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Evaluation of Effectiveness of ALBENDAZOLIVERMECTIN Coformulation vs ALBENDAZOLE for Treatment of Intestinal Worms (ALIVE)

Primary Purpose

Helminthes; Infestation, Intestinal

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Albendazole and Ivermectin fixed dose coformulation
Albendazole
Sponsored by
Barcelona Institute for Global Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Helminthes; Infestation, Intestinal focused on measuring soil-transmitted helminths, pediatric, adult, albendazole, ivermectin, coformulation

Eligibility Criteria

5 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Positive infection test by microscopy for at least one of the following STH: T. trichiura, hookworms and/or larvae of S. stercoralis.
  • Weight ≥15 Kg.
  • Male or female, aged 5 to 18 years.
  • Female participants who are ≥12 years old (or female post menarche) must have a negative urine pregnancy test at screening or at the time of randomization.
  • Ability to take oral medication and willingness to comply with all study procedures.
  • Parental acceptance to participate in the study by obtaining a signed and dated informed consent form approved by the Regulatory authorities. In addition, verbal assent will be obtained from children aged 12-18 years.

Exclusion Criteria:

  • Intake of ALB, mebendazole and/or IVM, or any potentially interacting drug three months before screening.
  • Residence outside the study area or planning to move away in the four weeks following recruitment.
  • Epidemiological risk of infection by Loa loa.
  • Serious medical illness, per investigator's criteria.
  • Any participant's condition that would prevent the appropriate evaluation and followup, as per investigator's criteria.
  • Known hypersensitivity to any components of either of the study treatment.
  • Positive pregnancy urine test, pregnant or first week postpartum.

Sites / Locations

  • Bahir Dar University, Colleges of Medicine and Health Sciences (BDU-CMHS)
  • Kenya Medical Research Institute (KEMRI)
  • Centro de Investigação em Saúde da Manhiça (CISM)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

Albendazole

FDCx1. Albendazole and Ivermectin Fixed Dose Coformulation

FDCx3. Albendazole and Ivermectin Fixed Dose Coformulation 3 days

Arm Description

Albendazole 400 mg single dose

Single dose of a tablet of FDC 400mg18mg or 400mg9mg. (i) For participants <45 kg of body weight at baseline: FDC of 400mg ALB 9mg IVM. (ii) For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB18mg IVM

Daily dose of a tablet of FDC 400mg18mg or 400mg 9mg for 3 days. (i)For participants <45 kg of body weight at baseline: FDC of 400mg ALB9mg IVM. (ii) For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB 18mg IVM.

Outcomes

Primary Outcome Measures

cure rate for T. trichiura CR
Cure rate (CR) for T. trichiura 21 days after treatment, as determined by microscopy (efficacy T. trichiura)
Frequency, type and severity of Adverse events associated with Albendazole and Ivermectin coformulation
Frequency, type, severity and relationship to study drug for all adverse events and severe adverse events for ALB, FDC and FDCx3 (safety)

Secondary Outcome Measures

Cure rates for for hookworm and S. stercoralis
Cure rate for hookworm and S. stercoralis 21 days after treatment, as determined by microscopy (efficacy hookworm and S. stercoralis).
Egg reduction rate for T. trichiuris
Egg reduction rate (ERR) for T. trichiura 21 days after treatment, by microscopy.
cure rate for T. trichiura, hookworm and S. stercoralis by PCR
Cure rate for T. trichiura, hookworm and S. stercoralis, determined by Polmerase chain reaction (PCR).
Parasite burden reduction by PCR
Parasite burden decrease after 21 days for hookworm, T. trichiura and S. stercoralis, by PCR.
Evaluation of genotypic albendazole resistance T. trichiura and hookworm in the three arms.
Whole genome sequencing, DNA sequencing and genomic approaches will be used to evaluate markers of anthelmintic resistance including assessment and evaluation of new protocols for sample processing and sequencing

Full Information

First Posted
November 16, 2021
Last Updated
April 18, 2023
Sponsor
Barcelona Institute for Global Health
Collaborators
Leiden University Medical Center, Bahir Dar University, Centro de Investigacao em Saude de Manhica, London School of Hygiene and Tropical Medicine, Kenya Medical Research Institute, Laboratorios Liconsa, Universidad de León, European and Developing Countries Clinical Trials Partnership (EDCTP)
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1. Study Identification

Unique Protocol Identification Number
NCT05124691
Brief Title
Evaluation of Effectiveness of ALBENDAZOLIVERMECTIN Coformulation vs ALBENDAZOLE for Treatment of Intestinal Worms
Acronym
ALIVE
Official Title
An Adaptive Phase II/III SingleBlinded, Randomized, MultiCentre, ParallelGroup, Active Controlled, Superiority Study to Evaluate the Safety and Efficacy of a Single Day or 3day Single Dose of an ALBENDAZOLE IVERMECTIN Coformulation vs ALBENDAZOLE for the Treatment of SoilTransmitted Helminth Infections (Trichuris Trichiura, Hookworm, Strongyloides Stercoralis) in Paediatric and Young Adult Population
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Terminated
Why Stopped
Primary Endpoint met
Study Start Date
January 20, 2022 (Actual)
Primary Completion Date
March 21, 2023 (Actual)
Study Completion Date
March 24, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Barcelona Institute for Global Health
Collaborators
Leiden University Medical Center, Bahir Dar University, Centro de Investigacao em Saude de Manhica, London School of Hygiene and Tropical Medicine, Kenya Medical Research Institute, Laboratorios Liconsa, Universidad de León, European and Developing Countries Clinical Trials Partnership (EDCTP)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this clinical trial is to evaluate a fixed-dose co-formulation (FDC) of ivermectin and albendazole for the treatment of all Soil Transmitted helminths (STH). The current strategy to control STH in endemic areas is mass administration of albendazole or mebendazole, mainly to pre-school and school-aged children. Although this treatment works well for some STH species, efficacy against Trichuris trichiura is poor and it is not effective Strongyloides stercoralis. Thus new drugs or drug combinations are an urgent priority to increase the effectiveness of control programmes. Furthermore, the World Health Organisation has recommended combination therapy of ivermectin with albendazole. The trial proposed, is an adaptive phase II/III trial where the phase II component will evaluate the safety of the FDC as a single dose or 3-day single dose regimen for the treatment of T. trichiura in paediatric population. After analysis of the safety results the phase III trial will be executed to evaluate the efficacy of the FDC as a single dose or 3-day single dose regimen compared to the standard single dose regimen of ALB (400 mg) for the treatment of T. trichiura, hookworm and S. stercoralis in paediatric and young adult population. The estimated total sample size for the adaptive design (phase II and III component) is 1223 participants. Of these, 126 will be enrolled in the phase II and 1097 in the phase III components respectively in an adaptive trial design.
Detailed Description
