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

TY - JOUR

T1 - 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

AU - Lewis, Roger J

AU - Angus, Derek C

AU - Laterre, Pierre-François

AU - Kjølbye, Anne Louise

AU - van der Meulen, Egbert

AU - Blemings, Allan

AU - Graves, Todd

AU - Russell, James A

AU - Carlsen, Jan E

AU - Jacobsen, Karsten

AU - Yealy, Donald M

AU - Opal, Steven M

AU - Windeløv, Nis A

AU - François, Bruno

AU - Perner, Anders

AU - Pickkers, Peter

AU - Berry, Scott M

PY - 2018/2

Y1 - 2018/2

N2 - 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 V1 a 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.

AB - 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 V1 a 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.

KW - Adult

KW - Clinical Protocols

KW - Dose-Response Relationship, Drug

KW - Drug Monitoring/methods

KW - Female

KW - Humans

KW - Hypotension/drug therapy

KW - Infusions, Intravenous

KW - Male

KW - Receptors, Vasopressin/agonists

KW - Research Design

KW - Risk Assessment/methods

KW - Shock, Septic/complications

KW - Treatment Outcome

KW - Vasoconstrictor Agents/administration & dosage

KW - Vasopressins/administration & dosage

U2 - 10.1513/AnnalsATS.201708-669SD

DO - 10.1513/AnnalsATS.201708-669SD

M3 - Journal article

C2 - 29388815

SN - 2325-6621

VL - 15

SP - 250

EP - 257

JO - Annals of the American Thoracic Society

JF - Annals of the American Thoracic Society

IS - 2

ER -