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Effects of the V1a Agonist FE 202158 in Patients With Septic Shock

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01000649
First Posted: October 23, 2009
Last Update Posted: September 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Ferring Pharmaceuticals
  Purpose
The purpose of this trial was to examine the safety and tolerability, pharmacokinetics of FE 202158 and to assess whether it can stabilize blood pressure and reduce vascular (blood vessel) leakage. FE 202158 had previously been tested in healthy volunteers.

Condition Intervention Phase
Septic Shock Drug: FE 202158 1.25 Drug: FE 202158 2.5 Drug: FE 202158 3.75 Other: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Infusion Proof-of-concept Trial Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ascending Doses of FE 202158 in Patients With Vasodilatory Hypotension in Early Septic Shock

Resource links provided by NLM:


Further study details as provided by Ferring Pharmaceuticals:

Primary Outcome Measures:
  • Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) [ Time Frame: Day 1 up to Day 7 ]

    Data were evaluated for target MAP of ≥ 60 mmHg. A 95% confidence interval (CI) was calculated and presented using Clopper-Pearson method.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE [ Time Frame: Day 1 up to Day 7 ]

    Data were evaluated for target MAP of ≥ 60 mmHg. A 95% confidence interval (CI) was calculated and presented using Clopper-Pearson method.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Cumulative Dose of Open Label NE. [ Time Frame: Day 1 up to Day 7 ]

    Cumulative Dose of Open Label NE over 7 days.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Infusion Rates of Open Label NE. [ Time Frame: Day 1 up to Day 7 ]

    Mean open label NE infusion rate within each predefined time period.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.



Secondary Outcome Measures:
  • Pharmacokinetic (PK) Parameter in Patients : Steady State Concentration [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • PK Parameter in Patients : Time to Steady State [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • PK Parameter in Patients : Clearance [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • PK Parameter in Patients : Steady State Volume of Distribution [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • PK Parameter in Patients : Initial Elimination Half-life [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • PK Parameter in Patients : Terminal Elimination Half-life [ Time Frame: Day 1 up to Day 7 ]

    PK parameters were calculated using nonlinear 2-compartment population PK model with random patient effects on clearance and volume of distribution.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in C-reactive Protein (CRP) [ Time Frame: Day 1 up to Day 7 ]

    The change from Baseline in CRP levels were analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha [ Time Frame: At Day 1, Day 2, Day 4, and Day 7 ]

    The change from Baseline in TNF-alpha levels were analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Interleukin-6 (IL-6) [ Time Frame: At Day 1, Day 2, Day 4, and Day 7 ]

    The change from Baseline in IL-6 levels were analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Interleukin-10 (IL-10) [ Time Frame: At Day 1, Day 2, Day 4, and Day 7 ]

    The change from Baseline in IL-10 levels were analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist [ Time Frame: At Day 1, Day 2, Day 4, and Day 7 ]

    The change from Baseline in IL-1R levels were analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Heart Rate [ Time Frame: Day 1 up to Day 7 ]

    The change from Baseline in heart rate was analysed and presented as per the planned time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Fluid Balance [ Time Frame: Day 1 up to Day 7 ]

    The change from Baseline in fluid balance were analysed and presented as per the planned time points. The fluid balance was adjusted for length of time interval and weight.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • SOFA Score [ Time Frame: Day 1 up to Day 7, Day 14 and Day 29 ]

    The SOFA score, is used to track a patient's status during the stay in an intensive care unit. This scoring system is used to determine the extent of a person's organ function or rate of failure. The scoring system comprise of scores for six different system: Respiratory System; Nervous System; Cardiovascular System; Liver; Coagulation; and Renal System. Score for each system ranges from 0-4 (0=normal, 4=worst).

    Total SOFA score is a sum of the individual system score and range from 0 to 24, 0 being the better and 24 being the worst patient status.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Pulmonary Function : Change From Baseline in PaO2/FiO2 [ Time Frame: Day 1 up to Day 7 ]

    Change from Baseline in PaO2/FiO2 was observed at each time-point.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Pulmonary Function : Change From Baseline in Tidal Volume [ Time Frame: Day 1 up to Day 7 ]

    Change from Baseline in tidal volume was observed at each time-point.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Change From Baseline in Arterial Blood Gas (Lactate) [ Time Frame: Day 1 up to Day 7 ]

    Change from Baseline in arterial blood gas (lactate) was observed at each time-point.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Days Alive and Free of Any Organ Dysfunction at Day 7 [ Time Frame: At Day 7 ]

    Percentage of days alive and free of any organ dysfunction (i.e. no. of days divided by 7).

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Percentage of Patients Alive and Free of All Vasopressors [ Time Frame: At Day 7, Day 14 and Day 28 ]

    Percentage of patients alive and free of all vasopressors was assessed on Days 7, 14, and 28.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Percentage of Days Alive and Free of Dialysis [ Time Frame: At Day 7, Day 14 and Day 28 ]

    Percentage of days alive and free of dialysis was assessed on Days 7, 14, and 28.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Percentage of Days Alive and Free of Ventilation [ Time Frame: At Day 7 ]

    Percentage of days alive and free of ventilation was assessed on Days 7, 14, and 28.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Mortality [ Time Frame: At Day 1, 7, 14, and 28 ]

    Mortality was assessed as percentage of patients dead at pre-specified time points.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.


  • Incidence of Abnormal Changes in ECG [ Time Frame: Day 1 up to Day 7 ]

    The number of patients having abnormal changes in ECG variables during the trial period was presented.

