Preparation of a Phase I/II safety and efficacy trial for a cholera phage cocktail intervention

Project Summary The World Health Organization (WHO) estimates that approximately 1.3 billion people globally are at risk for cholera, a severe diarrheal disease caused by the bacterium Vibrio cholerae that is spread through contaminated water sources and substantial secondary person-to-person transmission. In 2022, the world saw a surge in the number of cholera cases and associated deaths. Over 29 countries reported outbreaks with the highest recorded global case fatality ratio of 1.9% (2.9% in Africa) in over a decade. Of note, 13 of these countries did not report cases in 2021 and had not seen cases between 3 and 30 years, severely disrupting the disease elimination goals of the WHO Global Taskforce for Cholera Control. Current prevention methods, such as the oral cholera vaccine (OCV) and water, sanitation, and hygiene (WASH) campaigns, require significant investment of resources and time for efficacy, but household contacts of cholera patients often present with cholera symptoms two to three days after the initial patient becomes sick. In addition, the preventive use of antibiotics is not recommended due to widespread resistance for cholera and other pathogens in the same environment. There is a pressing need to develop a targeted clinical intervention to prevent the community spread of cholera using a fast-acting prophylactic treatment. PhagePro aims to fill this gap with its product ProphaLytic-VcTM (PVC). PVC is an orally administered bacteriophage (phage) cocktail comprised of Vibriophages ICP1, ICP2, and ICP3. In this R34 clinical trial planning proposal, we aim to partner with cholera physicians and researchers at the International Centre for Diarrhoeal Diseases Research, Bangladesh (icddr,b) to plan for the first-in-human Phase I/II trial for PVC to demonstrate safety and efficacy in household contacts of cholera patients. Phase I will test once or twice daily oral doses of PVC, self-administered, for 7 days. Each arm will have 10 healthy adult volunteers. After safety has been assessed, Phase II will commence with household contacts of cholera patients with daily doses of either a placebo or PVC for 7 days. Each arm will have ~224 volunteers. We hypothesize there will be at least a 43% reduction in cholera incidence among household contacts. To successfully implement this trial, we will perform the following activities during the R34 grant. First, we will develop clinical trial documentation such as the Clinical Protocol, Manual of Procedures, Investigator's Brochure, site management documents, data management plans, and tracking/monitoring documents. In addition, we will recruit needed expertise such as biostatisticians, clinical operations associates, quality control/assurance specialists, and Clinical Research Organizations to support these activities. Second, we will develop a regulatory plan for administration of PVC in Bangladeshi volunteers, which involves submitting materials to the icddr,b Institutional Review Board, Ethics Review Committee, Bangladeshi Medical Research Council, and Directorate General of Drug Administration. To ensure timely success, PhagePro will be using project management strategies for successful completion of deliverables. At the successful conclusion of the R34 grant, we will have established all the necessary documentation and submitted the relevant materials to Bangladeshi regulatory authorities for successful approval of the Phase I/II clinical trial for PVC.