Efficacy and Safety of MOX/ALB Co-administration

Study Overview
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Brief Summary
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This study is a double-blind randomized controlled superiority trial aiming at providing evidence on the efficacy and safety of co-administered moxidectin and albendazole versus albendazole monotherapy (standard of care) against whipworm (T. trichiura) infections in adolescents and adults (12-60 years) in Côte d'Ivoire. One arm of patients will be treated with albendazole-ivermectin. As measure of efficacy of the treatment the cure rate (percentage of egg-positive subjects at baseline who become egg-negative after treatment) will be determined 14-21 days post-treatment.

Detailed Description
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This study is a double-blind randomized clinical trial which aims at providing evidence on the efficacy and safety of co-administered moxidectin and albendazole versus albendazole monotherapy (standard of care) against T. trichiura infections in adolescents and adults (12-60 years) in Côte d'Ivoire. Additionally, this study aims to substantiate evidence on the efficacy and safety of co-administered ivermectin and albendazole compared to albendazole monotherapy against T. trichiura in the same age group. The primary objective of the trial is to comparatively assess the efficacy in terms of cure rate (CR) against T. trichiura infections among adolescents and adults (aged 12 to 60 years) of moxidectin/albendazole combination therapy and albendazole monotherapy. The secondary objectives of the trial are to compare the egg reduction rates (ERR) of these treatment regimens (moxidectin/albendazole combination therapy vs. albendazole monotherapy) against T. trichiura, to assess the CRs and ERRs in T. trichiura-infected participants given ivermectin/albendazole combination therapy compared to those given albendazole monotherapy, to determine the CRs and ERRs of the drugs in study participants co-infected with A. lumbricoides and hookworm, and to evaluate the safety and tolerability of the treatment regimens. In addition, this study aims to characterize population pharmacokinetics and drug-drug interactions of the study drugs albendazole and ivermectin in T. trichiura infected adolescents (aged 12 to 20 years), to evaluate pharmacogenomics of ivermectin using whole genome sequencing, and to assess the effect of the gut microbiota on pharmacokinetics parameters and treatment outcome (CRs and ERRs), and drug-specific off-target effects of anthelmintic treatment on gut microbial communities in post-treatment samples. After obtaining informed consent from individual/parents and/or caregivers, the medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical examination carried out by the study physician before treatment. Enrollment will be based on two stool samples, which will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days. All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians. Randomization of participants into the three treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours and 14-21 days after treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 days post-treatment by collecting another two stool samples. The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, a per-protocol analysis will be conducted. CRs will be calculated as the percentage of egg-positive subjects at baseline who become egg-negative after treatment. Differences among CRs between treatment arms will be analysed using crude and adjusted logistic regression modeling (adjustment for age, sex and weight). Geometric and arithmetic mean egg counts will be calculated for the different treatment arms before and after treatment to assess the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% confidence intervals (CIs) for differences in ERRs.

Official Title
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Efficacy and Safety of Combination Moxidectin and Albendazole, Ivermectin and Albendazole and Albendazole Alone in Adolescents and Adults Infected With Trichuris Trichiura: a Randomized Controlled Trial

Conditions
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Trichuriasis, Ascariasis, Hookworm Infections

Intervention / Treatment
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* Drug: Moxidectin 2 mg Oral Tablet
* Drug: Albendazole 400 mg Oral Tablet
* Drug: Ivermectin 3 mg Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 12 and 60 years Written informed consent signed by either parents/caregivers for underage adolescents (aged 12-17 years) or by the participant him/herself (18-60 years of age); and written assent by underage participant Agree to comply with study procedures, including provision of two stool samples at the beginning (baseline) and at follow-up assessment 14-21 days after treatment Willing to be examined by a study physician prior to treatment At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection intensities of at least 48 EPG Exclusion Criteria: Presence or signs of major systemic illnesses, e.g. body temperature ≥ 38°C, severe anemia (below 80g/l Hb according to WHO) upon initial clinical assessment Known or suspected infection with Loa loa History of acute or severe chronic disease Abnormal liver function assessed by multiple biochemical blood-based analyses Recent use of anthelmintic drug (within past 4 weeks) Attending other clinical trials during the study Pregnancy, lactating, and/or planning to become pregnant within the next 3 months Known allergy to study medications (i.e. albendazole, ivermectin or moxidectin) Taking medication with known contraindication to or interaction with study drugs

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 60 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: moxidectin and albendazole<br>Combination therapy of moxidectin (8 mg, i.e. 4 tablets of 2 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Moxidectin 2 mg Oral Tablet<br>* Tablets of 2 mg moxidectin<br>Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Placebo Comparator: Arm B: albendazole<br>Placebo (for moxidectin, 4 tablets) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Experimental: Arm C: ivermectin and albendazole<br>Combination therapy of ivermectin (Stromectol®, 200 µg/kg using tablets of 3 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;Drug: Ivermectin 3 mg Oral Tablet<br>* Tablets of 3 mg ivermectin<br>* Other names: Stromectol®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure Rate (CR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura | The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100. | 14-21 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Egg Reduction Rate (ERR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs. | 14-21 days after treatment | 
| Cure Rate (CR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura | The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100. | 14-21 days after treatment | 
| Egg Reduction Rate (ERR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs. | 14-21 days after treatment | 
| Cure Rates (CRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants | The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100. | 14-21 days after treatment | 
| Egg Reduction Rates (ERRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the three treatment arms before and after treatment to assess the corresponding ERRs. | 14-21 days after treatment | 
| Cure Rates (CRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants | The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100. | 14-21 days after treatment | 
| Egg Reduction Rates (ERRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants | Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the three treatment arms before and after treatment to assess the corresponding ERRs. | 14-21 days after treatment | 
| Adverse Events (AEs) | Participants will be monitored at the site for 3 hours following treatment for any acute AEs and reassessment will be done at 24h post-treatment. In addition, participants will be interviewed 3 and 24 hours after treatment and retrospectively at days 14-21 about the occurrence of AEs. | 3 hours, 24 hours and 14-21 days after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Albendazole, Moxidectin, Ivermectin, Anthelmintics, T. trichiura, A. lumbricoides, Hookworm, Whipworm, Soil-transmitted helminths