Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial (SEPSIS-ACT)

A Double-blind, Randomised, Placebo-Controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients With Vasopressor-dependent Septic Shock

This is a double-blind, randomised, placebo-controlled, two-part adaptive clinical trial. The trial is designed to investigate the efficacy and safety of multiple dosing regimens of selepressin and to confirm the efficacy and safety of one dosing regimen in treatment of adult patients with septic shock requiring vasopressor.

Study Overview

• Status: Terminated
• Conditions: Septic Shock
• Intervention / Treatment: Drug: placebo; Drug: selepressin

• Study Type: Interventional
• Enrollment (Actual): 868
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Cliniques Universitaires Saint-Luc (there may be other sites in this country)
• Denmark
  • Aalborg, Denmark
    • Aalborg Universitetshospital (there may be other sites in this country)
• France
  • Limoges, France
    • Centre Hospitalier et Universitaire de Limoges (there may be other sites in this country)
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Nijmegen Medical Centre (there may be other sites in this country)
• United States
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Memorial Hospital
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Eastern Idaho Regional Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem Research Institute
  • Kansas
    • Topeka, Kansas, United States, 66604
      • Stormont Vail Health Care
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Detroit, Michigan, United States
      • Henry Ford Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • HealthPartners Speciality Clinics
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Remington Davis Inc
    • Columbus, Ohio, United States, 43210-1252
      • Ohio State University
    • Toledo, Ohio, United States, 43608
      • St Vincent Mercy Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 years of age or older
• Proven or suspected infection
• Septic shock defined as hypotension requiring vasopressor treatment despite adequate fluid resuscitation
• Informed consent obtained in accordance with local regulations

Exclusion Criteria:

• Not possible to initiate trial drug treatment within 12 hours from onset of vasopressor treatment for septic shock
• Primary cause of hypotension not due to sepsis
• Previous severe sepsis with intensive care unit admission within this hospital stay
• Known/suspected acute mesenteric ischaemia
• Suspicion of concomitant acute coronary syndrome based on clinical symptoms and/or ECG during this episode of septic shock
• Chronic mechanical ventilation for any reason OR severe chronic obstructive pulmonary disease (COPD) requiring either continuous daily oxygen use during the preceding 30 days or mechanical ventilation (for acute exacerbation of COPD) during the preceding 30 days
• Received bone marrow transplant during the preceding 6 months or chemotherapy during the preceding 30 days for lymphoma or leukemia
• Known to be pregnant
• Decision to limit full care taken before obtaining informed consent
• Use of vasopressin in the past 12 hours prior to start of trial drug treatment or use of terlipressin within 7 days prior to start of trial drug treatment
• Prior enrolment in the trial
• Prior use of an investigational medicinal product within the last month OR planned or concurrent participation in a clinical trial for any investigational drug or investigational device

