1Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California2Los Angeles Biomedical Research Institute, Torrance, California3Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California4Berry Consultants, LLC, Austin, Texas5Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania6Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania7Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium8Ferring Pharmaceuticals A/S, Copenhagen, Denmark9Center for Heart Lung Innovation and the Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada10StraDevo A/S, Kongens Lyngby, Denmark11Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania12Infectious Disease Division, Alpert Medical School of Brown University, Providence, Rhode Island13Centre d'Investigation Clinique 1435 and Intensive Care Unit, Centre Hospitalier Universitaire, Limoges, France14Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark; and15Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
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Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock—Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size.Clinical Trial registered with www.clinicaltrials.gov (NCT02508649).