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

Primary Purpose

Trichuriasis, Ascariasis, Hookworm Infections

Status
Completed
Phase
Phase 2
Locations
Tanzania
Study Type
Interventional
Intervention
moxidectin (8 mg) / albendazole (400 mg)
ivermectin (200 µg/kg) / albendazole (400 mg)
ALBENDAZOLE 400 Mg ORAL TABLET [ZENTEL]
ivermectin (200 µg/kg)
moxidectin (8 mg)
Sponsored by
Jennifer Keiser
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Trichuriasis focused on measuring T. trichiura, A. lumbricoides, Hookworm, Soil-transmitted Helminths, Albendazole, Ivermectin, Moxidectin, Intestinal parasites, Anthelmintics

Eligibility Criteria

12 Years - 19 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Public Health Laboratory Ivo de Carneri

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

A: moxidectin (8 mg) / albendazole (400 mg)

B: ivermectin (200 µg/kg) / albendazole (400 mg)

C: albendazole (400 mg)

D: ivermectin (200 µg/kg)

E: moxidectin (8 mg)

Arm Description

Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0

Combination therapy of ivermectin (Stromectol®, 200 µg/kg using 3 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0

Monotherapy of albendazole (400 mg) administered orally at day 0 Other names: Zentel®

Monotherapy of ivermectin ( 200 µg/kg using 3 mg tablets) administered orally at day 0 Other names: Stromectol®

Monotherapy of moxidectin (8 mg using 2 mg tablets) administered orally at day 0

Outcomes

Primary Outcome Measures

Egg reduction rate against T. trichiura
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.

Secondary Outcome Measures

Superiority in terms of cure rates (CRs)
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)
CRs against T. trichiura
CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Safety and tolerability
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.
Cure rates and egg reduction rates against concomitant soil-transmitted helminth infections
CRs and ERR will be calculated for Ascaris lumbricoides and hookworm infections. CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative 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.
Extended effects on follow-up helminth prevalence
CRs and ERR will be calculated for T. trichiura, A. lumbricoides and hookworm infections.
Diagnostic performance
Comparison of CRs based on egg counts retrieved from novel diagnostic tools (FECPAK-G2 and/or PCR) compared to standard microscopy (Kato-Katz method)
Pharmacokinetics and drug-drug interactions
Characterization of 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

Full Information

First Posted
January 6, 2021
Last Updated
January 31, 2022
Sponsor
Jennifer Keiser
Collaborators
Public Health Laboratory Ivo de Carneri
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1. Study Identification

Unique Protocol Identification Number
NCT04700423
Brief Title
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

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Completed
Study Start Date
March 1, 2021 (Actual)
Primary Completion Date
August 18, 2021 (Actual)
Study Completion Date
September 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jennifer Keiser
Collaborators
Public Health Laboratory Ivo de Carneri

4. Oversight

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

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Trichuriasis, Ascariasis, Hookworm Infections, Helminthes; Infestation, Intestinal
Keywords
T. trichiura, A. lumbricoides, Hookworm, Soil-transmitted Helminths, Albendazole, Ivermectin, Moxidectin, Intestinal parasites, Anthelmintics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
Open Label with masked outcomes assessors
Allocation
Randomized
Enrollment
536 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A: moxidectin (8 mg) / albendazole (400 mg)
Arm Type
Experimental
Arm Description
Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
Arm Title
B: ivermectin (200 µg/kg) / albendazole (400 mg)
Arm Type
Active Comparator
Arm Description
Combination therapy of ivermectin (Stromectol®, 200 µg/kg using 3 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
Arm Title
C: albendazole (400 mg)
Arm Type
Active Comparator
Arm Description
Monotherapy of albendazole (400 mg) administered orally at day 0 Other names: Zentel®
Arm Title
D: ivermectin (200 µg/kg)
Arm Type
Active Comparator
Arm Description
Monotherapy of ivermectin ( 200 µg/kg using 3 mg tablets) administered orally at day 0 Other names: Stromectol®
Arm Title
E: moxidectin (8 mg)
Arm Type
Active Comparator
Arm Description
Monotherapy of moxidectin (8 mg using 2 mg tablets) administered orally at day 0
Intervention Type
Drug
Intervention Name(s)
moxidectin (8 mg) / albendazole (400 mg)
Other Intervention Name(s)
Zentel®
Intervention Description
Combination therapy of moxidectin (8 mg using 2 mg tablets) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
Intervention Type
Drug
Intervention Name(s)
ivermectin (200 µg/kg) / albendazole (400 mg)
Other Intervention Name(s)
Stromectol® / Zentel®
Intervention Description
Combination therapy of ivermectin ((200 µg/kg), 3 mg tablet) plus albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
Intervention Type
Drug
Intervention Name(s)
ALBENDAZOLE 400 Mg ORAL TABLET [ZENTEL]
Other Intervention Name(s)
Zentel®
Intervention Description
Monotherapy of albendazole (Zentel®, 400 mg, single tablet) administered orally at day 0
Intervention Type
Drug
Intervention Name(s)
ivermectin (200 µg/kg)
Other Intervention Name(s)
Stromectol®
Intervention Description
Monotherapy of ivermectin ((200 µg/kg), 3 mg tablet) administered orally at day 0
Intervention Type
Drug
Intervention Name(s)
moxidectin (8 mg)
Intervention Description
Monotherapy of moxidectin (8 mg, using 2 mg tablets) administered orally at day 0
Primary Outcome Measure Information:
Title
Egg reduction rate against T. trichiura
Description
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.
Time Frame
14-21 day post-treatment
Secondary Outcome Measure Information:
Title
Superiority in terms of cure rates (CRs)
Description
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)
Time Frame
14-21 day post-treatment
Title
CRs against T. trichiura
Description
CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment.
Time Frame
14-21 day post-treatment
Title
Safety and tolerability
Description
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.
Time Frame
treatment until 3 months post-treatment
Title
Cure rates and egg reduction rates against concomitant soil-transmitted helminth infections
Description
CRs and ERR will be calculated for Ascaris lumbricoides and hookworm infections. CRs of each treatment will be calculated as the percentage of egg-positive participants at baseline who become egg-negative 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.
Time Frame
14-21 days post-treatment
Title
Extended effects on follow-up helminth prevalence
Description
CRs and ERR will be calculated for T. trichiura, A. lumbricoides and hookworm infections.
Time Frame
5-6 weeks and 3 months post-treatment
Title
Diagnostic performance
Description
Comparison of CRs based on egg counts retrieved from novel diagnostic tools (FECPAK-G2 and/or PCR) compared to standard microscopy (Kato-Katz method)
Time Frame
baseline and 14-21 days post-treatment
Title
Pharmacokinetics and drug-drug interactions
Description
Characterization of 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
Time Frame
between 0 and 72 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
Public Health Laboratory Ivo de Carneri
City
Chake Chake
State/Province
Pemba
Country
Tanzania

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36354034
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.
Results Reference
derived
PubMed Identifier
34632308
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.
Results Reference
derived

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

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