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

Septic Shock Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01000649
• Other study ID #: FE 202158 CS02
• Secondary ID: EudraCT: 2009-01
• Status: Completed
• Phase: Phase 2
• First received: September 30, 2009
• Last updated: August 24, 2017
• Start date: November 2009
• Est. completion date: September 2011

Study information

• Verified date: August 2017
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: September 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Drug:
• FE 202158 1.25
FE 202158 at dose 1.25 ng/kg/min infused.
• FE 202158 2.5
FE 202158 at dose 2.5 ng/kg/min infused.
• FE 202158 3.75
FE 202158 at dose 3.75 ng/kg/min infused.

Other:
• Placebo
Isotonic saline infused.

Locations

Country	Name	City	State
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
Canada	Royal Columbian Hospital	Vancouver
Canada	St. Paul´s Hospital	Vancouver
Denmark	Bispebjerg Hospital	Bispebjerg
Denmark	Rigshospitalet	Copenhagen
Denmark	Hillerød Hospital	Hillerød
Denmark	Hvidovre Hospital	Hvidovre
United States	Cooper University Hospital	Camden	New Jersey
United States	Division of Education and Research SMDC Health System	Duluth	Minnesota
United States	Baylor College of Medicine	Houston	Texas
United States	Mount Sinai School of Medicine	New York	New York
United States	Christiana Care Health System	Newark	Delaware
United States	Baystate Medical Center	Springfield	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark, 

References & Publications (1)

Russell JA, Vincent JL, Kjølbye AL, Olsson H, Blemings A, Spapen H, Carl P, Laterre PF, Grundemar L. Selepressin, a novel selective vasopressin V(1A) agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled tria — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine)	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.	Day 1 up to Day 7
Primary	Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE	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.	Day 1 up to Day 7
Primary	Cumulative Dose of Open Label NE.	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.	Day 1 up to Day 7
Primary	Infusion Rates of Open Label NE.	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.	Day 1 up to Day 7
Secondary	Pharmacokinetic (PK) Parameter in Patients : Steady State Concentration	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.	Day 1 up to Day 7
Secondary	PK Parameter in Patients : Time to Steady State	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.	Day 1 up to Day 7
Secondary	PK Parameter in Patients : Clearance	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.	Day 1 up to Day 7
Secondary	PK Parameter in Patients : Steady State Volume of Distribution	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.	Day 1 up to Day 7
Secondary	PK Parameter in Patients : Initial Elimination Half-life	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.	Day 1 up to Day 7
Secondary	PK Parameter in Patients : Terminal Elimination Half-life	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.	Day 1 up to Day 7
Secondary	Change From Baseline in C-reactive Protein (CRP)	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.	Day 1 up to Day 7
Secondary	Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha	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.	At Day 1, Day 2, Day 4, and Day 7
Secondary	Change From Baseline in Interleukin-6 (IL-6)	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.	At Day 1, Day 2, Day 4, and Day 7
Secondary	Change From Baseline in Interleukin-10 (IL-10)	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.	At Day 1, Day 2, Day 4, and Day 7
Secondary	Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist	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.	At Day 1, Day 2, Day 4, and Day 7
Secondary	Change From Baseline in Heart Rate	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.	Day 1 up to Day 7
Secondary	Change From Baseline in Fluid Balance	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.	Day 1 up to Day 7
Secondary	SOFA Score	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.	Day 1 up to Day 7, Day 14 and Day 29
Secondary	Pulmonary Function : Change From Baseline in PaO2/FiO2	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.	Day 1 up to Day 7
Secondary	Pulmonary Function : Change From Baseline in Tidal Volume	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.	Day 1 up to Day 7
Secondary	Change From Baseline in Arterial Blood Gas (Lactate)	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.	Day 1 up to Day 7
Secondary	Days Alive and Free of Any Organ Dysfunction 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.	At Day 7
Secondary	Percentage of Patients Alive and Free of All Vasopressors	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.	At Day 7, Day 14 and Day 28
Secondary	Percentage of Days Alive and Free of Dialysis	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.	At Day 7, Day 14 and Day 28
Secondary	Percentage of Days Alive and Free of Ventilation	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.	At Day 7
Secondary	Mortality	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.	At Day 1, 7, 14, and 28
Secondary	Incidence of Abnormal Changes in ECG	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.	Day 1 up to Day 7