An adaptive phase II/III clinical trial to evaluate the Safety and Efficacy of a Single Day or 3-day Single Dose of an ALBENDAZOLE-IVERMECTIN Coformulation vs ALBENDAZOLE for the Treatment of Soil-Transmitted Helminth Infections. The estimated total sample size for the adaptive design (phase II and III components) is 1223 participants. Of these, 126 will be enrolled in the phase II and 1097 in the phase III components. Phase II component (Kenya only) Unicentric, 3-arm, parallel, open-label, individually randomised, phase II trial to determine in three weight groups, the safety of the ALBENDAZOLEIVERMECTIN Co-formulation given as a Single Day or 3-day Single Dose regimen for the treatment of Trichuris trichiura in children and young adult aged between 5 to 18 years. Estimated sample size: 126 participants Participants will be stratified in three different weight groups in order to gradually increase the dose of ivermectin in the Fixed Dose Co-formulation (FDC): Group 1 (38 participants): with body weight of 23-<30 Kg will receive 300-391 µg/Kg IVM (FDC 400mg-9mg) or ALB Group 2 (38 participants): with body weight of 30-45 Kg will receive 400-600 µg/Kg IVM (FDC 400mg-18mg) or ALB. Group 3 (50 participants): with body weight of 15-23 Kg will receive 391-600 µg/Kg IVM (FDC 400mg-9mg) or ALB. Where FDC stands for Fixed Dose Co-formulation and ALB stands for Albendazole. Then, the participants will be allocated to one of the three study arms with unequal probability (ALB: p=0.2, n=26; FDCx1: p=0.4, n=50; FDCx3: p=0.4, n=50) starting with group 1. Treatment Arm 1: Single dose of a tablet of ALBENDAZOLE 400 mg (active control arm). Treatment Arm 2: Single dose of a tablet of ALBENDAZOLEIVERMECTIN Co-formulation. Treatment Arm 3: Daily dose of a tablet of ALBENDAZOLE-IVERMECTIN Co-formulation for 3 consecutive days. Phase III Component A multi-centre, 3-arm, parallel, open-label, randomised, phase III trial to compare safety and efficacy of the active control arm (current standard of care) against 2 experimental arms for the treatment of T. trichiura, hookworm and S. stercoralis, in children and young adult aged between 5-18 years in three subSaharan African countries (Ethiopia, Kenya and Mozambique) We hypothesise that the FDC of Ivermectin (IVM) and ALB either at single or 3- day regimens will be more effective against some species of Soil Transmitted Helminths (STH) (T. trichiura, hookworm and S. stercoralis) compared to the current use of a single dose regimen of 400mg ALB. Estimated sample size: 1097 participants Participants will be randomly allocated with unequal probability, according to the specific expected cure rate by treatment and specie, to one of the three study treatment arms. Treatment Arm 1: Single dose of a tablet of ALB 400 mg (active control arm). Treatment Arm 2: Single dose of a tablet of FDC 400mg-18mg or 400mg-9mg. For participants <45 kg of body weight at baseline: FDC of 400mg ALB- 9mg IVM. For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB-18mg IVM. Treatment Arm 3: Daily dose of a tablet of FDC 400mg-18mg or 400mg9mg for 3 days. For participants <45 kg of body weight at baseline: FDC of 400mg ALB-9mg IVM. For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB- 18mg IVM. In the phase III component, allocation of participants to study arms will be done by block randomization and stratified by the species of STH. Treatment allocation for each study participant will be concealed in opaque sealed envelope that will be opened only after enrolment. Study participants will be assigned a unique number linked to the allocated treatment group. The phase II and III trial components comprise of a screening phase, an enrolment phase, a treatment phase, a post-treatment phase with follow-up visits, and early withdrawal/end-of-study evaluations. Participants recruited in Mozambique will be offered to be tested for HIV serostatus due to the high HIV prevalence in the country, but the result will not determine the participant's eligibility. In Kenya and Ethiopia, the low HIV prevalence does not justify HIV testing

