Efficacy and Safety of IVM/ALB Co-administration

Study Overview
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Brief Summary
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This study is a double-blind randomized clinical trial conducted with two settings in Africa and one in Asia, namely Côte d'Ivoire, Pemba (Zanzibar, Tanzania) and Lao PDR. This study aims at providing evidence on the efficacy and safety of co-administered albendazole and ivermectin versus albendazole monotherapy (standard of care) against whipworm (T. trichiura) infections in children and adults (6-60 years). The efficacy of the treatment and potential extended effects on follow-up prevalence will be determined 14-21 days, 6 months and 12 months post-treatment by collecting another two stool samples. The cure rate will be calculated as the percentage of egg-positive subjects at baseline who become egg-negative after 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 albendazole and ivermectin versus albendazole monotherapy (standard of care) against T. trichiura infections in children and adults (6-60 years) in different transmission settings and geographies. Embedded in this trial a smaller dose-finding (DF) study with the goal to investigate efficacy, safety and pharmacokinetic parameters of ascending doses of ivermectin ((i) 200 µg/kg, (ii) 400 µg/kg, and (iii) 600 µg/kg) co-administered with albendazole (400 mg) in school-aged children infected with T. trichiura will take place. The primary objective of the trial is to comparatively assess the efficacy in terms of cure rate against T. trichiura infections among school-aged children and adults from three different epidemiological settings and monitored over a 12-month period of albendazole/ivermectin combination therapy and albendazole monotherapy. A DF study will be implemented in the trial with the objective to understand the dose-dependent efficacy and pharmacokinetic profile of the co-administration of albendazole and ivermectin in school-aged children (6-12 years) with the following four oral treatment regimens: i) albendazole (400 mg) /ivermectin (200 µg/kg) combination, ii) albendazole (400 mg) /ivermectin (400 µg/kg) combination, iii) albendazole (400 mg) /ivermectin (600 µg/kg) combination, and iv) placebo. The secondary objectives of the trial are to evaluate the safety and tolerability of the treatment regimens, compare the ERRs of the treatment regimens (combination vs. monotherapy and ascending doses of the combination) against T. trichiura, determine the CRs and ERRs of the drugs in study participants (6-60 years) infected with hookworm, A lumbricoides and S stercoralis, investigate potential extended effects on follow-up helminth prevalences (6 and 12 months post-treatment) of the two standard-dose treatment regimens (as assessed among participants with cleared infection on days 21 and 180), compare CRs based on infection status determined by novel polymerase chain reaction (PCR)-based and standard microscopic diagnosis, assess potential differences in susceptibility to the treatment regimen between the three hookworm species, Necator americanus, Ancylostoma duodenale and A. ceylanicum, as classified through the novel PCR-based diagnosis, characterize T. trichiura strains from different epidemiological settings through genotyping, evaluate potential benefits from deworming on morbidity (clinically evaluated and self-rated from questionnaire interviews) and nutritional indicators, and determine an exposure (including length of time that the drug concentration is above the minimal inhibitory concentration (MIC), Cmax, area under the curve (AUC))-response correlation of ivermectin and albendazole in school-aged children. After obtaining informed consent from individual/parents and/or caregiver, 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 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 two treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 3 and 24 hours and 3 weeks after treatment about the occurrence of adverse events. Children aged 6-16 years will additionally be asked to rate their own physical functioning by replying to a pre-tested questionnaire at baseline and 6 and 12 months after treatment. The efficacy of the treatment and potential extended effects on follow-up prevalence will be determined 14-21 days, 6 months and 12 months post-treatment by collecting another two stool samples. Subjective treatment satisfaction will be assessed 3 hours, 3 weeks and 6 months after treatment to investigate relationship with treatment compliance and observed efficacy in reducing egg output and morbidity. 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 and between diagnostic approaches) will be analysed by 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 Ivermectin and Albendazole Co-administration in School-aged Children and Adults Infected With Trichuris Trichiura: a Multi-country Randomized Controlled Trial

Conditions
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Trichuriasis

Intervention / Treatment
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* Drug: Albendazole
* Drug: Albendazole and Ivermectin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed by either the participant him/herself (≥21 years of age) or by parents and/or caregivers for children/adolescents; and written assent by child/adolescent (aged 6-20 years). Agree to comply with study procedures, including provision of two stool samples at the beginning (baseline) and on three follow-up assessments (approximately 3 weeks, 6 months, and 12 months later). Aged ≥6 to <= 60 years for parallel group trial and ≥6 to <=12 years for DF study. At least two slides of the quadruple Kato-Katz thick smears positive for T. trichiura and infection intensities of at least 100 EPG. Exclusion Criteria: No written informed consent by individual/parents and/or caregiver. Presence of major systemic illnesses, e.g. severe anemia (below 80 g/l Hb according to WHO [28]), clinical malaria as assessed by a medical doctor (positive Plasmodium RDT and ≥38 °C ear temperature), upon initial clinical assessment. History of acute or severe chronic disease (e.g. cancer, diabetes, chronic heart, liver or renal disease). Recent use of anthelmintic drug (within past 4 weeks). Attending other clinical trials during the study. Negative or low egg count (less than 100 EPG or less than 2 out of 4 slides positive) diagnostic result for T. trichiura eggs in the stool. Known allergy to study medications (i.e. albendazole and ivermectin). Pregnancy or lactating in the 1st week after birth (according to WHO guidelines within LF control programs [29]). Currently taking medication with known interaction (e.g. for albendazole: cimetidine, praziquantel and dexamethasone; for ivermectin: warfarin).

Ages Eligible for Study
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Minimum Age: 6 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 |
| --- | --- |
| Placebo Comparator: Arm A: albendazole<br>400 mg albendazole single tablet (Zentel®) and 200µg/kg using 3mg tablets of placebo at day 0 administered orally | Drug: Albendazole<br>* Monotherapy of albendazole (400 mg)<br>* Other names: Zentel®;|
| Experimental: Arm B: albendazole and ivermectin<br>400 mg albendazole single tablet (Zentel®) and 200µg/kg using 3mg tablets of ivermectin (Stromectol®) at day 0 administered orally | Drug: Albendazole and Ivermectin<br>* Combination therapy of albendazole (400 mg) and ivermectin (200 µg/kg)<br>* Other names: Zentel® and Stromectol®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate against T. trichiura | The conversion from being egg positive pre-treatment to egg negative post-treatment, or cure rate (CR). | 14-21 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate against T. trichiura | CRs will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. | 6 and 12 months after treatment | 
| 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, 6 months and 12 months after treatment | 
| Cure rates (CRs) against concomitant soil-transmitted helminth infections. | CRs will be calculated for Ascaris lumbricoides, hookworm and Strongyloides stercoralis infections as described in primary outcome. | 14-21 days, 6 months and 12 months after treatment | 
| Egg-reduction rates (ERRs) against concomitant soil-transmitted helminth infections. | ERRs will be calculated for Ascaris lumbricoides, hookworm and Strongyloides stercoralis infections as described in outcome 3. | 14-21 days, 6 months and 12 months after treatment | 
| Adverse events | Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any abnormal finding, the local study physician will perform a full clinical, physical and biochemical examination and findings will be recorded. An emergency kit will be available on site to treat any medical conditions that warrant urgent medical intervention. In addition patients will also be interviewed 3 and 24 hours and again 3 weeks after treatment about the occurrence of AEs. | 3 hours, 24 hours and 14-21 days |