dose (750 μg/kg) we observed a maximal blood concentration of 50.3 ng/mL and an area under the curve of 895.2 ng × h/mL. The half-life in rats was 9 h, and Moxidectin was cleared to undetectable blood levels within 7 d (<10 ng/mL). No exposure-response relationship was observed. This work contributes to the characterization of Moxidectin in the treatment of S. ratti as a model of Strongyloides spp. and, as such, supports moving Moxidectin further along the drug development pipeline in the treatment of human strongyloidiasis.
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Efficacy and tolerability of Moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial
The Lancet. Infectious diseases, 2018Co-Authors: Beatrice Barda, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Shaali M Ame, Said M Ali, Marco Albonico, Jennifer KeiserAbstract:Summary Background The recommended anthelmintics show low efficacy in a single-dose regimen against Trichuris trichiura . Moxidectin, a new treatment for river blindness, might complement the drug armamentarium for the treatment and control of soil-transmitted helminthiasis. However, its efficacy against T trichiura has not yet been studied. The aim of the study was to assess the efficacy of Moxidectin alone and in co-administrations against T trichiura infection. Methods A randomised, single-blind, non-inferiority trial was done in two primary schools and one secondary school in Pemba, Tanzania. Adolescents aged 12–18 years who tested positive for T trichiura were randomly assigned (5:5:3:3) with a computer-generated sequence to receive Moxidectin (8 mg) plus albendazole (400 mg), albendazole (400 mg) plus oxantel pamoate (25 mg/kg; reference treatment), Moxidectin (8 mg) plus tribendimidine (200 mg or 400 mg), or Moxidectin (8 mg) alone. Study group assignments were masked from participants and laboratory technicians. The primary outcome was non-inferiority with a 2 percentage point margin for egg reduction rate (ERR) against T trichiura assessed as the relative change in the geometric mean egg counts from baseline to 14–21 days after treatment with the Kato-Katz method, based on the available case population. Cure rates (CR) and tolerability (assessed 3, 24, and 48 h post treatment) were secondary outcomes. The study is registered at ISRCTN (number 20398469) and is closed to accrual. Findings 701 students were enrolled between April 1, and Aug 7, 2017. Primary outcome data were available for 634 students. We observed ERRs of 98·5% for Moxidectin plus albendazole and 99·8% for albendazole plus oxantel pamoate, resulting in an absolute difference of −1·2 percentage points (95% CI −1·8 to −0·8), meeting the non-inferiority margin. 100 (51%) of 197 students receiving Moxidectin plus albendazole and 166 (83%) of 200 receiving albendazole plus oxantel pamoate were cured, indicating a difference of 32 percentage points (odds ratio 5·3, 95% CI 3·3 to 8·7). ERRs were 91·6% for Moxidectin–tribendimidine and 83·2% for Moxidectin. Only mild adverse events (mainly headache and stomach pain) were reported. The largest number of adverse events (126 [20%] of 632 students) was observed 24 h post treatment, with no difference among the individual treatment arms (ranging from 23 [19%] of 118 students treated with Moxidectin to 38 [19%] of 199 with Moxidectin plus albendazole). Interpretation Moxidectin plus albendazole showed non-inferiority to albendazole plus oxantel pamoate in terms of ERR; however, albendazole plus oxantel pamoate showed a considerably higher cure rate. Dose-optimisation studies with Moxidectin and Moxidectin plus albendazole should be considered since the efficacy of the dose used for the treatment of onchocerciasis (8 mg) in this study might not be optimal for the treatment of T trichiura infections. Funding Thrasher Foundation.
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Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.
PLoS neglected tropical diseases, 2016Co-Authors: Beatrice Barda, Jean T. Coulibaly, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer KeiserAbstract: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.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Cote 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.; 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).; 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.
