The Design of an Adaptive Clinical Trial to Evaluate the Efficacy of Platelets Stored at Low-Temperature in Surgical Patients

AbstractBackgroundStorage of platelets at 4°C compared to 22°C may increase both hemostatic activity and storage duration; however, the maximum duration of cold storage is unknown. We report the design of an innovative, prospective, randomized, Bayesian adaptive, “duration-finding” clinical trial to evaluate the efficacy and maximum duration of storage of platelets at 4°C.MethodsPatients undergoing cardiac surgery and requiring platelet transfusions will be enrolled. Patients will be randomized to receive platelets stored at 22°C up to 5 days or platelets stored at 4°C up to 5, 10, or 15 days. Longer durations of cold storage will only be used if shorter durations at 4°C appear non-inferior to standard storage, based on a 4-level clinical hemostatic efficacy score with a non-inferiority margin of a half level. A Bayesian linear model is used to estimate the hemostatic efficacy of platelet transfusions based on the actual duration of storage at 4°C.ResultsThe type I error rate, if platelets stored at 4°C are inferior, is 0.0247 with an 82% probability of early stopping for futility. With a maximum sample size of 1500, the adaptive trial design has a power of over 90% to detect non-inferiority and a high probability of correctly identifying the maximum duration of storage at 4°C that is non-inferior to 22°C.ConclusionsAn adaptive, duration-finding trial design will generate level I evidence and allow the determination of the maximum duration platelet storage at 4°C that is non-inferior to standard storage at 22°C with respect to hemostatic efficacy. The adaptive trial design helps to ensure that longer cold storage durations are only explored once substantial supportive data are available for the shorter duration(s) and that the trial stops early if continuation is likely to be futile. Background Storage of platelets at 4°C compared to 22°C may increase both hemostatic activity and storage duration; however, the maximum duration of cold storage is unknown. We report the design of an innovative, prospective, randomized, Bayesian adaptive, “duration-finding” clinical trial to evaluate the efficacy and maximum duration of storage of platelets at 4°C. Methods Patients undergoing cardiac surgery and requiring platelet transfusions will be enrolled. Patients will be randomized to receive platelets stored at 22°C up to 5 days or platelets stored at 4°C up to 5, 10, or 15 days. Longer durations of cold storage will only be used if shorter durations at 4°C appear non-inferior to standard storage, based on a 4-level clinical hemostatic efficacy score with a non-inferiority margin of a half level. A Bayesian linear model is used to estimate the hemostatic efficacy of platelet transfusions based on the actual duration of storage at 4°C. Results The type I error rate, if platelets stored at 4°C are inferior, is 0.0247 with an 82% probability of early stopping for futility. With a maximum sample size of 1500, the adaptive trial design has a power of over 90% to detect non-inferiority and a high probability of correctly identifying the maximum duration of storage at 4°C that is non-inferior to 22°C. Conclusions An adaptive, duration-finding trial design will generate level I evidence and allow the determination of the maximum duration platelet storage at 4°C that is non-inferior to standard storage at 22°C with respect to hemostatic efficacy. The adaptive trial design helps to ensure that longer cold storage durations are only explored once substantial supportive data are available for the shorter duration(s) and that the trial stops early if continuation is likely to be futile. Revision Date: February 23, 2018 Conflicts of Interest: Drs. Krachey, Viele, and Lewis are employees of Berry Consultant, LLC, a statistical consulting firm that specializes in the design of adaptive clinical trials. Dr. Lewis also provides clinical trial oversight services to Octapharma. Nicole Dodge Zantek has a financial interest in ENDO International PLC and Boston Scientific; research funding from Terumo BCT, Octapharma, Bayer HealthCare and is a member of the North American Special Coagulation Laboratory Association Executive Board and College of American Pathologists Transfusion Medicine Resource Committee. Funding: No funding was received for this work. Address for Correspondence: Roger J. Lewis, MD, PhD, Professor and Chair, Department of Emergency Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, Building D9, Torrance, CA 90509, Email: roger@emedharbor.edu © 2018 Lippincott Williams & Wilkins, Inc.

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