EmpowerHer: Protocol for a Multicentre Randomized Controlled Trial Evaluating a Hybrid Digital Exercise and Education Intervention for Breast Cancer Survivors Across Five European Countries

METHODOLOGICAL DESIGN AND STANDARDIZATION This study is a multicentre, parallel-group, randomized controlled trial (RCT) with a 1:1 allocation ratio conducted across five European countries: Spain, Poland, Ireland, the Netherlands, and Greece. The protocol follows the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. To ensure consistency across all five clinical sites, all physical activity facilitators and researchers will undergo standardized training regarding the delivery of the hybrid program, data collection procedures, and participant safety monitoring prior to study initiation.

RANDOMIZATION AND BLINDING Following baseline assessments, eligible participants will be randomly assigned to either the hybrid digital-facilitator intervention group or the usual care control group. Randomization will be performed using a centralized web-based computerized system to ensure allocation concealment. Due to the nature of the exercise and lifestyle intervention, participants and exercise facilitators cannot be blinded to group assignment. However, outcome assessors responsible for performing the physical and functional tests, as well as the data analysts, will remain strictly blinded to the allocation groups throughout the study.

SAMPLE SIZE CALCULATION The total sample size was determined based on the primary outcome measure (health-related quality of life). To detect a statistically significant and clinically meaningful difference between the intervention and control groups, assuming a statistical power of 80% (1 - beta = 0.80) and a significance level of 5% (alpha = 0.05), a minimum sample size of 118 participants is required. Accounting for an anticipated dropout and attrition rate of approximately 20% over the 12-week intervention and the subsequent 3-month follow-up period, the final recruitment target was established at 147 participants (approximately 29 to 30 participants per country site).

STATISTICAL ANALYSIS PLAN Data will be analyzed using an intention-to-treat (ITT) approach, ensuring that all randomized participants are included in their originally assigned groups regardless of compliance or dropouts. Missing data will be handled using appropriate imputation techniques (e.g., multiple imputation). Descriptive statistics will characterize the sample's baseline demographics and clinical variables. To evaluate the effectiveness of the intervention over time (baseline, 12 weeks, and 3-month follow-up) and between groups, linear mixed-effects models will be utilized. These models will account for the multicentre nature of the trial by treating the study site as a random or fixed effect as appropriate. Statistical significance will be set a priori at p < 0.05.