Jan Hattendorf - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of ascending doses of Moxidectin against strongyloides stercoralis infections in adults a randomised parallel group single blinded placebo controlled dose ranging phase 2a trial
Lancet Infectious Diseases, 2021Co-Authors: Jennifer Keiser, Jan Hattendorf, Daniela Hofmann, Somphou Sayasone, Khanpaseuth Sengngam, Bounthunh ChongvilayAbstract:Summary Background Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that Moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of Moxidectin in Strongyloides stercoralis-infected patients. Methods We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18–65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of Moxidectin, 4 mg of Moxidectin, 6 mg of Moxidectin, 8 mg of Moxidectin, 10 mg of Moxidectin, 12 mg of Moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of Moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato–Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic Emax models. Safety was evaluated in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT04056325 , and is complete. Findings Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of Moxidectin had a predicted cure rate of 75% (95% CI 59–87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5–31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76–88; 26 [90%] of 29 cured) at 4 mg to 86% (79–90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80–92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80–93; 29 [97%] of 30 cured) at 10 mg and 88% (80–93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild. Interpretation 4–12 mg of Moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of Moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy. Funding Fondazione Adiuvare.
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efficacy and safety of ascending dosages of Moxidectin and Moxidectin albendazole against trichuris trichiura in adolescents a randomized controlled trial
Clinical Infectious Diseases, 2019Co-Authors: Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Ladina Keller, Marta S Palmeirim, Shaali M Ame, Said M AliAbstract:Background Preventive chemotherapy is the main strategy to control soil-transmitted helminth (STH) infections. Albendazole and mebendazole are ubiquitously used, but they are not sufficiently effective against Trichuris trichiura. Moxidectin might be a useful addition to the small drug armamentarium. However, the optimal dosage of Moxidectin alone and in combination with albendazole against T. trichiura and other STHs has not yet been determined. Methods A Phase II, randomized, placebo-controlled, dose-finding trial was conducted in 2 secondary schools on Pemba Island, Tanzania. Using a computer-generated list, T. trichiura-infected adolescents were randomly assigned to 7 treatment arms: 8, 16, or 24 mg of Moxidectin monotherapy; 8, 16, or 24 mg of Moxidectin plus 400 mg of albendazole combination therapy; or placebo. The primary outcome was cure rate (CR) against T. trichiura, analyzed 13 to 20 days after treatment by quadruple Kato-Katz thick smears. Results A total of 290 adolescents were enrolled (41 or 42 per arm). CRs against T. trichiura were 43, 46, and 44% for 8, 16, and 24 mg of Moxidectin alone, respectively; 60, 62, and 66% for the same Moxidectin dosages plus 400 mg of albendazole, respectively; and 12% for placebo. The Moxidectin-albendazole arms also revealed higher CRs and egg reduction rates against hookworm than the monotherapy arms. Moxidectin and its combination with albendazole were well tolerated. Conclusions Moxidectin-albendazole is superior to Moxidectin. There is no benefit of using doses above 8 mg, which is the recommended dose for onchocerciasis. The Moxidectin-albendazole combination of 8 mg plus 400 mg should be investigated further to develop recommendations for appropriate control of STH infections. Clinical trials registration NCT03501251.
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Efficacy and tolerability of Moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial
The Lancet. Infectious diseases, 2018Co-Authors: Beatrice Barda, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Shaali M Ame, Said M Ali, Marco Albonico, Jennifer KeiserAbstract:Summary Background The recommended anthelmintics show low efficacy in a single-dose regimen against Trichuris trichiura . Moxidectin, a new treatment for river blindness, might complement the drug armamentarium for the treatment and control of soil-transmitted helminthiasis. However, its efficacy against T trichiura has not yet been studied. The aim of the study was to assess the efficacy of Moxidectin alone and in co-administrations against T trichiura infection. Methods A randomised, single-blind, non-inferiority trial was done in two primary schools and one secondary school in Pemba, Tanzania. Adolescents aged 12–18 years who tested positive for T trichiura were randomly assigned (5:5:3:3) with a computer-generated sequence to receive Moxidectin (8 mg) plus albendazole (400 mg), albendazole (400 mg) plus oxantel pamoate (25 mg/kg; reference treatment), Moxidectin (8 mg) plus tribendimidine (200 mg or 400 mg), or Moxidectin (8 mg) alone. Study group assignments were masked from participants and laboratory technicians. The primary outcome was non-inferiority with a 2 percentage point margin for egg reduction rate (ERR) against T trichiura assessed as the relative change in the geometric mean egg counts from baseline to 14–21 days after treatment with the Kato-Katz method, based on the available case population. Cure rates (CR) and tolerability (assessed 3, 24, and 48 h post treatment) were secondary outcomes. The study is registered at ISRCTN (number 20398469) and is closed to accrual. Findings 701 students were enrolled between April 1, and Aug 7, 2017. Primary outcome data were available for 634 students. We observed ERRs of 98·5% for Moxidectin plus albendazole and 99·8% for albendazole plus oxantel pamoate, resulting in an absolute difference of −1·2 percentage points (95% CI −1·8 to −0·8), meeting the non-inferiority margin. 