Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial

Phase 3TerminatedNCT02508649

Ferring Pharmaceuticals868 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

868

Conditions

Septic Shock

Interventions

selepressinDRUG

placeboDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (21)

Memorial Hospital

Colorado Springs, Colorado, United States

Outcomes

Primary Outcomes

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: 1. 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; 2. 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; 3. 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.

Time frame: Up to Day 30

Secondary Outcomes

All-cause Mortality

All-cause mortality defined as the percentage of subjects that have died, regardless of cause.

Time frame: 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.

Time frame: 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).

Time frame: Up to Day 30

Data from ClinicalTrials.gov

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Eastern Idaho Regional Medical Center

Idaho Falls, Idaho, United States

Rush University Medical Center

Chicago, Illinois, United States

Northshore University Healthsystem Research Institute

Evanston, Illinois, United States

Stormont Vail Health Care

Topeka, Kansas, United States

Baystate Medical Center

Springfield, Massachusetts, United States

Henry Ford Hospital

Detroit, Michigan, United States

HealthPartners Speciality Clinics

Saint Paul, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Cooper University Hospital

Camden, New Jersey, United States

...and 11 more locations

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: Baseline and Days 1-7

Daily Urine Output Until ICU Discharge (for a Maximum of 7 Days)

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: Days 30, 60, 90 and 180