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo
Experimental: Selepressin 1; Starting dose 1.7 ng/kg/min	Drug: selepressin
Experimental: Selepressin 2; Starting dose 2.5 ng/kg/min	Drug: selepressin
Experimental: Selepressin 3; Starting dose 3.5 ng/kg/min	Drug: selepressin
Experimental: Selepressin 4; Starting dose 5.0 ng/kg/min The highest dosing regimen of selepressin was not investigated in the trial as the desired primary outcome for selepressin 3 arm was not achieved, and the trial was terminated for futility.	Drug: selepressin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasopressor- and Mechanical Ventilator-free Days (PVFDs)	Composite endpoint defined as number of days from start of treatment to 30 days thereafter during which subject is: Alive. However, if patient dies within these 30-days then PVFDs will be zero even if there is a period during which subject is alive and free of both vasopressor treatment and mechanical ventilation;; Free of treatment with vasopressors: Less than 60 min during any contiguous 24-h period. If a patient requires vasopressors longer than 60 min in total during any 24-h period, the intervening intervals during which they are free of vasopressors will not be included in the determination of PVFDs;; Free of any mechanical ventilation: Less than 60 min during any contiguous 24-h period. If a patient requires mechanical ventilation longer than 60 min in total during any 24-h period, the intervening intervals during which they are not receiving mechanical ventilation will not be included in the period free of mechanical ventilation in the determination of PVFDs.	Up to Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality	All-cause mortality defined as the percentage of subjects that have died, regardless of cause.	At Day 90
Renal Replacement Therapy (RRT)-Free Days	RRT-free days was defined as the number of days a subject is free of treatment with any form of RRT (continuous RRT, intermittent hemodialysis or peritoneal dialysis) and the intermittent periods were not included. RRT-free days was analyzed excluding subjects on RRT for chronic renal failure at time of randomization.	Up to Day 30
Intensive Care Unit (ICU)-Free Days	The ICU free days, as for the PVFDs, reflect the time from last discharge of the ICU to Day 30 with an absolute penalty for mortality, i.e., any subject that died within this 30-day period was assigned zero value).	Up to Day 30
Vasopressor-free Days up to Day 30	Number of days from start of treatment to 30 days thereafter during which the subject is free of treatment with vasopressors, i.e. less than 60 min during any contiguous 24-h period.	Up to Day 30
Mechanical Ventilator-free Days up to Day 30	Number of days from start of treatment to 30 days thereafter during which the subject is free of any mechanical ventilation, i.e. less than 60 min during any contiguous 24-h period.	Up to Day 30
Duration of Septic Shock (i.e. Vasopressor Use) up to Day 30	The duration of septic shock was defined as the cumulative periods (>1 h), from start of investigational medicinal product (IMP) treatment until Day 30, on IMP or vasopressors.	Up to Day 30
Duration of Mechanical Ventilation up to Day 30	The duration of mechanical ventilation was defined as the cumulative periods (>1 h), from start of the IMP treatment until Day 30, on mechanical ventilation.	Up to Day 30
The Percentage of Subjects With RRT up to Day 30 (Counting Subjects Who Died as on RRT and Excluding Subjects on RRT for Chronic Renal Failure at the Time of Randomization)	Renal replacement therapy is defined as continuous RRT, intermittent hemodialysis, or peritoneal dialysis. In order to ensure that any reduction in the incidence of RRT was not caused by an increase in mortality, all subjects dying within the 30-day period were counted as on RRT.	Up to Day 30
Duration of RRT up to Day 90 (Excluding Subjects on RRT for Chronic Failure at the Time of Randomization)	The duration of RRT was defined as the cumulative periods (>1 h) from start of IMP until Day 90 with RRT (continuous renal replacement therapy, intermittent hemodialysis, or peritoneal dialysis). Subjects on RRT for chronic renal failure at time of randomization were not included in the analysis.	Up to Day 90
Overall and Individual Organ (Cardiovascular, Respiratory, Renal, Hepatic, Coagulation) Scores Using a Modified Version of the SOFA up to Day 7 or Until ICU Discharge	The presence of 5 organ dysfunctions (cardiovascular, respiratory, renal, hepatic, coagulation) was assessed using a modified Sequential Organ Failure Assessment (SOFA) (i.e. SOFA except the Glasgow Coma Scale). In addition, any dose of vasopressors or positive ionotropes will attribute 3 or 2 points on the cardiovascular scale, respectively. Each organ has a possible dysfunction score of 0 (no organ dysfunction) to 4 (dysfunctional organ), for a total modified SOFA score range of 0 (no organ dysfunction) to 23 (all organs with dysfunction).	Days 1, 3, and 7 or discharge from ICU
Percentage of Subjects With New Organ Dysfunction and New Organ Failure (Based on the SOFA Score) up to Day 7 and Day 30	The presence of 5 organ dysfunctions (cardiovascular, respiratory, renal, hepatic, coagulation) was assessed using a SOFA score. Each organ has a possible dysfunction score of 0 (no organ dysfunction) to 4 (all organs with dysfunction). Incidence of new organ dysfunction is defined as an increase ≥ 1 from baseline to post baseline up until the end of the period (e.g. going from 1-2) in any of the individual SOFA scores. Incidence of new organ failures is defined as a change in any of the individual SOFA scores from (0-2) at baseline to (3-4) post baseline up until the end of the period (Day 7 or 30) (if the SOFA scores goes from (0-2) to (3-4) and back to (0-2) again within the period, that will still count as a new organ failure). Percentage of subjects with new organ dysfunction and new organ failure (based on the SOFA Score) up to Day 7 and Day 30 are reported.	Up to Day 7 and Day 30
ICU Length of Stay up to Day 30	ICU length of stay is defined as the cumulative periods (>1 h) spent in ICU from start of IMP to 30 days after.	Up to Day 30
All-cause Mortality (Defined as the Percentage of Subjects That Have Died, Regardless of Cause) at Day 30 and Day 180	All-cause mortality defined as the percentage of subjects that have died, regardless of cause.	At Day 30 and Day 180
Daily Fluid Balance Until ICU Discharge (for a Maximum of 7 Days)	Fluid balance (as a rate of time) calculated for fluid administered during episode of severe sepsis/septic shock will be presented until ICU discharge (for a maximum of 7 days).	Baseline and Days 1-7
Cumulative Fluid Balance Until ICU Discharge (for a Maximum of 7 Days)	Cumulative fluid balance (total volume) calculated for fluid administered during episode of severe sepsis/septic shock will be presented until ICU discharge (for a maximum of 7 days).	Baseline and Days 1-7
Daily Urine Output Until ICU Discharge (for a Maximum of 7 Days)		Baseline and Days 1-7
Cumulative Urine Output Until ICU Discharge (for a Maximum of 7 Days)	Cumulative urinary output (absolute values) will be presented until ICU discharge (for a maximum of 7 Days).	Baseline and Days 1-7
Utility, Based on the EuroQol Group's 5-dimension 5-level (EQ-5D-5L) Questionnaire, up to Day 180	The EuroQoL-5-Dimensions (EQ-5D™) was used to assess the overall health of each subject. EQ-5D™ is a standardised instrument for use as a measure of health outcome. The first part of the instrument includes 5 dimensions where the subject indicates which of the given statements best describes the health state on the day of questionnaire completion. The second part contains a visual analogue scale (VAS) where the subject indicates how good or bad his or her own health is on the day of questionnaire completion. EQ-5D-5L will be analyzed by the index value (Range: 0-1; 0=dead state, 1=full health state), the overall quality-adjusted life year (QALY), and the VAS score (Range: 0-100; 0=worst health state, 100=best health state). The EQ-5D-5L was completed at baseline and at the scheduled follow-up days (i.e. Day 30, Day 60, Day 90, and Day 180). Data for EQ VAS score and EQ-5D-5L index score are reported in this endpoint.	Baseline and Days 30, 60, 90 and 180
Utility, Based on the EuroQol Group's 5-dimension 5-level (EQ-5D-5L) Questionnaire, up to Day 180	The EQ-5D™ was used to assess the overall health of each subject. EQ-5D™ is a standardised instrument for use as a measure of health outcome. The first part of the instrument includes 5 dimensions where the subject indicates which of the given statements best describes the health state on the day of questionnaire completion. The second part contains a VAS where the subject indicates how good or bad his or her own health is on the day of questionnaire completion. EQ-5D-5L will be analyzed by the index value (Range: 0-1; 0=dead state, 1=full health state), the overall QALY, and the VAS score (Range: 0-100; 0=worst health state, 100=best health state). The EQ-5D-5L was completed at baseline and at the scheduled follow-up days (i.e. Day 30, Day 60, Day 90, and Day 180). Data for EQ-5D-5L QALY is reported in this endpoint.	Days 30, 60, 90 and 180

