Statistical Analysis Plan for the Dig-RHD trial evaluating Digoxin in patients with rheumatic heart disease

This Statistical Analysis Plan (SAP) describes the planned analyses for the Dig-RHD trial, a multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of digoxin in adults with rheumatic heart disease (RHD) and heart failure or atrial fibrillation/flutter. The primary objective is to assess the effect of digoxin, compared with placebo, on the composite endpoint of all-cause mortality or new or worsening HF over a follow-up period of up to 36 months. Secondary endpoints include time to death due to any cause, time to HF-related death, time to first and recurrent hospitalizations for HF, time to new-onset or worsening HF, and changes in quality of life (EQ-5D-5L scores). Efficacy analyses will be conducted in the modified intention-to-treat (mITT) population, defined as all randomized participants who received at least one dose of study medication. Time-to-event outcomes will be analyzed using Cox proportional hazards models, with additional sensitivity analyses including restricted mean survival time and joint frailty models for recurrent events. Quality of life outcomes will be analyzed using mixed-effects models for repeated measures. All analyses will be performed using R statistical software. This SAP was finalized prior to database lock and unblinding, in accordance with ICH-E9 guidelines, to ensure transparency and methodological rigor.