Efficacy, Safety and Acceptability of Ivermectin ODT in PSAC

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, the pharmacokinetics of the newly developed ODTs and the standard ivermectin tablets (Stromectol®) will be compared 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.

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, the pharmacokinetics of the newly developed ODTs and the standard ivermectin tablets (Stromectol®) will be compared 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.

Eligibility Criteria:
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