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Helminthes; Infestation, Intestinal
Keywords
soil-transmitted helminths, pediatric, adult, albendazole, ivermectin, coformulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
992 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Albendazole
Arm Type
Active Comparator
Arm Description
Albendazole 400 mg single dose
Arm Title
FDCx1. Albendazole and Ivermectin Fixed Dose Coformulation
Arm Type
Experimental
Arm Description
Single dose of a tablet of FDC 400mg18mg or 400mg9mg. (i) For participants <45 kg of body weight at baseline: FDC of 400mg ALB 9mg IVM. (ii) For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB18mg IVM
Arm Title
FDCx3. Albendazole and Ivermectin Fixed Dose Coformulation 3 days
Arm Type
Experimental
Arm Description
Daily dose of a tablet of FDC 400mg18mg or 400mg 9mg for 3 days. (i)For participants <45 kg of body weight at baseline: FDC of 400mg ALB9mg IVM. (ii) For participants ≥45 kg of body weight at baseline: FDC of 400mg ALB 18mg IVM.
Intervention Type
Combination Product
Intervention Name(s)
Albendazole and Ivermectin fixed dose coformulation
Intervention Description
400 mg Albendazole - 9 mg Ivermectin OR 400 mg Albendazole - 18 mg Ivermectin
Intervention Type
Drug
Intervention Name(s)
Albendazole
Intervention Description
Albendazole 400mg single dose
Primary Outcome Measure Information:
Title
cure rate for T. trichiura CR
Description
Cure rate (CR) for T. trichiura 21 days after treatment, as determined by microscopy (efficacy T. trichiura)
Time Frame
21 days
Title
Frequency, type and severity of Adverse events associated with Albendazole and Ivermectin coformulation
Description
Frequency, type, severity and relationship to study drug for all adverse events and severe adverse events for ALB, FDC and FDCx3 (safety)
Time Frame
21 days
Secondary Outcome Measure Information:
Title
Cure rates for for hookworm and S. stercoralis
Description
Cure rate for hookworm and S. stercoralis 21 days after treatment, as determined by microscopy (efficacy hookworm and S. stercoralis).
Time Frame
21
Title
Egg reduction rate for T. trichiuris
Description
Egg reduction rate (ERR) for T. trichiura 21 days after treatment, by microscopy.
Time Frame
21 days
Title
cure rate for T. trichiura, hookworm and S. stercoralis by PCR
Description
Cure rate for T. trichiura, hookworm and S. stercoralis, determined by Polmerase chain reaction (PCR).
Time Frame
21 days
Title
Parasite burden reduction by PCR
Description
Parasite burden decrease after 21 days for hookworm, T. trichiura and S. stercoralis, by PCR.
Time Frame
21 days
Title
Evaluation of genotypic albendazole resistance T. trichiura and hookworm in the three arms.
Description
Whole genome sequencing, DNA sequencing and genomic approaches will be used to evaluate markers of anthelmintic resistance including assessment and evaluation of new protocols for sample processing and sequencing
Time Frame
21 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Positive infection test by microscopy for at least one of the following STH: T. trichiura, hookworms and/or larvae of S. stercoralis. Weight ≥15 Kg. Male or female, aged 5 to 18 years. Female participants who are ≥12 years old (or female post menarche) must have a negative urine pregnancy test at screening or at the time of randomization. Ability to take oral medication and willingness to comply with all study procedures. Parental acceptance to participate in the study by obtaining a signed and dated informed consent form approved by the Regulatory authorities. In addition, verbal assent will be obtained from children aged 12-18 years. Exclusion Criteria: Intake of ALB, mebendazole and/or IVM, or any potentially interacting drug three months before screening. Residence outside the study area or planning to move away in the four weeks following recruitment. Epidemiological risk of infection by Loa loa. Serious medical illness, per investigator's criteria. Any participant's condition that would prevent the appropriate evaluation and followup, as per investigator's criteria. Known hypersensitivity to any components of either of the study treatment. Positive pregnancy urine test, pregnant or first week postpartum.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jose Munoz, MD, PhD
Organizational Affiliation
Barcelona institue for Global health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bahir Dar University, Colleges of Medicine and Health Sciences (BDU-CMHS)
City
Bahir Dar
ZIP/Postal Code
P.O. Box 79
Country
Ethiopia
Facility Name
Kenya Medical Research Institute (KEMRI)
City
Nairobi
ZIP/Postal Code
54840-00200
Country
Kenya
Facility Name
Centro de Investigação em Saúde da Manhiça (CISM)
City
Manhiça
State/Province
Maputo
ZIP/Postal Code
1929
Country
Mozambique

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Evaluation of Effectiveness of ALBENDAZOLIVERMECTIN Coformulation vs ALBENDAZOLE for Treatment of Intestinal Worms

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