100 (51%) of 197 students receiving Moxidectin plus albendazole and 166 (83%) of 200 receiving albendazole plus oxantel pamoate were cured, indicating a difference of 32 percentage points (odds ratio 5·3, 95% CI 3·3 to 8·7). ERRs were 91·6% for Moxidectin–tribendimidine and 83·2% for Moxidectin. Only mild adverse events (mainly headache and stomach pain) were reported. The largest number of adverse events (126 [20%] of 632 students) was observed 24 h post treatment, with no difference among the individual treatment arms (ranging from 23 [19%] of 118 students treated with Moxidectin to 38 [19%] of 199 with Moxidectin plus albendazole). Interpretation Moxidectin plus albendazole showed non-inferiority to albendazole plus oxantel pamoate in terms of ERR; however, albendazole plus oxantel pamoate showed a considerably higher cure rate. Dose-optimisation studies with Moxidectin and Moxidectin plus albendazole should be considered since the efficacy of the dose used for the treatment of onchocerciasis (8 mg) in this study might not be optimal for the treatment of T trichiura infections. Funding Thrasher Foundation.
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Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.
PLoS neglected tropical diseases, 2016Co-Authors: Beatrice Barda, Jean T. Coulibaly, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer KeiserAbstract: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.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Cote 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.; 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).; 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.
Beatrice Barda - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and tolerability of Moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial
The Lancet. Infectious diseases, 2018Co-Authors: Beatrice Barda, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Shaali M Ame, Said M Ali, Marco Albonico, Jennifer KeiserAbstract:Summary Background The recommended anthelmintics show low efficacy in a single-dose regimen against Trichuris trichiura . Moxidectin, a new treatment for river blindness, might complement the drug armamentarium for the treatment and control of soil-transmitted helminthiasis. However, its efficacy against T trichiura has not yet been studied. The aim of the study was to assess the efficacy of Moxidectin alone and in co-administrations against T trichiura infection. Methods A randomised, single-blind, non-inferiority trial was done in two primary schools and one secondary school in Pemba, Tanzania. Adolescents aged 12–18 years who tested positive for T trichiura were randomly assigned (5:5:3:3) with a computer-generated sequence to receive Moxidectin (8 mg) plus albendazole (400 mg), albendazole (400 mg) plus oxantel pamoate (25 mg/kg; reference treatment), Moxidectin (8 mg) plus tribendimidine (200 mg or 400 mg), or Moxidectin (8 mg) alone. Study group assignments were masked from participants and laboratory technicians. The primary outcome was non-inferiority with a 2 percentage point margin for egg reduction rate (ERR) against T trichiura assessed as the relative change in the geometric mean egg counts from baseline to 14–21 days after treatment with the Kato-Katz method, based on the available case population. Cure rates (CR) and tolerability (assessed 3, 24, and 48 h post treatment) were secondary outcomes. The study is registered at ISRCTN (number 20398469) and is closed to accrual. Findings 701 students were enrolled between April 1, and Aug 7, 2017. Primary outcome data were available for 634 students. We observed ERRs of 98·5% for Moxidectin plus albendazole and 99·8% for albendazole plus oxantel pamoate, resulting in an absolute difference of −1·2 percentage points (95% CI −1·8 to −0·8), meeting the non-inferiority margin. 100 (51%) of 197 students receiving Moxidectin plus albendazole and 166 (83%) of 200 receiving albendazole plus oxantel pamoate were cured, indicating a difference of 32 percentage points (odds ratio 5·3, 95% CI 3·3 to 8·7). ERRs were 91·6% for Moxidectin–tribendimidine and 83·2% for Moxidectin. Only mild adverse events (mainly headache and stomach pain) were reported. The largest number of adverse events (126 [20%] of 632 students) was observed 24 h post treatment, with no difference among the individual treatment arms (ranging from 23 [19%] of 118 students treated with Moxidectin to 38 [19%] of 199 with Moxidectin plus albendazole). Interpretation Moxidectin plus albendazole showed non-inferiority to albendazole plus oxantel pamoate in terms of ERR; however, albendazole plus oxantel pamoate showed a considerably higher cure rate. Dose-optimisation studies with Moxidectin and Moxidectin plus albendazole should be considered since the efficacy of the dose used for the treatment of onchocerciasis (8 mg) in this study might not be optimal for the treatment of T trichiura infections. Funding Thrasher Foundation.
