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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

Matthew R Sydes1*, Mahesh KB Parmar1, Malcolm D Mason2, Noel W Clarke3, Claire Amos1, John Anderson4, Johann de Bono5, David P Dearnaley5, John Dwyer6, Charlene Green1, Gordana Jovic1, Alastair WS Ritchie1, J Martin Russell7, Karen Sanders1, George Thalmann8 and Nicholas D James9

Author Affiliations

1 MRC Clinical Trials Unit, London, UK

2 School of Medicine, Cardiff University, Cardiff, UK

3 The Christie and Salford Royal Hospitals Foundations Trusts, Manchester, UK

4 The Royal Hallamshire Hospital, Sheffield, UK

5 Institute of Cancer Research and Royal Marsden Hospitals Foundation Trust, Sutton, UK

6 Prostate Cancer Support Federation, Stockport, UK

7 Beatson West of Scotland Cancer Centre, Glasgow, UK

8 Inselspital, Bern, Switzerland

9 School of Cancer Sciences, University of Birmingham, Birmingham, UK

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Trials 2012, 13:168  doi:10.1186/1745-6215-13-168

Published: 15 September 2012

Abstract

Background

Systemic 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.

Methods

STAMPEDE 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.

Conclusions

The 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 registration

ISRCTN78818544, NCT00268476

First patient into trial: 17 October 2005

First patient into abiraterone comparison: 15 November 2011

Keywords:
Novel design; Multi-arm multi-stage design; Implementation; Prostate cancer; Methodology; Randomized controlled trial