Statistical analysis plan
DISEASE, EVENT, RECRUITMENT
For stage I, the primary analysis will consist of a Cox proportional hazards model, where time will be time to progression or censoring, and the main covariate will be binary treatment, defined as standard-of-care (Arm A – standard frequency) or extended frequency (Arm B) ICI. The model will also adjust for the stratification variables. Each cohort will be analysed separately, using a 5% one-sided significance level. All patients will be included and analysed by their schedule allocation (intention to treat – ITT). The hazard ratio for Arm B vs Arm A will then be estimated and will inform the design of stage II, following discussion with relevant oversight committees (Trial Management Group (TMG), Independent Data Monitoring Committee (IDMC) and Trial Steering Committee (TSC)). Strict statistical rules will not be in place, but decisions will be based on the following guidelines:If the stage I analysis shows that the extended interval arm (2×) is significantly inferior to the standard interval arm (1×), i.e. the confidence interval (CI) for the hazard ratio lies entirely above 1, recruitment will not be continued in the 2× arm, and no arms with further extended intervals (2.5× or 3×) will be opened. The trial committees will discuss whether there is any scientific merit in opening the intermediate interval (1.5×) arm (If the extended frequency arm is not shown to be significantly inferior, an assessment of non-inferiority will be made. If non-inferiority is shown, (CI for the hazard ratio excludes the non-inferiority margin), then stage II can proceed as planned, opening up arms with further extended intervals (2.5× and 3×). The trial committees will further discuss whether there is merit in adding the intermediate interval (1.5×) arm at this stage.In the event that the stage I results show neither inferiority or noninferiority of the extended frequency arm, (CI for the hazard ratio includes both 1 and the non-inferiority margin), the trial committees will determine which arms will be available in stage II. Safety and quality of life data will be considered alongside the efficacy data, as well as any emerging external evidence, including information from other REFINE cohorts.Decisions will be made independently for each cohort; not all cohorts may continue to stage II, and different arms may be introduced in each cohort.Analysis of PFS in stage II will be performed as described for stage I, fitting a Cox model for PFS and estimating hazard ratios comparing extended frequency arms to the standard frequency arm. A 5% (one-sided) significance level will be used throughout. Analysis will begin by assessing the most extended frequency arm. If that arm demonstrates non-inferiority, no further arms will be compared, and all arms will be considered for the phase III expansion of REFINE. If non-inferiority is not demonstrated, the next most extended frequency arm is assessed in the same manner, and so on until either an arm demonstrates non-inferiority, or all arms have been assessed.If there is evidence of non-proportional hazards, or if other characteristics of the data suggest a likely gain in power, restricted mean survival (RMST) with a t-star of nine months will be used to analyse these data instead [For time to event analyses, patients without an observed event will be censored at the date of their last assessment. It is anticipated that the majority of censoring will be administrative censoring at the time of analysis, therefore the assumption of non-informative censoring should be valid. Patterns of censoring will be assessed and if necessary, for example if a high proportion of patients are lost to follow-up, sensitivity analyses may be performed to assess the robustness of results.Analysis of categorical variables will compare arms using the chi-squared or Mann-Whitney test, with analysis of continuous variables using a All estimates will be presented along with their 95% confidence interval. Additionally, to assess non-inferiority, PFS hazard ratios will also include a 90% confidence interval, corresponding to the 5% one-sided significance interval. All disease cohorts are designed to be independently powered and analysed.All analyses will be conducted using the intention-to-treat (ITT) population, including all randomised patients. The primary outcome measure of PFS will also be assessed using the per-protocol (PP) population, which will exclude any ineligible patients, and any patients who do not receive any treatment after randomisation.