Efficacy, Safety and Acceptability of Ivermectin ODT in PSAC

Study Overview
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Brief Summary
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This study is a single-blind randomized controlled dose-ranging trial aiming at providing evidence on the on the optimal dose of co-administered ivermectin and albendazole in terms of efficacy, safety and acceptability in preschool-aged children (PSAC; aged 2-5 years) infected with whipworm (Trichuris trichiura) on Pemba Island, Tanzania. Additionally, we aim to compare the pharmacokinetics of the newly developed ODTs and the standard ivermectin tablets (Stromectol®) in this age group. As measure of efficacy of the treatment the cure rate (percentage of egg-positive participants 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 single-blind randomized controlled dose-ranging trial aiming at providing evidence on the optimal dose of co-administered ivermectin and albendazole in terms of efficacy, safety and acceptability in preschool-aged children (PSAC; aged 2-5 years) infected with whipworm (Trichuris trichiura) on Pemba Island, Tanzania. Additionally, we aim to compare the pharmacokinetics of the newly developed ODTs and the standard ivermectin tablets (Stromectol®) in this 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 PSAC receiving different doses of ivermectin. The secondary objectives of the trial are to compare the egg reduction rates (ERRs) of the treatment regimens against T. trichiura, 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 of the ivermectin ODTs compared to standard tablets in T. trichiura infected individuals, and to assess the acceptability of the treatments. After obtaining informed consent from 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 six treatment arms will be stratified according to intensity of infection and age. All participants will be interviewed before treatment, and at 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 participants 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.Using the DoseFinding package of the statistical software environment R, Emax models will be implemented to predict the dose-response curves based on CRs and ERRs. Adverse events will be compiled into frequency tables and compared between treatment groups using descriptive summary statistics.

Official Title
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Efficacy, Safety and Acceptability of Ascending Doses of Ivermectin in Combination With Albendazole for Trichuris Trichiura Infections in Preschool-aged Children: a Single-blind Randomised Controlled Dose-ranging Trial

Conditions
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Trichuriasis, Ascariasis, Hookworm Infections

Intervention / Treatment
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* Drug: Ivermectin 1.5 mg ODT
* Drug: Ivermectin 3 mg Oral Tablet
* Drug: Albendazole 400 mg Oral Tablet
* Drug: Placebo IVM ODT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: individuals aged 2-5 years (24-71 months; confirmed by birth certificate or similar document) having given written informed consent signed by parents/caregivers being able and willing to provide two stool samples at baseline and at follow-up assessment (14-21 days) having at least two out of four Kato-Katz slides positive for T. trichiura at baseline being able and willing to be examined by a study physician before and after treatment Exclusion Criteria: presence or signs of major systemic illness, e.g. fever (temporal body temperature of >38.0°C), severe anaemia (haemoglobin level of <70 g/l) history of severe acute disease or unmanaged, severe chronic disease (i.e., condition is not as therapeutically controlled as necessary) use of anthelminthic drugs during study period known allergy to study medication (i.e., ivermectin or albendazole) being prescribed or taking concomitantly medication with known contraindications or drug interactions with the study medication concurrent participation in other clinical trials

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 5 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm A: IVM ODT Placebo<br>Placebo for ivermectin (oro-dispersible 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®;Drug: Placebo IVM ODT<br>* Placebo for ivermectin ODT<br>|
| Experimental: Arm B: IVM ODT 100 µg/kg<br>Combination therapy of ivermectin (100 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Ivermectin 1.5 mg ODT<br>* Oro-dispersible tablets of 1.5 mg ivermectin<br>Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Experimental: Arm C: IVM ODT 200 µg/kg<br>Combination therapy of ivermectin (200 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Ivermectin 1.5 mg ODT<br>* Oro-dispersible tablets of 1.5 mg ivermectin<br>Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Experimental: Arm D: IVM ODT 300 µg/kg<br>Combination therapy of ivermectin (300 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Ivermectin 1.5 mg ODT<br>* Oro-dispersible tablets of 1.5 mg ivermectin<br>Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Experimental: Arm E: IVM ODT 400 µg/kg<br>Combination therapy of ivermectin (400 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 | Drug: Ivermectin 1.5 mg ODT<br>* Oro-dispersible tablets of 1.5 mg ivermectin<br>Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|
| Active Comparator: Arm F: IVM standard tablets<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: Ivermectin 3 mg Oral Tablet<br>* Tablets of 3 mg ivermectin<br>* Other names: Stromectol®;Drug: Albendazole 400 mg Oral Tablet<br>* Tablets of 400 mg albendazole<br>* Other names: Zentel®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate (CR) 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. | 14-21 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Egg reduction rate (ERR) 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 post-treatment | 
| Cure rate (CR) against A. lumbricoides | The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment. | 14-21 days post-treatment | 
| Egg reduction rate (ERR) against A. lumbricoides | 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 post-treatment | 
| Cure rate (CR) against Hookworm | The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment. | 14-21 days post-treatment | 
| Egg reduction rate (ERR) against Hookworm | 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 post-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 post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ivermectin, Albendazole, Anthelminthics, Trichuris trichiura, Ascaris lumbricoides, Hookworm, Whipworm, Soil-transmitted helminths