title: 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: 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.
  
  
  BACKGROUND
  ISRCTN78818544, NCT00268476. First patient into trial: 17 October 2005. First patient into abiraterone comparison: 15 November 2011.
authors.affiliation: MRC Clinical Trials Unit, London, UK. matthew.sydes@ctu.mrc.ac.uk
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Mason
authors.forename: Noel W
authors.initials: NW
authors.lastname: Clarke
authors.forename: Claire
authors.initials: C
authors.lastname: Amos
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: David P
authors.initials: DP
authors.lastname: Dearnaley
authors.forename: John
authors.initials: J
authors.lastname: Dwyer
authors.forename: Charlene
authors.initials: C
authors.lastname: Green
authors.forename: Gordana
authors.initials: G
authors.lastname: Jovic
authors.forename: Alastair W S
authors.initials: AW
authors.lastname: Ritchie
authors.forename: J Martin
authors.initials: JM
authors.lastname: Russell
authors.forename: Karen
authors.initials: K
authors.lastname: Sanders
authors.forename: George
authors.initials: G
authors.lastname: Thalmann
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D018579:Patient Selection; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012107:Research Design; D016019:Survival Analysis; D013557:Switzerland; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D018931:Antineoplastic Agents, Hormonal