Efficacy and Safety of Emodepside Compared to Albendazole in Adolescents and Adults Infected with Hookworm in Pemba Island, Tanzania: A Double-Blind, Superiority, Phase 2b, Randomised Controlled Trial

Background: Human hookworm is a cause of enormous global morbidity. Nutritional deficiencies, such as iron deficiency anaemia, may predicate a larger socioeconomic burden in endemic regions. Whilst control efforts mainly rely on the periodic distribution of anthelminthics, the treatment options are limited and their efficacy insufficient. Furthermore, their mass distribution to at- risk populations may result in drug resistance. Thus, novel treatments are urgently needed. Emodepside is a strong anthelmintic candidate repurposed from the veterinary field and is currently undergoing clinical development for onchocerciasis and soil-transmitted helminth infections. Methods: We conducted a double-blind, superiority, phase 2b, randomised control clinical trial comparing a single oral dose of 30 mg emodepside with 400 mg albendazole. The investigators, participants, laboratory technicians, and study physicians were blinded to the treatment assignment. Participants were recruited in seven endemic villages or secondary schools on Pemba Island, Tanzania. Duplicate Kato-Katz thick smear slides were prepared from each of two stool samples at screening. Participants aged 12 to 60 years were eligible for treatment if they were positive for hookworm infection and their eggs per gram totaled ≥ 48 from four Kato-Katz thick smears and at least two slides had more than one hookworm egg present. Participants’ treatment allocation was stratified by infection intensity and efficacy was measured by cure rates: hookworm-positive participants who became hookworm-negative after treatment. Adverse events were reported at three, 24, 48 hours, and 14 to 21 days post-treatment. The trial is registered at clinicaltrials.gov (# NCT05538767). Findings: Between 14 November 2022 and 21 March 2023, 293 participants were treated, 147 with albendazole and 146 with emodepside. Emodepside demonstrated superiority, with an observed cure rate against hookworm at 96.6%, and was significantly higher compared with albendazole (cure rate 81.2%, OR: 0.14, 95% CI: 0.04 to 0.35, P = 0.0001). The most common adverse event in the emodepside treatment arm was vision blur at 3-hours post-treatment, with reports from 39% (57/146) of participants. Other common adverse events were vision blur at 24-hours post-treatment, with reports from 38% (55/146) of participants, and headache and dizziness at 3-hours post-treatment, with reports from 38% (55/146) and 29% (43/146) participants respectively. In the emodepside treatment arm, 96% of adverse events were mild. The most commonly reported adverse event in the albendazole treatment arm was headache, with reports from 18% (27/147) of participants, followed by dizziness, with reports from 10% (14/147) of participants at 3-hours post-treatment. No serious adverse events were reported. Interpretation: This phase 2b clinical trial confirms the high efficacy of emodepside against hookworm infections, solidifying emodepside as a promising anthelmintic candidate. However, whilst the observed safety events were generally mild in severity, considerations must be made in tempering the strong efficacy outcomes with the increased frequency of adverse events compared with albendazole. Trial Registration: This trial has been registered with clinicaltrials.gov (# NCT05538767). Funding: This study was funded by the European Research Council, who had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Declaration of Interest: We have no competing interest to declare. Ethical Approval: This trial was managed in accordance to the Declaration of Helsinki, Version 2012 and the International Council of Harmonization Guideline E6(R2) Good Clinical Practice. Ethical approvals were obtained from the Zanzibar Health Research Ethical Committee (reference #: ZAHREC/04/AMEND/AUG/2022/07) and the Ethics Committee of Northern and Central Switzerland (EKNZ, reference # AO_2021_00028). Regulatory approval was received by Zanzibar Food and Drug Authority (reference #: A.41/89/01/31).