Periodic Reporting for period 1 - eWHORM (Enabling the WHO-Roadmap 2030)
Reporting period: 2023-04-01 to 2024-09-30
Approximately 1.5 billion people globally are affected by worm infections. In this project we aim to develop a new treatment for four different tropical worm (helminth) diseases, namely 1) onchocerciasis (river blindness) 2) loiasis (African eye worm), 3) mansonellosis (with ~114 million people infected the most prevalent filarial (thread-worm) infection), and 4) soil-transmitted helminths (STH), especially trichuriasis. These diseases can cause severe morbidity, but the drugs currently used for mass drug administration (MDA) do not kill the helminths efficiently. Despite this urgent need and due to the lack of a clinical candidate pipeline, we opted to implement an adaptive clinical basket trial to provide the proof of concept for oxfendazole (OXF) for the four diseases and support the future registration of OXF. We will perform a mid-term interim analysis and adapt the recruitment of participants to effective treatment arms to reduce the total number of trial participants and required costs. To harmonize the methods used in this trial among our four African partner sites in the Democratic Republic of the Congo (DRC), Gabon, Cameroon, and Tanzania and the four helminth diseases, we will establish a master protocol, use a joint electronic case report form (eCRF) and data management platform. In addition, we aim to build capacity for adaptive clinical trial conduct and improve the diagnostic capability for parasite infections, as laboratory services are integral for surveillance, control and elimination of infectious diseases. We aim to improve the diagnostic capacity by establishing sensitive molecular assays at the four African partner sites. Furthermore, we will establish a virtual training and assessment tool to identify parasitic infections at the African partner sites. Finally, we will train scientists at all stages in clinical trial conduct, data management and communication.
Within the first 18 months of the eWHORM project, we completed the master protocol and simulations were preformed to evaluate the trial design and sample size for the four diseases. For the three filarial diseases an adaptive design with dose selection in the interim analysis was selected, for trichuriasis a fixed design. The protocol was favorably reviewed by the European Medicines Agency and the proposed interim analyses and adaptation strategy was confirmed to prioritize efficacy and safety in the development of OXF. A harmonized data management plan for the clinical trial and an eCRF was prepared. The protocol submissions to the ethics committees and regulatory authorities are currently prepared. The investigational medicinal product (OXF) as well as placebo tablets were prepared by Syngene, India. To boost diagnostic expertise, a workshop was held by our partners from the University of Buea in Cameroon to train partners from Gabon, the DRC and Swiss TPH (for the Tanzania partner site) in highly sensitive LAMP assays to diagnose onchocerciasis, loiasis and mansonellosis. To further assess and improve the microscopic diagnostic expertise of laboratory staff at the African partner sites, a virtual training tool is currently being established for diagnosis of parasites in blood and stool. A proof of concept has been delivered, and first tutorials have been developed in English. A series of videos to Gender Equality were made available to raise awareness and offer solutions to tackle disadvantages for women in science. In addition a mentorship as well as MSc and PhD program was established to support and train early-career scientists. To specifically strengthen clinical trial expertise, a clinical trial workshop is prepared that encompasses one week of virtual training and one week of face-to-face training at the partner site in Gabon. Besides partners from the different African and European sites, partners from other international projects in NTDs will join.
Global efforts to eliminate helminth infections and to provide individual care for patients are hampered by the absence of effective medicines that kill the adult worms and field diagnostics. eWHORM’s candidate OXF is a veterinary drug with excellent efficacy against helminth infections in companion animals and rodent models of filariasis. Repurposing of OXF is expected to reduce development costs, timelines and risk of failure and has the potential to treat multiple helminth diseases. OXF was shown to have a good human safety profile and a field applicable tablet has been developed and validated. Importantly, OXF is selective for the adult stage, which should prevent drug-induced severe adverse events in onchocerciasis and loiasis patients. Thus, if proven effective, OXF will be a major step for a better treatment of filariasis and STH patients and boost elimination efforts. Within eWHORM we will use an adaptive basket trial for the first time in NTDs, which allows the simultaneous evaluation of OXF regimens on multiple diseases, including co-infected patients. Thus, we expect to reduce the number of trials and costs, accelerate drug development and registration for human use. In addition, our harmonized protocol and multi-country approach will allow the analysis of country-specific drug differences. As elimination efforts further require trained staff and sensitive diagnostic tests to map the infection areas and to identify infected individuals, we implement sensitive, field applicable LAMP assays to diagnose filarial infections and a virtual training tool to diagnose parasitic infections at our clinical research sites in Africa. Additional workshops and trainings, e.g. on clinical trial conduct, are scheduled to sustainably build capacity. Our proposed activities will be placed within the landscape of national programmes, NGOs, academic institutions and existing global health and funding networks to maximize the output of global investment.