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efficacy of Moxidectin versus ivermectin against strongyloides stercoralis infections a randomized controlled noninferiority trial
Clinical Infectious Diseases, 2017Co-Authors: Beatrice Barda, Maxim Puchkov, Somphou Sayasone, Khampheng Phongluxa, Syda Xayavong, Khonsavanh Keoduangsy, Peter Odermatt, Jörg HuwylerAbstract:Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin.; We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of Moxidectin (8 mg) vs ivermectin (200 μg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points.; A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for Moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (Moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed.; Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed.; Current Controlled Trials: ISRCTN11983645.
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Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.
PLoS neglected tropical diseases, 2016Co-Authors: Beatrice Barda, Jean T. Coulibaly, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer KeiserAbstract: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.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Cote 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.; 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).; 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.
Jörg Huwyler - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of ascending dosages of Moxidectin and Moxidectin albendazole against trichuris trichiura in adolescents a randomized controlled trial
Clinical Infectious Diseases, 2019Co-Authors: Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Ladina Keller, Marta S Palmeirim, Shaali M Ame, Said M AliAbstract:Background Preventive chemotherapy is the main strategy to control soil-transmitted helminth (STH) infections. Albendazole and mebendazole are ubiquitously used, but they are not sufficiently effective against Trichuris trichiura. Moxidectin might be a useful addition to the small drug armamentarium. However, the optimal dosage of Moxidectin alone and in combination with albendazole against T. trichiura and other STHs has not yet been determined. Methods A Phase II, randomized, placebo-controlled, dose-finding trial was conducted in 2 secondary schools on Pemba Island, Tanzania. Using a computer-generated list, T. trichiura-infected adolescents were randomly assigned to 7 treatment arms: 8, 16, or 24 mg of Moxidectin monotherapy; 8, 16, or 24 mg of Moxidectin plus 400 mg of albendazole combination therapy; or placebo. The primary outcome was cure rate (CR) against T. trichiura, analyzed 13 to 20 days after treatment by quadruple Kato-Katz thick smears. Results A total of 290 adolescents were enrolled (41 or 42 per arm). CRs against T. trichiura were 43, 46, and 44% for 8, 16, and 24 mg of Moxidectin alone, respectively; 60, 62, and 66% for the same Moxidectin dosages plus 400 mg of albendazole, respectively; and 12% for placebo. The Moxidectin-albendazole arms also revealed higher CRs and egg reduction rates against hookworm than the monotherapy arms. Moxidectin and its combination with albendazole were well tolerated. Conclusions Moxidectin-albendazole is superior to Moxidectin. There is no benefit of using doses above 8 mg, which is the recommended dose for onchocerciasis. The Moxidectin-albendazole combination of 8 mg plus 400 mg should be investigated further to develop recommendations for appropriate control of STH infections. Clinical trials registration NCT03501251.
