Clinical trial NCT04700423: Efficacy and Safety of MOX/ALB vs. IVM/ALB Co-administration
Official title: Efficacy and Safety of Moxidectin and Albendazole Compared to Ivermectin and Albendazole Co-administration in Adolescents Infected With Trichuris Trichiura: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Trichuriasis
Ascariasis
Hookworm Infections
Helminthes; Infestation, Intestinal
Keywords: T. trichiura
A. lumbricoides
Hookworm
Soil-transmitted Helminths
Albendazole
Ivermectin
Moxidectin
Intestinal parasites
Anthelmintics
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: Public Health Laboratory Ivo de Carneri
First posted: 2021-01-07
Enrollment: 536
Sex: ALL
Minimum age (years): 12
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. 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.
2. to determine the CRs of the drug regimens against T. trichiura
3. to evaluate the safety and tolerability of the treatment
4. to determine the CRs and ERRs of the treatment schemes in study participants infected with hookworm and A. lumbricoides
5. to investigate potential extended effects on follow-up helminth prevalences (5-6 weeks and 3 months post-treatment) of the treatment regimens
6. 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
7. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Egg Reduction Rate Against T. Trichiura
timeFrame: 14-21 day post-treatment
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 3 hours, 24 hours, 14-21 days, 5-6 weeks and 3 months post-treatment
measure: Superiority in Terms of Cure Rates (CRs)
timeFrame: 14-21 day post-treatment
measure: Cure Rates Against T. Trichiura
timeFrame: 14-21 day post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of T. Trichiura: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Cure Rate) on Follow-up of T. Trichiura: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of T. Trichiura: 3 Months
timeFrame: 3 months post-treatment
measure: Extended Effects (Cure Rates) on Follow-up of T. Trichiura: 3 Months
timeFrame: 3 months post-treatment
measure: Egg Reduction Rates Against Concomitant Soil-transmitted Helminth Infections: Hookworm
timeFrame: 14-21 days post-treatment
measure: Cure Rates Against Concomitant Soil-transmitted Helminth Infections: Hookworm
timeFrame: 14-21 days post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of Hookworm: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Cure Rate) on Follow-up of Hookworm: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of Hookworm: 3 Months
timeFrame: 3 months post-treatment
measure: Extended Effects (Cure Rate) on Follow-up of Hookworm: 3 Months
timeFrame: 3 months post-treatment
measure: Egg Reduction Rates Against Concomitant Soil-transmitted Helminth Infections: Ascaris Lumbricoides
timeFrame: 14-21 days post-treatment
measure: Cure Rates Against Concomitant Soil-transmitted Helminth Infections: Ascaris Lumbricoides
timeFrame: 14-21 days post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of A. Lumbricoides: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Cure Rate) on Follow-up of A. Lumbricoides: 5-6 Weeks
timeFrame: 5-6 weeks post-treatment
measure: Extended Effects (Egg Reduction Rate) on Follow-up of A. Lumbricoides: 3 Months
timeFrame: 3 months post-treatment
measure: Extended Effects (Cure Rate) on Follow-up of A. Lumbricoides: 3 Months
timeFrame: 3 months post-treatment
Other outcomes:
Locations:
city: Chake Chake
country: Tanzania
facility: Public Health Laboratory Ivo de Carneri
state: Pemba
Study officials:
References:
citation: Welsche S, Mrimi EC, Hattendorf J, Hurlimann E, Ali SM, Keiser J. Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Infect Dis. 2023 Mar;23(3):331-340. doi: 10.1016/S1473-3099(22)00589-8. Epub 2022 Oct 28.
citation: Welsche S, Mrimi EC, Keller L, Hurlimann E, Hofmann D, Hattendorf J, Ali SM, Keiser J. Efficacy and safety of moxidectin and albendazole compared to ivermectin and albendazole co-administration in adolescents infected with Trichuris trichiura: a randomized controlled trial protocol. Gates Open Res. 2021 Sep 27;5:106. doi: 10.12688/gatesopenres.13299.2. eCollection 2021.