Albendazole-ivermectin co-formulation for the treatment of Trichuris trichiura and other soil-transmitted helminths: a randomised phase 2/3 trial.

BACKGROUND

Treatments for soil-transmitted helminthiases face challenges, especially in addressing Trichuris trichiura. Combination regimens, particularly of ivermectin and albendazole, are promising. We aimed to assess the safety, efficacy, and palatability of a combination tablet for the treatment of T trichiura, hookworm, and Strongyloides stercoralis infections among school-aged children in Ethiopia, Kenya, and Mozambique.

METHODS

We conducted an adaptive phase 2/3, randomised, parallel-group, active-controlled, superiority trial in 15 schools in Ethiopia, Kenya, and Mozambique. Eligible participants for both phases were aged 5-18 years, weighed at least 15 kg, and were infected with T trichiura, hookworms, or S stercoralis. Participants were randomly assigned via a computer-generated sequence to either a single dose of a fixed-dose combination (FDC×1) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), three consecutive daily doses of an FDC (FDC×3) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), or a single dose of albendazole alone (400 mg) via block randomisation, stratified by soil-transmitted helminth species. Participants and those administering the treatments were not masked to treatment assignment, but those assessing the outcomes were masked. The primary outcome of phase 2 (conducted in Kenya only) was safety during the first 3 h after the intervention and for 7 days, and the primary outcome of phase 3 was efficacy (ie, the proportion of individuals cured at day 21 out of the total number infected at baseline) for T trichiura; both primary outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT05124691, and is terminated.

FINDINGS

Between Jan 20, 2022, and March 24, 2023, 1001 participants were recruited (465 [46%] were female and 536 [54%] were male). 636 (64%) were infected with T trichiura, 360 (36%) with hookworm, and 104 (10%) with S stercoralis; 94 (9%) of 1001 participants had co-infections and were included in the analysis of each infecting species. A total of 243 participants were allocated to the albendazole group, 381 to the FDC×1 group, and 377 to the FDC×3 group. In both phase 2 and 3, gastrointestinal symptoms were the most common mild-to-moderate adverse events in the FDC groups, but resolved within 48 h without intervention. At least one treatment-related adverse event occurred in 34 (14%) of 243 participants in the albendazole group, 75 (20%) of 381 participants in the FDC×1 group, and 88 (23%) of 377 participants in the FDC×3 group. No serious adverse events occurred. For T trichiura, both FDC groups had a higher cure rate (97·2% [95% CI 95·2- 99·3] for FDC×3 and 82·9% [78·2-87·5] for FDC×1) than albendazole (35·9% [27·7-44·1]), with absolute differences of 61·3% (98% CI 50·2-71·2) and 47·0% (34·7-58·1), respectively. For hookworms, FDC×3 had a higher cure rate (95·0% [95% CI 91·1-98·9]) than albendazole (65·1% [56·0-74·2]), with absolute differences of 29·9% (98% CI 17·2-42·4), whereas FDC×1 had a similar cure rate (79·8% [72·8-86·9]) to albendazole. The sample size for efficacy evaluation of S stercoralis was not met.

INTERPRETATION

An FDC of albendazole plus ivermectin has a similar safety profile but superior efficacy to albendazole alone against T trichiura infection and hookworms. These findings open opportunities for control of all soil-transmitted helminth species of interest, including potentially S stercoralis. Evaluation of safety in larger populations and implementation scenarios are the next steps for this innovation to promote its incorporation into programmatic activities.

FUNDING

European and Developing Countries Clinical Trials Partnership.

TRANSLATION

For the Portuguese translation of the abstract see Supplementary Materials section.