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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04726969

Enrollment

255

Registered

2021-01-27

Start date

2021-06-15

Completion date

2021-09-09

Last updated

2024-01-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ascariasis, Hookworm Infections, Trichuriasis

Keywords

Albendazole, Moxidectin, Ivermectin, Anthelmintics, T. trichiura, A. lumbricoides, Hookworm, Whipworm, Soil-transmitted helminths

Brief summary

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.

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.

Interventions

DRUGMoxidectin 2 mg Oral Tablet

Tablets of 2 mg moxidectin

DRUGAlbendazole 400 mg Oral Tablet

Tablets of 400 mg albendazole

DRUGIvermectin 3 mg Oral Tablet

Tablets of 3 mg ivermectin

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

The parallel group trial co-administered moxidectin/albendazole versus albendazole alone will be double blinded (i.e. study participants and the trial team/researchers conducting the treatment and assessing the outcomes will be blinded) using tablets including appearance-matched placebos, while the ivermectin/albendazole arm will be open label due to the nature of ivermectin (i.e. requiring bodyweight-dependent doses).

Eligibility

Sex/Gender

ALL

Age

12 Years to 60 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Cure Rate (CR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	14-21 days after treatment	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.

Secondary

Measure	Time frame	Description
Egg Reduction Rate (ERR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	14-21 days 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.
Egg Reduction Rates (ERRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants	14-21 days 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 three treatment arms before and after treatment to assess the corresponding ERRs.
Cure Rates (CRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants	14-21 days after treatment	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.
Egg Reduction Rates (ERRs) of the Study Drugs Against Hookworm Infections in Co-infected Participants	14-21 days 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 three treatment arms before and after treatment to assess the corresponding ERRs.
Number of Participants Reporting Adverse Events (AEs)	3 hours, 24 hours and 14-21 days after treatment	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.
Egg Reduction Rate (ERR) of Moxidectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	14-21 days 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.
Cure Rate (CR) of Ivermectin/Albendazole Combination Therapy Compared to Albendazole Monotherapy Against T. Trichiura	14-21 days after treatment	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.
Cure Rates (CRs) of the Study Drugs Against Ascaris Lumbricoides Infections in Co-infected Participants	14-21 days after treatment	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.

Other

Measure	Time frame	Description
Gut Bacterial Communities in Stool Samples	before treatment, i.e. at screening, and 14-21 days after treatment	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.
Exploratory Outcome: Number of Participants Within Each Blood Type Category (A, B, AB and 0)	before treatment, i.e. at enrolment	Blood type of participants will be collected during clinical examination prior treatment using blood type determination cards.
Concentrations of Albendazole and Ivermectin/Albendazole Combination in Adolescents (Aged 12 to 20 Years)	0 to 24 hours after treatment	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.
Genetic Variants in Ivermectin/Albendazole Participants	before treatment, i.e. at enrolment	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.

Countries

Côte d’Ivoire

Participant flow

Participants by arm

Arm	Count
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 Moxidectin 2 mg Oral Tablet: Tablets of 2 mg moxidectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	85
Arm B: Albendazole Placebo (for moxidectin, 4 tablets) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	84
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 Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole Ivermectin 3 mg Oral Tablet: Tablets of 3 mg ivermectin	86
Total	255

Baseline characteristics

Characteristic	Arm B: Albendazole	Arm C: Ivermectin and Albendazole	Arm A: Moxidectin and Albendazole	Total
Age, Categorical <=18 years	39 Participants	33 Participants	38 Participants	110 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	45 Participants	53 Participants	47 Participants	145 Participants
Age, Continuous	26.7 years STANDARD_DEVIATION 14.5	29.9 years STANDARD_DEVIATION 15.4	30.1 years STANDARD_DEVIATION 16.1	28.9 years STANDARD_DEVIATION 15.4
Race and Ethnicity Not Collected	—	—	—	0 Participants
Region of Enrollment Côte D'Ivoire	84 Participants	86 Participants	85 Participants	255 Participants
Sex: Female, Male Female	44 Participants	49 Participants	44 Participants	137 Participants
Sex: Female, Male Male	40 Participants	37 Participants	41 Participants	118 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 85	0 / 84	0 / 86
other Total, other adverse events	31 / 85	26 / 84	34 / 86
serious Total, serious adverse events	0 / 85	0 / 84	0 / 86

Outcome results

Primary

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.