title: A surrogate-primary replacement algorithm for response-adaptive randomization in stroke clinical trials.
abstract: Response-adaptive randomization (RAR) offers clinical investigators benefit by modifying the treatment allocation probabilities to optimize the ethical, operational, or statistical performance of the trial. Delayed primary outcomes and their effect on RAR have been studied in the literature; however, the incorporation of surrogate outcomes has not been fully addressed. We explore the benefits and limitations of surrogate outcome utilization in RAR in the context of acute stroke clinical trials. We propose a novel surrogate-primary (S-P) replacement algorithm where a patient's surrogate outcome is used in the RAR algorithm only until their primary outcome becomes available to replace it. Computer simulations investigate the effect of both the delay in obtaining the primary outcome and the underlying surrogate and primary outcome distributional discrepancies on complete randomization, standard RAR and the S-P replacement algorithm methods. Results show that when the primary outcome is delayed, the S-P replacement algorithm reduces the variability of the treatment allocation probabilities and achieves stabilization sooner. Additionally, the S-P replacement algorithm benefit proved to be robust in that it preserved power and reduced the expected number of failures across a variety of scenarios.
authors.affiliation: 1 Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Nowacki
authors.affiliation: 2 Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Wenle
authors.initials: W
authors.lastname: Zhao
authors.affiliation: 2 Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Yuko Y
authors.initials: YY
authors.lastname: Palesch
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D006801:Humans; D011336:Probability; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010959:Tissue Plasminogen Activator
keywords: Response-adaptive randomization; clinical trials; randomization; surrogate endpoints; unequal allocation