Background <p>Diarrhoeal disease caused by multiple communicable and non-communicable factors, including pathogens transmitted mechanically by common filth flies, remains the third leading global cause of child mortality. In humanitarian crises, inadequate water, sanitation, and hygiene and poor waste management are highly conducive to filth fly breeding, for which there is a paucity of clinical trial evidence supporting vector control to interrupt diarrhoeal disease transmission.</p> Methods <p>This is a 3-period, 3-group, interventional non-randomized cross-over trial with parallel control. The unit of intervention will be an individual refugee camp. Each implementation phase will be 6 months, followed by a 1-month wash-out period. This trial, conducted in 4 refugee camps in Maban County, Upper Nile State, South Sudan, will evaluate the efficacy of insecticidal paint (Inesfly^® Carbapaint 10, containing 1.0% propoxur) or larvicide (Dimilin^® GR-2, containing 2% diflubenzuron) or both interventions combined, when applied to temporary pit latrines, on epidemiological and entomological outcomes. Both study interventions are intended to disrupt filth flies at different life cycle stages; the larvicide will impact larvae / pupae development, while the insecticidal paint will kill newly emerged adult flies and gravid flies attempting to oviposit. The primary trial outcome will be all-cause diarrhoeal case incidence in children ≤ 5 and individuals ≥ 15 years old, detected through active cohort monitoring. Secondary outcomes will be filth fly density and species composition, enteric pathogen species composition, density and antimicrobial resistance prevalence post-intervention.</p> Discussion <p>To our knowledge, this will be the first clinical trial of targeted filth fly vector control to mitigate diarrhoeal disease transmission in a humanitarian crisis. Robust, contemporary data are needed to guide policy on vector control for diarrhoeal disease prevention, providing an evidence base that links entomological reductions in filth fly population density to measurable decreases in disease incidence. Targeting simple, standard issue pit latrines for filth fly control will yield results that are not only applicable to emergency settings worldwide, but to other contexts where people reside in temporary shelters, including mobile populations and military deployments.</p> Trial registration <p>ClinicalTrials.gov, NCT07272122, registered on 9th December 2025. <a href="https://clinicaltrials.gov/study/NCT07272122">https://clinicaltrials.gov/study/NCT07272122</a>.</p>