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

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.

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

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.