Challenges of decision making regarding futility in a randomized trial: the Interventional Management of Stroke III experience

Abstract

Background and purpose: Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue-type plasminogen activator followed by endovascular treatment with intravenous tissue-type plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power<20%.

Methods: Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results.

Results: The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial.

Conclusions: Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Keywords: clinical trial; endovascular techniques.

Figure 1

Stratum Specific Treatment Effects. The absolute risk difference and corresponding 95% confidence interval are depicted on the vertical axis, with the time of each interim analysis on the x-axis. Effects pertaining to the severe stratum are represented with squares; effects pertaining to the moderate stratum are represented with circles. Negative values favor IV tPA; positive values favor endovascular therapy. The dashed line indicates a 0 risk difference; inclusion of this line in the confidence interval implies a non-significant effect of treatment within the corresponding stratum.

Figure 2

Adjusted Treatment Effect and Associated Conditional Power. The absolute risk difference and corresponding 95% confidence interval, adjusted for severity stratum via CMH weights, are depicted with solid circles according to the left vertical axis, with the time of each interim analysis on the x-axis. Corresponding conditional power estimates are depicted with open squares according to the right vertical axis.