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• Laterre PF, Berry SM, Blemings A, Carlsen JE, Francois B, Graves T, Jacobsen K, Lewis RJ, Opal SM, Perner A, Pickkers P, Russell JA, Windelov NA, Yealy DM, Asfar P, Bestle MH, Muller G, Bruel C, Brule N, Decruyenaere J, Dive AM, Dugernier T, Krell K, Lefrant JY, Megarbane B, Mercier E, Mira JP, Quenot JP, Rasmussen BS, Thorsen-Meyer HC, Vander Laenen M, Vang ML, Vignon P, Vinatier I, Wichmann S, Wittebole X, Kjolbye AL, Angus DC; SEPSIS-ACT Investigators. Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial. JAMA. 2019 Oct 15;322(15):1476-1485. doi: 10.1001/jama.2019.14607. Erratum In: JAMA. 2019 Nov 12;322(18):1830.
• Lewis RJ, Angus DC, Laterre PF, Kjolbye AL, van der Meulen E, Blemings A, Graves T, Russell JA, Carlsen JE, Jacobsen K, Yealy DM, Opal SM, Windelov NA, Francois B, Perner A, Pickkers P, Berry SM. 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): October 3, 2017
• Study Completion (Actual): February 26, 2018

Study Registration Dates

• First Submitted: July 17, 2015
• First Submitted That Met QC Criteria: July 24, 2015
• First Posted (Estimate): July 27, 2015

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: March 11, 2021
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: 000133; 2014-003973-41 (EudraCT Number)