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


BACKGROUND
http://www.clinicaltrials.gov. Unique identifier: NCT00359424.
From the Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (S.D.Y., R.H.M., L.D.F., R.F.W., Y.Y.P.); Department of Biostatistics, University of Iowa, Iowa City, IA (C.S.C.); Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.D.L.); Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH (J.P.B.); Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY (M.R.D.T); and Department of Radiology, Temple University School of Medicine, Philadelphia, PA (C.A.J.).
Sharon D
SD
Yeatts
Renee H
RH
Martin
Christopher S
CS
Coffey
Patrick D
PD
Lyden
Lydia D
LD
Foster
Robert F
RF
Woolson
Joseph P
JP
Broderick
Marco R
MR
Di Tullio
Charles A
CA
Jungreis
Yuko Y
YY
Palesch
D002545:Brain Ischemia / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy / Q000592:standards; D003627:Data Interpretation, Statistical; D003657:Decision Making / Q000502:physiology; D019468:Disease Management; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D018447:Medical Futility; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D012107:Research Design / Q000592:standards*; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000592:standards*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
clinical trial; endovascular techniques