Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial

Abstract

BackgroundSystemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.MethodsSTAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.Results(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.ConclusionsThe STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.Trial registrationISRCTN78818544, NCT00268476First patient into trial: 17 October 2005First patient into abiraterone comparison: 15 November 2011

Adaptive designs undertaken in clinical research: a review of registered clinical trials

“…The trial is predominantly funded by the UK public sector. Sydes et al [26, 27] describe the rationale and design aspects of the trial. James et al [28] present the first interim results with decisions to discontinue certain intervention arms.NCT01545232The PROPPR study is a GSD with SSR, funded by the public sector in the USA, investigating the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio.…”

The STAMPEDE trial: paradigm-changing data through innovative trial design

“…A key feature of the MAMS format is the proper choice of an intermediate assessment endpoint. No effect on an intermediate outcome measure (null hypothesis being true) makes it likely that there would be no effect on the primary outcome measure (8–10). …”

Evaluating Competing and Emerging Technologies for Stereotactic Body Radiotherapy and Other Advanced Radiotherapy Techniques

“…Arms can be discontinued if recruitment numbers have been reached, or if a preliminary analysis shows poor outcome. This design has been used in the STAMPEDE prostate cancer trial, and merits consideration in other sites [58]. This underlines the value of considering alternative trial methods to provide more sophisticated methods for evaluation of the complex interventions that we use [49].…”