Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial

Abstract

Background: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.

Methods: STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously.

Results: The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity.

Conclusion: It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials.

Trial registration: ISRCTN78818544, NCT00268476.

Figure 1

STAMPEDE trial arms. The randomisation ratio is 2A : 1B : 1C : 1D : 1E : 1F. HT = hormone therapy, bid = twice daily.

Figure 2

Progress of STAMPEDE through the trial stages.

Figure 3

Hazard ratio cutpoints for intermediate reviews. HR = Hazard ratio; CI = Confidence interval.

Figure 4

Example output from -nstage- for the reference scenario. This figure shows the exact output from using -nstage-. This does not include the Pilot stage for safety, concentrating only the particular issues relating to the application of the MAMS activity and efficacy stages. In this example, the durations are expressed in quarter-years. The variable factors have been chosen such that no arms are stopped early for lack-of-efficacy (there is 1 control arm and 5 research arms in each stage); the accrual rate is set at 500 patients/year; the median progression-free survival (PFS) and overall survival are estimated to be 24 months and 48 months, respectively; and accrual is uncapped ie recruitment continues to the point of overall maturity. The power was set at 95% for the three activity stages and the observed values are consistent with this.

Figure 5

Hypothetical intermediate results at the end of an intermediate trial stage. HR = Hazard ratio; CI = Confidence interval. In this example, the research arms are drug A, drug B and the combination of drugs A and B; the common control arm is neither drug. The guideline for continuation of recruitment into the next stage is 0·92 compared with the control arm. The research arms containing drug B and drug A+B have met the criteria in this instance; the arm containing drug A has not met the criteria but is showing some evidence of an advantage in terms of the intermediate outcome measure. In this instance and in the absence of safety concerns, the IDMC may decide that recruitment should be continued to all 3 arms.