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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
53
FE 202158 at dose 1.25 ng/kg/min infused.
FE 202158 at dose 2.5 ng/kg/min infused.
FE 202158 at dose 3.75 ng/kg/min infused.
Christiana Care Health System
Newark, Delaware, United States
Baystate Medical Center
Springfield, Massachusetts, United States
Division of Education and Research SMDC Health System
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
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Isotonic saline infused.
Duluth, Minnesota, United States
Cooper University Hospital
Camden, New Jersey, United States
Mount Sinai School of Medicine
New York, New York, United States
Baylor College of Medicine
Houston, Texas, United States
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
...and 6 more locations
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: At Day 1, Day 2, Day 4, and Day 7
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.
Time frame: At Day 1, Day 2, Day 4, and Day 7
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.
Time frame: At Day 1, Day 2, Day 4, and Day 7
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.
Time frame: At Day 1, Day 2, Day 4, and Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7, Day 14 and Day 29
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: Day 1 up to Day 7
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.
Time frame: At Day 7
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.
Time frame: At Day 7, Day 14 and Day 28
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.
Time frame: At Day 7, Day 14 and Day 28
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.
Time frame: At Day 7
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.
Time frame: At Day 1, 7, 14, and 28
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.
Time frame: Day 1 up to Day 7