An adaptive phase II/III safety and efficacy randomized controlled trial of single day or three-day fixed-dose albendazole-ivermectin co-formulation versus albendazole for the treatment of Trichuris trichiura and other STH infections. ALIVE trial protocol

Abstract

Background: Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against Trichuris trichiura and a predictable low efficacy against Strongyloides stercoralis. Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH. Methods: An adaptive phase II/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126 T. trichiura-infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with T. trichiura, hookworm and S. stercoralis will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance. Conclusions: This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of providing an anthelmintic regimen with improved efficacy and spectrum of coverage against STH. ClinicalTrials.gov registration: NCT05124691 (18/11/2021).

Feasibility and safety of integrating mass drug administration for helminth control with seasonal malaria chemoprevention among Senegalese children: a randomized controlled, observer-blind trial

“…A similar effort is currently underway to develop and evaluate a combination of effective drug treatments against all ve species of STH. [37] Conclusion…”

Feasibility and safety of integrating mass drug administration for helminth control with seasonal malaria chemoprevention among Senegalese children: a randomized controlled, observer-blind trial

“…The incidental findings of a high prevalence of intestinal protozoans in a community where STH and schistosomiasis have been nearly eliminated calls for a strong consideration of an addition of appropriate medications to address the silent burden of intestinal protozoans in the study population. A similar effort is currently underway to develop and evaluate a combination of effective drug treatments against all five species of STH [ 37 ].…”

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers

“…The trial was conducted with the objective of characterizing the pharmacokinetic profile of this new formulation and to compare with the corresponding references already marketed, in accordance with the EMA guidelines on the clinical development of fixed-dose combination medicinal products ( European Medicines Agency, 2017 ), which requires the demonstration of similar pharmacokinetics (usually through demonstrating bioequivalence) of the fixed-dose combination medicinal product versus its individual active substances taken simultaneously. The subsequent clinical program has been recently published ( Krolewiecki et al, 2022 ) and will include a phase II trial to reveal the safety of the investigational product in children above 15 kg body weight. In case of a positive outcome, a sub-sequent phase III clinical trial to demonstrate the efficacy and safety will be carried out.…”