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

Phase 2

Completed

Conditions: Hookworm Infections
Ascariasis
Trichuriasis
Helminthes; Infestation, Intestinal

Interventions: 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)

Registration Number: NCT04700423

Lead Sponsor: Jennifer Keiser

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 536

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A: moxidectin (8 mg) / albendazole (400 mg)	moxidectin (8 mg) / albendazole (400 mg)	Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
B: ivermectin (200 µg/kg) / albendazole (400 mg)	ivermectin (200 µg/kg) / albendazole (400 mg)	Combination therapy of ivermectin (Stromectol®, 200 µg/kg using 3 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
C: albendazole (400 mg)	ALBENDAZOLE 400 Mg ORAL TABLET [ZENTEL]	Monotherapy of albendazole (400 mg) administered orally at day 0 Other names: Zentel®
D: ivermectin (200 µg/kg)	ivermectin (200 µg/kg)	Monotherapy of ivermectin ( 200 µg/kg using 3 mg tablets) administered orally at day 0 Other names: Stromectol®
E: moxidectin (8 mg)	moxidectin (8 mg)	Monotherapy of moxidectin (8 mg using 2 mg tablets) administered orally at day 0

Primary Outcome Measures

Name	Time	Method
Egg Reduction Rate Against T. Trichiura	14-21 day post-treatment	Egg reduction rate is calculated as the relative reduction in the group geometric mean egg output after co-administration of moxidectin/ albendazole and ivermectin/ albendazole assessed at 14-21 days post-treatment compared to the baseline levels.

Secondary Outcome Measures

Name	Time	Method
Extended Effects (Cure Rate) on Follow-up of A. Lumbricoides: 5-6 Weeks	5-6 weeks post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Extended Effects (Egg Reduction Rate) on Follow-up of A. Lumbricoides: 3 Months	3 months post-treatment	Eggs per gram of stool 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.
Extended Effects (Cure Rate) on Follow-up of A. Lumbricoides: 3 Months	3 months post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Number of Participants With Adverse Events	3 hours, 24 hours, 14-21 days, 5-6 weeks and 3 months post-treatment	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.
Superiority in Terms of Cure Rates (CRs)	14-21 day post-treatment	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). Cure rates is defined as the percentages of participants treated with Moxidectin (8 mg)/Albendazole (400 mg), Ivermectin (200 μg/kg)/Albendazole (400 mg), Albendazole (400 mg), Ivermectin (200 μg/kg) or Moxidectin (8 mg) who were cured of infections with T. trichiura.
Cure Rates Against T. Trichiura	14-21 day post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Extended Effects (Egg Reduction Rate) on Follow-up of T. Trichiura: 5-6 Weeks	5-6 weeks post-treatment	Eggs per gram of stool 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.
Extended Effects (Cure Rate) on Follow-up of T. Trichiura: 5-6 Weeks	5-6 weeks post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Extended Effects (Egg Reduction Rate) on Follow-up of T. Trichiura: 3 Months	3 months post-treatment	Eggs per gram of stool 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.
Extended Effects (Cure Rates) on Follow-up of T. Trichiura: 3 Months	3 months post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Egg Reduction Rates Against Concomitant Soil-transmitted Helminth Infections: Hookworm	14-21 days post-treatment	Eggs per gram of stool 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.
Cure Rates Against Concomitant Soil-transmitted Helminth Infections: Hookworm	14-21 days post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Extended Effects (Egg Reduction Rate) on Follow-up of Hookworm: 5-6 Weeks	5-6 weeks post-treatment	Eggs per gram of stool 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.
Extended Effects (Cure Rate) on Follow-up of Hookworm: 5-6 Weeks	5-6 weeks post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Extended Effects (Egg Reduction Rate) on Follow-up of Hookworm: 3 Months	3 months post-treatment	Eggs per gram of stool 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.
Extended Effects (Cure Rate) on Follow-up of Hookworm: 3 Months	3 months post-treatment	Cure rates of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Egg Reduction Rates Against Concomitant Soil-transmitted Helminth Infections: Ascaris Lumbricoides	14-21 days post-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.
Cure Rates Against Concomitant Soil-transmitted Helminth Infections: Ascaris Lumbricoides	14-21 days post-treatment	Cure rates is defined as the percentages of participants treated with Moxidectin (8 mg)/Albendazole (400 mg), Ivermectin (200 μg/kg)/Albendazole (400 mg), Albendazole (400 mg), Ivermectin (200 μg/kg) or Moxidectin (8 mg) who were cured of infections with A. lumbricoides.
Extended Effects (Egg Reduction Rate) on Follow-up of A. Lumbricoides: 5-6 Weeks	5-6 weeks post-treatment	Eggs per gram of stool 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.