Efficacy and Safety of MOX/ALB vs. IVM/ALB Co-administration

Study Overview
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Brief Summary
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The aim of this randomized controlled trial is to provide evidence on the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole, and to assess the efficacy of the drug combinations compared to monotherapies in adolescents aged 12-19 years against infection with T. trichiura. The efficacy of the different treatments will be determined 14-21 days, 5-6 weeks and 3 months post-treatment. Two fecal samples will be collected at each time-point assessment. The geometric mean based egg reduction rate (ERR) of T. trichiura egg counts will be assessed by Kato-Katz microscopy pre-treatment and 14-21 days post-treatment. This trial will be conducted as a school-based study on Pemba Island (Zanzibar, Tanzania).

Detailed Description
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We designed a non-inferiority trial to show that co-administered moxidectin and albendazole is non-inferior compared to co-administered ivermectin and albendazole in adolescents aged 12-19 years on Pemba Island (Tanzania). From previous studies conducted by our group, we expect similar efficacies from the combination moxidectin/ albendazole compared to ivermectin/ albendazole. However, moxidectin might be advantageous in terms of the drug's longer half-life and in areas with possible emerging ivermectin resistance. This study will allow comparing the efficacy of the two available co-administrations and will provide further insights on the potential value of moxidectin/ albendazole. Our data will pave the way for possible large scale, multi country follow-up studies. As recommended for new combination therapies, we simultaneously assess superiority of the drug combinations compared to monotherapies. The primary objective is to demonstrate that co-administered moxidectin (8 mg) / albendazole (400 mg) is non-inferior to ivermectin (200 µg/kg) / albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment in adolescents aged 12-19 years using a non-inferiority margin of 2 percentage-points. The secondary objectives of the trial are: Efficacy assessments of combination therapies require demonstration of superiority against the respective monotherapies. Therefore, the trial has five different treatment groups: moxidectin (8 mg) / albendazole (400 mg) combination, ivermectin (200 µg/kg) / albendazole (400 mg) combination, albendazole (400 mg) monotherapy, ivermectin (200 µg/kg) monotherapy and moxidectin (8 mg) monotherapy. to determine the CRs of the drug regimens against T. trichiura to evaluate the safety and tolerability of the treatment to determine the CRs and ERRs of the treatment schemes in study participants infected with hookworm and A. lumbricoides to investigate potential extended effects on follow-up helminth prevalences (5-6 weeks and 3 months post-treatment) of the treatment regimens to assess diagnostic performance and compare CRs based on egg counts retrieved from novel diagnostic tools (FECPAK-G2 and/or PCR) compared to standard microscopy to characterize population PK parameters, as well as drug-drug interactions of active study treatments following single and co-administration in T. trichiura infected adolescents. If a dose-response is observed, a PK/PD analysis will further be performed The study will be carried out in adolescents aged 12-19 years attending secondary schools on Pemba Island, Tanzania. After consenting, all participants will be asked to provide two stool samples (within a maximum of 7 days) at each time-point assesment. From each stool specimen, duplicate Kato-Katz thick smears (41.7 mg each) will be prepared and read under a microscope for eggs of T. trichiura, A. lumbricoides and hookworm by experienced technicians. After randomization, all eligible adolescents will be treated with the respective single or combination treatment regimen according to their assigned treatment arm at day 0. All drugs will be administered in the presence of the PI and/ co-PI, and ingestion confirmed. This will be recorded with the time and date of dosing. Participants will be kept for 3 hours after treatment administration to observe any possible acute AEs and reassessment will be done at 24h post-treatment. Additionally, interviews will be conducted to determine the emergence of clinical symptoms such as headache, abdominal pain, itching, nausea, vomiting and diarrhea directly before treatment within the scope of baseline assessment. At 3 and 24 hours after treatment and retrospectively at days 14 - 21 as well as 5-6 weeks and 3 months post-treatment, participants will again be interviewed for the assessment of adverse events (AEs). Egg reduction rate calculated from the geometric means of co-administered moxidectin/ albendazole and ivermectin/ albendazole against T. trichiura assessed at 14-21 days post-treatment is the primary endpoint in our study.

