Statistical analyses
ICH
REGRESSION, SENSITIVITY, MYOCARDIAL FIBROSIS
The trial will be analysed and reported using the Consolidated Standard of Reporting Trials and the ICH E9 guidelines. A full and detailed statistical analysis plan has been developed, the main features of which are described briefly here. Data management and statistical analysis are performed independently by the clinical trials unit.Primary analysis will be by intention to treat, using complete case analysis, with a sensitivity regression analysis for the primary outcome (adjusting for variables which predict outcome to account for missingness).An additional sensitivity analysis will estimate causal effect of treatment on the primary outcome by appropriately allowing for dose received using instrumental variable regression, thus accounting for informative premature treatment discontinuation.Potential mediators of treatment on LVMi include myocardial fibrosis (extracellular mass), cellular mass, PCr:ATP ratio and copper excretion. In order to test whether these variables predict change in LVMi, mediation analysis will be carried out, adjusting for baseline covariates that predict both the mediator and LVMi. Sensitivity analyses will be conducted to assess the potential impact of unmeasured confounding between the mediator and outcome.