Efficacy and Safety of MOX/ALB Co-administration
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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 Design
Arms and Interventions
| 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:
|
| 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:
|
| 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:
Drug: Ivermectin 3 mg Oral Tablet
Tablets of 3 mg ivermectin
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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.
Secondary Outcome Measures
- 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) and egg reduction rate (ERR) of ivermectin/albendazole combination therapy compared to albendazole monotherapy against T. trichiura [14-21 days after treatment]
CR and ERR will be calculated as described in primary outcome measure and secondary outcome measure 1, respectively.
- Cure rates (CRs) and egg reduction rates (ERRs) of the study drugs against Ascaris lumbricoides and hookworm infections in co-infected participants [14-21 days after treatment]
CRs and ERRs will be calculated as described in primary outcome measure and secondary outcome measure 1, respectively.
- 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.
- 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.
- 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.
- Genetic variants in ivermectin/albendazole participants [before treatment, i.e. at enrolment]
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.
Other Outcome Measures
- 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.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Centre Suisse de Recherches Scientifiques en Côte d'Ivoire (CSRS) | Abidjan | Côte D'Ivoire |
Sponsors and Collaborators
- Jennifer Keiser
- Centre Suisse de Recherches Scientifiques en Cote d'Ivoire
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MAC_CI_1