Official Title
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Efficacy and Safety of Moxidectin and Albendazole Compared to Ivermectin and Albendazole Co-administration in Adolescents Infected With Trichuris Trichiura: a Randomized Controlled Trial

Conditions
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Trichuriasis, Ascariasis, Hookworm Infections, Helminthes; Infestation, Intestinal

Intervention / Treatment
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* Drug: moxidectin (8 mg) / albendazole (400 mg)
* Drug: ivermectin (200 µg/kg) / albendazole (400 mg)
* Drug: ALBENDAZOLE 400 Mg ORAL TABLET [ZENTEL]
* Drug: ivermectin (200 µg/kg)
* Drug: moxidectin (8 mg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 12 and 19 years. Written informed consent signed by either parents/caregivers for underage adolescents (aged 12-17 years) or by the participant him/herself (18-19 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 on three follow-up assessments (14-21 days, 5-6 weeks and 3 months 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: No written informed consent by individual or caregiver and/or no written assent by minors 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. History of acute or severe chronic disease. 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 6 months. Known allergy to study medications (i.e. albendazole, ivermectin or moxidectin). Taking medication with known interaction on study drugs.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 19 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 |
| --- | --- |
| Experimental: A: moxidectin (8 mg) / albendazole (400 mg)<br>Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0 | Drug: moxidectin (8 mg) / albendazole (400 mg)<br>* Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0<br>* Other names: Zentel®;|
| Active Comparator: B: ivermectin (200 µg/kg) / albendazole (400 mg)<br>Combination therapy of ivermectin (Stromectol®, 200 µg/kg using 3 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0 | Drug: ivermectin (200 µg/kg) / albendazole (400 mg)<br>* Combination therapy of ivermectin ((200 µg/kg), 3 mg tablet) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0<br>* Other names: Stromectol® / Zentel®;|
| Active Comparator: C: albendazole (400 mg)<br>Monotherapy of albendazole (400 mg) administered orally at day 0 Other names: Zentel® | Drug: ALBENDAZOLE 400 Mg ORAL TABLET [ZENTEL]<br>* Monotherapy of albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0<br>* Other names: Zentel®;|
| Active Comparator: D: ivermectin (200 µg/kg)<br>Monotherapy of ivermectin ( 200 µg/kg using 3 mg tablets) administered orally at day 0 Other names: Stromectol® | Drug: ivermectin (200 µg/kg)<br>* Monotherapy of ivermectin ((200 µg/kg), 3 mg tablet) administered orally at day 0<br>* Other names: Stromectol®;|
| Active Comparator: E: moxidectin (8 mg)<br>Monotherapy of moxidectin (8 mg using 2 mg tablets) administered orally at day 0 | Drug: moxidectin (8 mg)<br>* Monotherapy of moxidectin (8 mg, using 2 mg tablets) administered orally at day 0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Egg reduction rate against T. trichiura | Egg reduction rate calculated from the geometric means of co-administered moxidectin/ albendazole and ivermectin/ albendazole against T. trichiura assessed at 14-21 days post-treatment is the primary endpoint in our study. | 14-21 day post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Superiority in terms of cure rates (CRs) | Assessment of superiority in terms of CRs of the drug combinations compared to their corresponding monotherapies: Arm C: Albendazole (400 mg) Arm D: Ivermectin (200 μg/kg) and Arm E: Moxidectin (8 mg) | 14-21 day post-treatment | 
| CRs against T. trichiura | CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. | 14-21 day post-treatment | 
| Safety and tolerability | The observation time for AE starts when the treatment is initiated. Subjects will be kept for observation for at least 3 hours following treatment for any acute AE and. If there is any abnormal finding, the local study physician will perform a full clinical examination and findings will be recorded. An emergency kit will be available on site to treat any medical conditions that warrant urgent medical intervention. Participants will also be interviewed at 3h and 24h as well as retrospectively 14 -21 days, 5-6 weeks and 3 months after treatment about the occurrence of AEs. | treatment until 3 months post-treatment | 
| Cure rates and egg reduction rates against concomitant soil-transmitted helminth infections | CRs and ERR will be calculated for Ascaris lumbricoides and hookworm infections. CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. 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 | 
| Extended effects on follow-up helminth prevalence | CRs and ERR will be calculated for T. trichiura, A. lumbricoides and hookworm infections. | 5-6 weeks and 3 months post-treatment | 
| Diagnostic performance | Comparison of CRs based on egg counts retrieved from novel diagnostic tools (FECPAK-G2 and/or PCR) compared to standard microscopy (Kato-Katz method) | baseline and 14-21 days post-treatment | 
| Pharmacokinetics and drug-drug interactions | Characterization of population PK parameters, as well as drug-drug interactions of active study treatments following single and co-administration in T. trichiura infected adolescents. If a dose-response is observed, a PK/PD analysis will further be performed | between 0 and 72 hours | 

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