FocaL mass drug Administration for Plasmodium vivax Malaria Elimination (FLAME): study protocol for an open-label cluster randomized controlled trial in Peru

Background Outside of sub-Saharan Africa, Plasmodium vivax has become the dominant species of malaria. Focal mass drug administration (fMDA) is a potential strategy to support elimination efforts, but controlled studies are lacking. Methods The FocaL mass drug Administration for Plasmodium vivax Malaria Elimination (FLAME) study is a 3-year cluster randomized controlled trial to determine the impact and safety of fMDA to reduce P. vivax transmission. The study will be conducted in Loreto, Peru, where standard interventions have reduced P. vivax cases, but transmission persists due to a high proportion of subclinical infections. Thirty low transmission communities (API < 250 cases/1000 population) will be randomized 1:1 to fMDA versus control using a restricted randomization. All communities will receive Peruvian national standard malaria control measures. In the intervention arm, high-risk individuals (living within 200 meters of a P. vivax case reported in the prior two years) without contraindication to study medications, including G6PD deficiency, will receive three cycles of fMDA over a two-year period. Each cycle will include two rounds of directly observed therapy delivered 2 months apart. The fMDA regimen will include 25mg/kg chloroquine (CQ) plus a single 300mg dose of tafenoquine (TQ) for individuals age ≥16 years, and 25mg/kg of CQ plus 7 days of 0.5mg/kg/day of primaquine (PQ) if younger. The primary outcome is the cumulative incidence of symptomatic P. vivax malaria. The sample size provides 80% power to detect at least a 68% relative reduction in cumulative P. vivax incidence, based on alpha of 0.05 and a coefficient of variation ( k ) of 0.87. Secondary outcomes include safety, cost-effectiveness, and infection prevalence and seroprevalence which will be assessed in annual cross-sectional surveys. Safety will be assessed in passive and active pharmacovigilance, including post-treatment screening for G6PD-associated hemolysis by assessing for anemia and hematuria in a sample. Discussion The trial will generate evidence regarding fMDA for P. vivax and inform malaria elimination efforts in Peru and similarly endemic settings. Findings will be in peer-reviewed publications and through stakeholder meetings in Peruvian and international policy and research forums. Trial registration Clinicaltrials.gov NCT05690841. This trial was registered on 09 January 2023.