Efficacy and Safety of MOX/ALB Co-administration

Efficacy and Safety of Combination Moxidectin and Albendazole, Ivermectin and Albendazole and Albendazole Alone in Adolescents and Adults Infected With Trichuris Trichiura: a Randomized Controlled Trial

This study is a double-blind randomized controlled superiority trial aiming at providing evidence on the efficacy and safety of co-administered moxidectin and albendazole versus albendazole monotherapy (standard of care) against whipworm (T. trichiura) infections in adolescents and adults (12-60 years) in Côte d'Ivoire. One arm of patients will be treated with albendazole-ivermectin.

As measure of efficacy of the treatment the cure rate (percentage of egg-positive subjects at baseline who become egg-negative after treatment) will be determined 14-21 days post-treatment.

Study Overview

• Status: Completed
• Conditions: Hookworm Infections; Ascariasis; Trichuriasis
• Intervention / Treatment: Drug: Moxidectin 2 mg Oral Tablet; Drug: Albendazole 400 mg Oral Tablet; Drug: Ivermectin 3 mg Oral Tablet

Detailed Description

This study is a double-blind randomized clinical trial which aims at providing evidence on the efficacy and safety of co-administered moxidectin and albendazole versus albendazole monotherapy (standard of care) against T. trichiura infections in adolescents and adults (12-60 years) in Côte d'Ivoire. Additionally, this study aims to substantiate evidence on the efficacy and safety of co-administered ivermectin and albendazole compared to albendazole monotherapy against T. trichiura in the same 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 adolescents and adults (aged 12 to 60 years) of moxidectin/albendazole combination therapy and albendazole monotherapy.

The secondary objectives of the trial are to compare the egg reduction rates (ERR) of these treatment regimens (moxidectin/albendazole combination therapy vs. albendazole monotherapy) against T. trichiura, to assess the CRs and ERRs in T. trichiura-infected participants given ivermectin/albendazole combination therapy compared to those given albendazole monotherapy, 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 and drug-drug interactions of the study drugs albendazole and ivermectin in T. trichiura infected adolescents (aged 12 to 20 years), to evaluate pharmacogenomics of ivermectin using whole genome sequencing, and to assess the effect of the gut microbiota on pharmacokinetics parameters and treatment outcome (CRs and ERRs), and drug-specific off-target effects of anthelmintic treatment on gut microbial communities in post-treatment samples.

After obtaining informed consent from individual/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 three treatment arms will be stratified according to intensity of infection. All participants will be interviewed before treatment, 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 subjects 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.

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 3

Contacts and Locations

Study Locations

• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Centre Suisse de Recherches Scientifiques en Côte d'Ivoire (CSRS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged between 12 and 60 years
• Written informed consent signed by either parents/caregivers for underage adolescents (aged 12-17 years) or by the participant him/herself (18-60 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 at follow-up assessment 14-21 days 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:

• 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
• Known or suspected infection with Loa loa
• History of acute or severe chronic disease
• Abnormal liver function assessed by multiple biochemical blood-based analyses
• 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 3 months
• Known allergy to study medications (i.e. albendazole, ivermectin or moxidectin)
• Taking medication with known contraindication to or interaction with study drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: moxidectin and albendazole; Combination therapy of moxidectin (8 mg, i.e. 4 tablets of 2 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0	Drug: Moxidectin 2 mg Oral Tablet; Tablets of 2 mg moxidectin; Drug: Albendazole 400 mg Oral Tablet; Tablets of 400 mg albendazole; Other Names: Zentel®
Placebo Comparator: Arm B: albendazole; Placebo (for moxidectin, 4 tablets) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0	Drug: Albendazole 400 mg Oral Tablet; Tablets of 400 mg albendazole; Other Names: Zentel®
Experimental: Arm C: ivermectin and albendazole; Combination therapy of ivermectin (Stromectol®, 200 µg/kg using tablets of 3 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0	Drug: Albendazole 400 mg Oral Tablet; Tablets of 400 mg albendazole; Other Names: Zentel®; Drug: Ivermectin 3 mg Oral Tablet; Tablets of 3 mg ivermectin; Other Names: Stromectol®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cure Rate (CR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100.	14-21 days after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Egg Reduction Rate (ERR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy 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 after treatment
Cure Rate (CR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100.	14-21 days after treatment
Egg Reduction Rate (ERR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy 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 after treatment
Cure Rates (CRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants	The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100.	14-21 days after treatment
Egg Reduction Rates (ERRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants	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 three treatment arms before and after treatment to assess the corresponding ERRs.	14-21 days after treatment
Cure Rates (CRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants	The CR will be calculated as the proportion of participants converting from being egg positive pre-treatment to egg negative post-treatment, multiplied by 100.	14-21 days after treatment
Egg Reduction Rates (ERRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants	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 three treatment arms before and after treatment to assess the corresponding ERRs.	14-21 days after treatment
Number of Participants Reporting Adverse Events (AEs)	Participants will be monitored at the site for 3 hours following treatment for any acute AEs and reassessment will be done at 24h post-treatment. In addition, participants will be interviewed 3 and 24 hours after treatment and retrospectively at days 14-21 about the occurrence of AEs.	3 hours, 24 hours and 14-21 days after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of Albendazole and Ivermectin/Albendazole Combination in Adolescents (Aged 12 to 20 Years)	For characterization of population pharmacokinetics (PK) and drug-drug interaction parameters ivermectin, albendazole and its metabolites will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a lower limit of quantification of 1-5 ng/ml.	0 to 24 hours after treatment
Genetic Variants in Ivermectin/Albendazole Participants	In case of unexpected results for outcome measure 10 (Concentrations of Albendazole and Ivermectin/Albendazole Combination in Adolescents (Aged 12 to 20 Years)), whole genome sequencing will be performed on blood samples from participants in the ivermectin/albendazole arm to analyse genetic variation of relevance for ivermectin metabolism.	before treatment, i.e. at enrolment
Gut Bacterial Communities in Stool Samples	Taxonomic relative abundances of gut bacterial communities will be analysed with high-throughput sequencing. Absolute abundances of specific taxa will be measured using taxon-specific qPCR. Changes in relative and absolute abundances will be measured before and after treatment.	before treatment, i.e. at screening, and 14-21 days after treatment
Exploratory Outcome: Number of Participants Within Each Blood Type Category (A, B, AB and 0)	Blood type of participants will be collected during clinical examination prior treatment using blood type determination cards.	before treatment, i.e. at enrolment

Collaborators and Investigators

• Sponsor: Jennifer Keiser
• Collaborators: Centre Suisse de Recherches Scientifiques en Cote d'Ivoire

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Actual): September 9, 2021
• Study Completion (Actual): September 9, 2021

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: January 25, 2021
• First Posted (Actual): January 27, 2021

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Hookworm; Ivermectin; Albendazole; Anthelmintics; T. trichiura; A. lumbricoides; Moxidectin; Whipworm; Soil-transmitted helminths
• Additional Relevant MeSH Terms: Infections; Parasitic Diseases; Secernentea Infections; Nematode Infections; Helminthiasis; Strongylida Infections; Enoplida Infections; Adenophorea Infections; Ascaridida Infections; Hookworm Infections; Ancylostomiasis; Trichuriasis; Ascariasis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiprotozoal Agents; Antiparasitic Agents; Antinematodal Agents; Anthelmintics; Antiplatyhelmintic Agents; Anticestodal Agents; Ivermectin; Moxidectin; Albendazole
• Other Study ID Numbers: MAC_CI_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes