Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial

Ann Am Thorac Soc. 2018 Feb;15(2):250-257. doi: 10.1513/AnnalsATS.201708-669SD.


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).

Keywords: adaptive clinical trial design; septic shock; vasopressor treatment.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Clinical Protocols*
  • Dose-Response Relationship, Drug*
  • Drug Monitoring / methods
  • Female
  • Humans
  • Hypotension* / drug therapy
  • Hypotension* / etiology
  • Infusions, Intravenous
  • Male
  • Receptors, Vasopressin / agonists
  • Research Design
  • Risk Assessment / methods*
  • Shock, Septic* / complications
  • Shock, Septic* / therapy
  • Treatment Outcome
  • Vasoconstrictor Agents / administration & dosage
  • Vasoconstrictor Agents / adverse effects
  • Vasopressins* / administration & dosage
  • Vasopressins* / adverse effects


  • Receptors, Vasopressin
  • Vasoconstrictor Agents
  • vasopressin, Phe(2)-Ile(3)-Hgn(4)-Orn(iPr)(8)-
  • Vasopressins

Associated data

  • ClinicalTrials.gov/NCT02508649