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Efficacy and tolerability of Moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial
The Lancet. Infectious diseases, 2018Co-Authors: Beatrice Barda, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Shaali M Ame, Said M Ali, Marco Albonico, Jennifer KeiserAbstract:Summary Background The recommended anthelmintics show low efficacy in a single-dose regimen against Trichuris trichiura . Moxidectin, a new treatment for river blindness, might complement the drug armamentarium for the treatment and control of soil-transmitted helminthiasis. However, its efficacy against T trichiura has not yet been studied. The aim of the study was to assess the efficacy of Moxidectin alone and in co-administrations against T trichiura infection. Methods A randomised, single-blind, non-inferiority trial was done in two primary schools and one secondary school in Pemba, Tanzania. Adolescents aged 12–18 years who tested positive for T trichiura were randomly assigned (5:5:3:3) with a computer-generated sequence to receive Moxidectin (8 mg) plus albendazole (400 mg), albendazole (400 mg) plus oxantel pamoate (25 mg/kg; reference treatment), Moxidectin (8 mg) plus tribendimidine (200 mg or 400 mg), or Moxidectin (8 mg) alone. Study group assignments were masked from participants and laboratory technicians. The primary outcome was non-inferiority with a 2 percentage point margin for egg reduction rate (ERR) against T trichiura assessed as the relative change in the geometric mean egg counts from baseline to 14–21 days after treatment with the Kato-Katz method, based on the available case population. Cure rates (CR) and tolerability (assessed 3, 24, and 48 h post treatment) were secondary outcomes. The study is registered at ISRCTN (number 20398469) and is closed to accrual. Findings 701 students were enrolled between April 1, and Aug 7, 2017. Primary outcome data were available for 634 students. We observed ERRs of 98·5% for Moxidectin plus albendazole and 99·8% for albendazole plus oxantel pamoate, resulting in an absolute difference of −1·2 percentage points (95% CI −1·8 to −0·8), meeting the non-inferiority margin. 100 (51%) of 197 students receiving Moxidectin plus albendazole and 166 (83%) of 200 receiving albendazole plus oxantel pamoate were cured, indicating a difference of 32 percentage points (odds ratio 5·3, 95% CI 3·3 to 8·7). ERRs were 91·6% for Moxidectin–tribendimidine and 83·2% for Moxidectin. Only mild adverse events (mainly headache and stomach pain) were reported. The largest number of adverse events (126 [20%] of 632 students) was observed 24 h post treatment, with no difference among the individual treatment arms (ranging from 23 [19%] of 118 students treated with Moxidectin to 38 [19%] of 199 with Moxidectin plus albendazole). Interpretation Moxidectin plus albendazole showed non-inferiority to albendazole plus oxantel pamoate in terms of ERR; however, albendazole plus oxantel pamoate showed a considerably higher cure rate. Dose-optimisation studies with Moxidectin and Moxidectin plus albendazole should be considered since the efficacy of the dose used for the treatment of onchocerciasis (8 mg) in this study might not be optimal for the treatment of T trichiura infections. Funding Thrasher Foundation.
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efficacy of Moxidectin versus ivermectin against strongyloides stercoralis infections a randomized controlled noninferiority trial
Clinical Infectious Diseases, 2017Co-Authors: Beatrice Barda, Maxim Puchkov, Somphou Sayasone, Khampheng Phongluxa, Syda Xayavong, Khonsavanh Keoduangsy, Peter Odermatt, Jörg HuwylerAbstract:Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin.; We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of Moxidectin (8 mg) vs ivermectin (200 μg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points.; A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for Moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as -1.5% percentage points (95% CI, -9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (Moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed.; Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed.; Current Controlled Trials: ISRCTN11983645.
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Efficacy and Safety of Moxidectin, Synriam, Synriam-Praziquantel versus Praziquantel against Schistosoma haematobium and S. mansoni Infections: A Randomized, Exploratory Phase 2 Trial.
PLoS neglected tropical diseases, 2016Co-Authors: Beatrice Barda, Jean T. Coulibaly, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer KeiserAbstract: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.; We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Cote 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.; 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).; 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.
