Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Protocol non-adherence will be handled by performing the analyses according to the ITT principle, specifically, patients will be analyzed considering their allocation group regardless of the intervention they will follow. Moreover, deviation from the protocol will be registered as well as the reason for deviation. The missing rate is expected to be very low, therefore no specific analyses to handle missing data are planned. However, if needed (i.e., missing rate between 20 and 40%) multiple imputation through expectation–maximization algorithm will be applied and the results obtained from analysis of the new data will be considered as sensitivity analysis.