    The patients (n=2) in the FE 202158 3.75 ng/kg/min dose group were both discontinued within 5 hours after start of infusion. Therefore, no adequate data was available to perform the analysis for the outcome.



Enrollment: 53
Study Start Date: November 2009
Study Completion Date: September 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: FE 202158 1.25

Patients in the arm received an intravenous infusion for up to 7 days of FE 202158 at an initial rate of 1.25 ng/kg/min.

FE 202158 was provided as an isotonic acetate buffered stock solution of pH 4.0 in vials appropriately diluted with isotonic saline prior to use.

Drug: FE 202158 1.25
FE 202158 at dose 1.25 ng/kg/min infused.
Experimental: FE 202158 2.5

Patients in the arm received an intravenous infusion for up to 7 days of FE 202158 at an initial rate of 2.5 ng/kg/min.

FE 202158 was provided as an isotonic acetate buffered stock solution of pH 4.0 in vials appropriately diluted with isotonic saline prior to use.

Drug: FE 202158 2.5
FE 202158 at dose 2.5 ng/kg/min infused.
Experimental: FE 202158 3.75

Patients in the arm received an intravenous infusion for up to 7 days of FE 202158 at an initial rate of 3.75 ng/kg/min.

FE 202158 was provided as an isotonic acetate buffered stock solution of pH 4.0 in vials appropriately diluted with isotonic saline prior to use.

Drug: FE 202158 3.75
FE 202158 at dose 3.75 ng/kg/min infused.
Placebo Comparator: PLCBO
Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Other: Placebo
Isotonic saline infused.

Detailed Description:

This was a multi-centre, double-blind, randomized, placebo-controlled, parallel group trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of FE 202158 (using three ascending doses) in patients with vasodilatory hypotension in early septic shock, when given as continuous infusion for up to 7 days.

The trial comprised of three treatment arms where FE 202158 was administered in 1.25 ng, 2.5 ng and 3.75 ng dose, respectively. A placebo arm was also included in the trial where patients received isotonic saline.

Efficacy of FE 202158 was determined by evaluating its ability to maintain mean arterial pressure (MAP) >60 mmHg and its modulating effect on inflammatory markers. Effects of FE 202158 on other variables like vital signs, morbidity, mortality and pulmonary function were also determined.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed informed consent form by the patient or a legal representative according to local regulations
  • Man or woman 18 years of age or older
  • Proven or suspected infection
  • Low blood pressure
  • Signs of decreased circulation in the tissues
  • Willing to use an adequate barrier method or hormonal method of contraception, if not abstinent, from the day of informed consent to one week after the end of infusion of study medication.

Exclusion Criteria:

  • Present or a history (within the last 5 years) of acute coronary syndrome (myocardial infarction or unstable angina). Patients who have been asymptomatic for 6 months after coronary revascularisation are eligible.
  • Hypovolaemia suspected on clinical grounds, e.g. cold extremities with delayed capillary filling, low cardiac filling pressure, marked systolic or pulse pressure variation or positive leg raising test.
  • Known or suspected cardiac failure
  • Pregnancy or breastfeeding
  • Any cause of hypotension other than early septic shock
  • Use of vasopressin or terlipressin for blood pressure support during the current hospital admission
  • Proven or suspected acute mesenteric ischemia, as judged by the investigator
  • Known episode of septic shock within 1 month prior to randomisation
  • Underlying chronic heart disease
  • Traumatic brain injury
  • Present hospitalisation with burn injury
  • Symptomatic peripheral vascular disease including Raynaud's syndrome
  • Previously randomized in this trial
  • Intake of an investigational drug within the last 3 months (or longer if judged by the Investigator to possibly influence the outcome of the current study)
  • Known participation in another clinical trial
  • Considered by the investigator to be unsuitable to participate in the trial for any other reason
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01000649


Locations
United States, Delaware
Christiana Care Health System
Newark, Delaware, United States
United States, Massachusetts
Baystate Medical Center
Springfield, Massachusetts, United States
United States, Minnesota
Division of Education and Research SMDC Health System
Duluth, Minnesota, United States
United States, New Jersey
Cooper University Hospital
Camden, New Jersey, United States
United States, New York
Mount Sinai School of Medicine
New York, New York, United States
United States, Texas
Baylor College of Medicine
Houston, Texas, United States
Belgium
Clinique Universitaire St-Luc
Brussels, Belgium
Erasme Hospital (Free University of Brussels)
Brussels, Belgium
University Hospital Vrije Universiteit
Brussels, Belgium
Service des Soins Intensits
Dinant, Belgium
Canada
Royal Columbian Hospital
Vancouver, Canada
St. Paul´s Hospital
Vancouver, Canada
Denmark
Bispebjerg Hospital
Bispebjerg, Denmark
Rigshospitalet
Copenhagen, Denmark
Hillerød Hospital
Hillerød, Denmark
Hvidovre Hospital
Hvidovre, Denmark
Sponsors and Collaborators
Ferring Pharmaceuticals
Investigators
Study Director: Clinical Development Support Ferring Pharmaceuticals
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ferring Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01000649     History of Changes
Other Study ID Numbers: FE 202158 CS02
EudraCT: 2009-010798-19
First Submitted: September 30, 2009
First Posted: October 23, 2009
Results First Submitted: December 13, 2016
Results First Posted: June 2, 2017
Last Update Posted: September 22, 2017
Last Verified: August 2017

Keywords provided by Ferring Pharmaceuticals:
V1a agonist

Additional relevant MeSH terms:
Shock
Shock, Septic
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation