Statistical considerations
deaths
EVENTS
The primary analysis for INTEGRATE IIa and IIb is a comparison of OS between the experimental and control arms using a log-rank test accounting for stratification factors. A HR for OS will be estimated from a stratified Cox proportional hazards model accounting for stratification factors. PFS will be analysed in a comparable fashion to OS. ORR will be compared using Cochran-Mantel–Haenszel test accounting for stratification factors or Fisher’s exact test if expected cell counts are low. Quality of life will be analysed using the approaches applied to the INTEGRATE trial [When the INTEGRATE platform protocol was proposed, the original sample size target for INTEGRATE II (regorafenib vs placebo) of • Pooled cohort [INTEGRATE + INTEGRATE IIa] (• INTEGRATE IIa cohort (• Asian region pooled cohort [INTEGRATE + INTEGRATE IIa] (• Asian region INTEGRATE IIa cohort (For INTEGRATE IIb, a sample of 450 participants will be randomised 2:1 (regorafenib and nivolumab: chemotherapy) and followed until 380 deaths occur to provide at least 90% power to detect a HR for OS of 0.70 with a 2-sided α of 0.05. The design also accommodates early stopping for benefit/harm at an interim analysis performed at 2/3 of the required events using the error spending approach of Lan-DeMets. A safety analysis will be undertaken when a minimum of 8 participants are enrolled from Japan, 16 from Asia and the remainder from USA, Europe and Australasia. The final analysis on OS will involve testing the following two null hypotheses: (1) no treatment effect on OS in the whole trial cohort (