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A randomized, blinded, controlled, multi-centered field study assessing the treatment of gastrointestinal nematode infections in cats with fluralaner plus Moxidectin spot-on solution (Bravecto® Plus)
Parasites & Vectors, 2018Co-Authors: Nadja Rohdich, Eva Zschiesche, Oliver Wolf, Wolfgang Loehlein, Zvezdelina Kirkova, Petar Iliev, Dhimitër Rapti, Rezart Postoli, Balázs Capári, Róbert FarkasAbstract:Background A spot-on formulation containing fluralaner (280 mg/ml) plus Moxidectin (14 mg/ml) (Bravecto® Plus) was developed for the treatment of nematode infections as well as providing 12 weeks of protection against insect and acarine parasites in cats. The effectiveness and safety of this product against feline gastrointestinal nematodes was assessed in naturally-infested, client-owned cats under field conditions in Albania, Bulgaria, Germany and Hungary. Methods To be eligible for enrollment in this investigator-blinded study cats had to be at least 10 weeks-old, weigh at least 1.2 kg, be clinically healthy, and have a faecal sample testing positive for nematodes no more than eight days prior to treatment. Cats were stratified into blocks of three in order of presentation at each center and randomly allocated in a 2:1 ratio to be treated topically on Day 0 with fluralaner plus Moxidectin (minimum dose rates 40 mg/kg and 2 mg/kg, respectively) or emodepside plus praziquantel (minimum dose rates 3 mg/kg and 12 mg/kg, respectively) (Profender®). Faecal samples were collected from cats prior to treatment and 14 ± 4 days later. Results There were 182 cats randomized to the fluralaner plus Moxidectin group, and 91 to the emodepside plus praziquantel group. Prior to treatment the most commonly identified nematode egg was Toxocara cati , found in 79.1 and 82.4% of cats in the fluralaner plus Moxidectin and emodepside plus praziquantel groups, respectively. Eggs of Toxascaris leonina were found in 8.2 and 6.6% of cats; of hookworms in 30.8 and 24.2%; and of Capillaria spp. in 7.1 and 4.3%, respectively. After treatment, faecal samples from 98.3% of fluralaner plus Moxidectin treated and 96.6% of emodepside plus praziquantel-treated cats were free of nematode ova. Geometric mean faecal egg count reductions for T. cati , the only eggs found in post-treatment faecal samples, were 99.97% and 99.93%, respectively. Treatment with fluralaner plus Moxidectin was non-inferior to emodepside plus praziquantel. Both products were safe and well tolerated by cats treated under field conditions. Conclusions This field study confirms that, in addition to 12-week extended duration flea and tick control, fluralaner plus Moxidectin provides broad spectrum treatment of nematodes in cats.
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a randomized blinded controlled multi centered field study assessing the treatment of gastrointestinal nematode infections in cats with fluralaner plus Moxidectin spot on solution bravecto plus
Parasites & Vectors, 2018Co-Authors: Nadja Rohdich, Eva Zschiesche, Oliver Wolf, Wolfgang Loehlein, Zvezdelina Kirkova, Petar Iliev, Dhimitër Rapti, Rezart Postoli, Balázs Capári, Róbert FarkasAbstract:A spot-on formulation containing fluralaner (280 mg/ml) plus Moxidectin (14 mg/ml) (Bravecto® Plus) was developed for the treatment of nematode infections as well as providing 12 weeks of protection against insect and acarine parasites in cats. The effectiveness and safety of this product against feline gastrointestinal nematodes was assessed in naturally-infested, client-owned cats under field conditions in Albania, Bulgaria, Germany and Hungary. To be eligible for enrollment in this investigator-blinded study cats had to be at least 10 weeks-old, weigh at least 1.2 kg, be clinically healthy, and have a faecal sample testing positive for nematodes no more than eight days prior to treatment. Cats were stratified into blocks of three in order of presentation at each center and randomly allocated in a 2:1 ratio to be treated topically on Day 0 with fluralaner plus Moxidectin (minimum dose rates 40 mg/kg and 2 mg/kg, respectively) or emodepside plus praziquantel (minimum dose rates 3 mg/kg and 12 mg/kg, respectively) (Profender®). Faecal samples were collected from cats prior to treatment and 14 ± 4 days later. There were 182 cats randomized to the fluralaner plus Moxidectin group, and 91 to the emodepside plus praziquantel group. Prior to treatment the most commonly identified nematode egg was Toxocara cati, found in 79.1 and 82.4% of cats in the fluralaner plus Moxidectin and emodepside plus praziquantel groups, respectively. Eggs of Toxascaris leonina were found in 8.2 and 6.6% of cats; of hookworms in 30.8 and 24.2%; and of Capillaria spp. in 7.1 and 4.3%, respectively. After treatment, faecal samples from 98.3% of fluralaner plus Moxidectin treated and 96.6% of emodepside plus praziquantel-treated cats were free of nematode ova. Geometric mean faecal egg count reductions for T. cati, the only eggs found in post-treatment faecal samples, were 99.97% and 99.93%, respectively. Treatment with fluralaner plus Moxidectin was non-inferior to emodepside plus praziquantel. Both products were safe and well tolerated by cats treated under field conditions. This field study confirms that, in addition to 12-week extended duration flea and tick control, fluralaner plus Moxidectin provides broad spectrum treatment of nematodes in cats.
