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

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

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.

Study Overview

• Status: Terminated
• Conditions: Helminthes; Infestation, Intestinal
• Intervention / Treatment: Drug: Albendazole; Combination product: Albendazole and Ivermectin fixed dose coformulation

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

• Study Type: Interventional
• Enrollment (Actual): 992
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Ethiopia
  • Bahir Dar, Ethiopia, P.O. Box 79
    • Bahir Dar University, Colleges of Medicine and Health Sciences (BDU-CMHS)
• Kenya
  • Nairobi, Kenya, 54840-00200
    • Kenya Medical Research Institute (KEMRI)
• Mozambique
  • Maputo
    • Manhiça, Maputo, Mozambique, 1929
      • Centro de Investigação em Saúde da Manhiça (CISM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Albendazole; Albendazole 400 mg single dose	Drug: Albendazole; Albendazole 400mg single dose
Experimental: FDCx1. Albendazole and Ivermectin Fixed Dose Coformulation; 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	Combination product: Albendazole and Ivermectin fixed dose coformulation; 400 mg Albendazole - 9 mg Ivermectin OR 400 mg Albendazole - 18 mg Ivermectin
Experimental: FDCx3. Albendazole and Ivermectin Fixed Dose Coformulation 3 days; 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.	Combination product: Albendazole and Ivermectin fixed dose coformulation; 400 mg Albendazole - 9 mg Ivermectin OR 400 mg Albendazole - 18 mg Ivermectin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cure rate for T. trichiura CR	Cure rate (CR) for T. trichiura 21 days after treatment, as determined by microscopy (efficacy T. trichiura)	21 days
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)	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	21
Egg reduction rate for T. trichiuris	Egg reduction rate (ERR) for T. trichiura 21 days after treatment, by microscopy.	21 days
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).	21 days
Parasite burden reduction by PCR	Parasite burden decrease after 21 days for hookworm, T. trichiura and S. stercoralis, by PCR.	21 days
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	21 days

Collaborators and Investigators

• Sponsor: Barcelona Institute for Global Health
• Collaborators: London School of Hygiene and Tropical Medicine; Leiden University Medical Center; European and Developing Countries Clinical Trials Partnership (EDCTP); Kenya Medical Research Institute; Centro de Investigação em Saúde de Manhiça; Universidad de León; Bahir Dar University; Laboratorios Liconsa
• Investigators: Principal Investigator: Jose Munoz, MD, PhD, Barcelona institue for Global health

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2022
• Primary Completion (Actual): March 21, 2023
• Study Completion (Actual): March 24, 2023

Study Registration Dates

• First Submitted: November 16, 2021
• First Submitted That Met QC Criteria: November 17, 2021
• First Posted (Actual): November 18, 2021

Study Record Updates

• Last Update Posted (Actual): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: adult; pediatric; ivermectin; soil-transmitted helminths; albendazole; coformulation
• Additional Relevant MeSH Terms: Infections; Parasitic Diseases; Helminthiasis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiprotozoal Agents; Antiparasitic Agents; Anthelmintics; Antiplatyhelmintic Agents; Anticestodal Agents; Ivermectin; Albendazole
• Other Study ID Numbers: ALIVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data from the ALIVE clinical trial (phase II and phase III) have been upload to the Infectious Diseases Data Observatory (IDDO). IDDO is a scientifically independent, multi-disciplinary coalition of the global infectious disease and emerging infections communities. Thus, data will be available upon request in a collaborative data repository for verification and re-use.
• IPD Sharing Time Frame: Data is already available upon request to IDDO
• IPD Sharing Access Criteria: All data sharing request received by IDDO will be addressed to the project consortium members who will approve/reject the data sharing based on the relevance of the proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

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