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27 Background: STAMPEDE ( NCT00268476 ) is a multi-centre, RCT using novel multi-arm, multi-stage (MAMS) methods. We describe the methodological and practical issues arising with early stopping of recruitment to some arms following an intermediate analysis and the issues in adding new research arms during the trial.The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research and 1 control arm assessed over 3 intermediate activity stages I-III [outcome measure: failure-free survival (FFS)] and a final efficacy stage IV [outcome measure: overall survival]. At the end of each stage, research arms are formally compared to the control arm. Accrual of further patients is discontinued early for research arms not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to the other arms; this interim hurdle is increasingly stringent at each stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm pts using the same intermediate guidelines in a time-delayed manner.(1) After the second intermediate activity analysis (Mar-2011), the IDMC recommended and the Trial Steering Committee ratified discontinuation of recruitment to two research arms for lack-of-sufficient activity. Nearly 100 recruiting centres in UK and Switzerland had to promptly implement changes. Detailed advanced preparation meant that activation was swift and recruitment continued seamlessly into Activity Stage III. (2) An application to add a new research arm, abiraterone, has been agreed by funders, industry partner and ethics committee; regulatory approval awaited. Details on methodological and practical issues and implementation of these changes will be presented.The STAMPEDE experiences shows that recruitment to MAMS trials is achievable and that mid-flow changes to trial design are practicable and encouraged.

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial