Clinical trial NCT01000649: Effects of the V1a Agonist FE 202158 in Patients With Septic Shock
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Septic Shock
Keywords: V1a agonist
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2009-10-23
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine)
timeFrame: Day 1 up to Day 7
measure: Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE
timeFrame: Day 1 up to Day 7
measure: Cumulative Dose of Open Label NE.
timeFrame: Day 1 up to Day 7
measure: Infusion Rates of Open Label NE.
timeFrame: Day 1 up to Day 7
Secondary outcomes:
measure: Pharmacokinetic (PK) Parameter in Patients : Steady State Concentration
timeFrame: Day 1 up to Day 7
measure: PK Parameter in Patients : Time to Steady State
timeFrame: Day 1 up to Day 7
measure: PK Parameter in Patients : Clearance
timeFrame: Day 1 up to Day 7
measure: PK Parameter in Patients : Steady State Volume of Distribution
timeFrame: Day 1 up to Day 7
measure: PK Parameter in Patients : Initial Elimination Half-life
timeFrame: Day 1 up to Day 7
measure: PK Parameter in Patients : Terminal Elimination Half-life
timeFrame: Day 1 up to Day 7
measure: Change From Baseline in C-reactive Protein (CRP)
timeFrame: Day 1 up to Day 7
measure: Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha
timeFrame: At Day 1, Day 2, Day 4, and Day 7
measure: Change From Baseline in Interleukin-6 (IL-6)
timeFrame: At Day 1, Day 2, Day 4, and Day 7
measure: Change From Baseline in Interleukin-10 (IL-10)
timeFrame: At Day 1, Day 2, Day 4, and Day 7
measure: Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist
timeFrame: At Day 1, Day 2, Day 4, and Day 7
measure: Change From Baseline in Heart Rate
timeFrame: Day 1 up to Day 7
measure: Change From Baseline in Fluid Balance
timeFrame: Day 1 up to Day 7
measure: SOFA Score
timeFrame: Day 1 up to Day 7, Day 14 and Day 29
measure: Pulmonary Function : Change From Baseline in PaO2/FiO2
timeFrame: Day 1 up to Day 7
measure: Pulmonary Function : Change From Baseline in Tidal Volume
timeFrame: Day 1 up to Day 7
measure: Change From Baseline in Arterial Blood Gas (Lactate)
timeFrame: Day 1 up to Day 7
measure: Days Alive and Free of Any Organ Dysfunction at Day 7
timeFrame: At Day 7
measure: Percentage of Patients Alive and Free of All Vasopressors
timeFrame: At Day 7, Day 14 and Day 28
measure: Percentage of Days Alive and Free of Dialysis
timeFrame: At Day 7, Day 14 and Day 28
measure: Percentage of Days Alive and Free of Ventilation
timeFrame: At Day 7
measure: Mortality
timeFrame: At Day 1, 7, 14, and 28
measure: Incidence of Abnormal Changes in ECG
timeFrame: Day 1 up to Day 7
Other outcomes:
Locations:
city: Newark
country: United States
facility: Christiana Care Health System
state: Delaware
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Duluth
country: United States
facility: Division of Education and Research SMDC Health System
state: Minnesota
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Brussels
country: Belgium
facility: Clinique Universitaire St-Luc
city: Brussels
country: Belgium
facility: Erasme Hospital (Free University of Brussels)
city: Brussels
country: Belgium
facility: University Hospital Vrije Universiteit
city: Dinant
country: Belgium
facility: Service des Soins Intensits
city: Vancouver
country: Canada
facility: Royal Columbian Hospital
city: Vancouver
country: Canada
facility: St. Paul´s Hospital
city: Bispebjerg
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Hillerød
country: Denmark
facility: Hillerød Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
Study officials:
affiliation: Ferring Pharmaceuticals
name: Clinical Development Support
role: STUDY_DIRECTOR
References:
citation: Russell JA, Vincent JL, Kjolbye AL, Olsson H, Blemings A, Spapen H, Carl P, Laterre PF, Grundemar L. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017 Aug 15;21(1):213. doi: 10.1186/s13054-017-1798-7.
citation: Rehberg S, Yamamoto Y, Sousse L, Bartha E, Jonkam C, Hasselbach AK, Traber LD, Cox RA, Westphal M, Enkhbaatar P, Traber DL. Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. Am J Physiol Heart Circ Physiol. 2012 Nov 15;303(10):H1245-54. doi: 10.1152/ajpheart.00390.2012. Epub 2012 Sep 7.