IMPROVE-IT2: Implementing non-invasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer - Intervention Trial 2: Statistical analysis plan

BackgroundSurveillance after curative intended surgery and adjuvant chemotherapy for localized colorectal cancer (CRC) aim at detecting recurrence sufficiently early to allow efficient treatment. Minimally invasive blood-based analysis of circulating tumor DNA (ctDNA) has the potential to identify patients with microscopic residual disease early after surgery and adjuvant chemotherapy for CRC, with a median lead time of 9 months compared to standard-of-care CT-based surveillance. The IMPROVE-IT2 study is a randomized controlled trial investigating the effect of ctDNA-guided surveillance compared to standard-of-care CT-based surveillance in high-risk stage II and stage III CRC patients after curative intended surgery and adjuvant chemotherapy. The primary trial endpoint is the fraction of recurrence patients receiving curative intended surgery or local metastasis directed treatment within 3 years after primary surgery for CRC. Secondary endpoints include time-to-clinical-recurrence, overall survival, quality-of-life, and quality-adjusted life-years cost-effectiveness. ObjectiveTo outline a pre-determined statistical analysis plan (SAP) before patients have completed the first year of follow-up after primary surgery. MethodsThe SAP describes the IMPROVE-IT2 study design and endpoints, the randomization procedure, sample size estimation, and the specific statistical procedures and methods for analyzing efficacy outcomes. Health economics and quality of life analyses are not included in this SAP but will be analyzed separately. The SAP outlines the planned primary analyses, subgroup analyses, and a range of specific sensitivity analyses. To avoid bias, the final analyses of the IMPROVE-IT2 trial will adhere to the SAP. The SAP was approved after end of recruitment and before completion of the first 12 months of follow-up after primary surgery. Trial RegistrationClinicaltrials.gov NCT04084249, registered in April 2019.