Trial Outcomes & Findings for Effects of the V1a Agonist FE 202158 in Patients With Septic Shock (NCT NCT01000649)

Last Updated: 2017-09-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

53 participants

Primary outcome timeframe

Day 1 up to Day 7

Results posted on

2017-09-25

Participant Flow

Total 55 patients were screened and 53 were randomized. One patient randomized to placebo died before dosing, and one patient randomized to 2.5 ng/kg/min was erroneously dosed with placebo.

Participant milestones

Participant milestones
Measure	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.	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.	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.The two patients randomized to FE 202158 3.75 ng group were excluded from the efficacy evaluation since meaningful analyses were not possible. 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Overall Study STARTED	10	19	2	21
Overall Study Intention-to-Treat (ITT) Analysis Set	10	20	2	21
Overall Study COMPLETED	5	16	0	15
Overall Study NOT COMPLETED	5	3	2	6

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.The two patients randomized to FE 202158 3.75 ng group were excluded from the efficacy evaluation since meaningful analyses were not possible. 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Overall Study Adverse Event	5	1	2	4
Overall Study Lost to Follow-up	0	2	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	FE 202158 3.75 n=2 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.	Total n=52 Participants Total of all reporting groups
Age, Continuous	59.3 years STANDARD_DEVIATION 19.6 • n=5 Participants	57.1 years STANDARD_DEVIATION 15.4 • n=7 Participants	69 years STANDARD_DEVIATION 12.7 • n=5 Participants	63.2 years STANDARD_DEVIATION 18 • n=4 Participants	60.4 years STANDARD_DEVIATION 17.1 • n=21 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	9 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants	23 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	10 Participants n=7 Participants	1 Participants n=5 Participants	15 Participants n=4 Participants	29 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants	19 Participants n=7 Participants	2 Participants n=5 Participants	20 Participants n=4 Participants	51 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	18 Participants n=7 Participants	2 Participants n=5 Participants	20 Participants n=4 Participants	50 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Weight	64.8 Kilogram STANDARD_DEVIATION 14.3 • n=5 Participants	87.6 Kilogram STANDARD_DEVIATION 28.6 • n=7 Participants	77.5 Kilogram STANDARD_DEVIATION 17.7 • n=5 Participants	75.1 Kilogram STANDARD_DEVIATION 15.3 • n=4 Participants	77.8 Kilogram STANDARD_DEVIATION 22.2 • n=21 Participants
Sequential Organ Failure Assessment (SOFA) Score	9.3 Score on a scale STANDARD_DEVIATION 2.16 • n=5 Participants	11.2 Score on a scale STANDARD_DEVIATION 3.73 • n=7 Participants	12 Score on a scale STANDARD_DEVIATION 0 • n=5 Participants	10.4 Score on a scale STANDARD_DEVIATION 3.46 • n=4 Participants	10.5 Score on a scale STANDARD_DEVIATION 3.31 • n=21 Participants

PRIMARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Full Analysis Set, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) Day 1 - 12 hrs	0.0 Percentage of patients Interval 0.0 to 30.8	47.1 Percentage of patients Interval 23.0 to 72.2	0.0 Percentage of patients Interval 0.0 to 16.8
Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) Day 1 - 24 hrs	10.0 Percentage of patients Interval 0.3 to 44.5	68.8 Percentage of patients Interval 41.3 to 89.0	20.0 Percentage of patients Interval 5.7 to 43.7
Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) Day 2 - 48 hrs	55.6 Percentage of patients Interval 21.2 to 86.3	66.7 Percentage of patients Interval 38.4 to 88.2	38.9 Percentage of patients Interval 17.3 to 64.3
Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) Day 4 - 96 hrs	75.0 Percentage of patients Interval 34.9 to 96.8	66.7 Percentage of patients Interval 29.9 to 92.5	70.6 Percentage of patients Interval 44.0 to 89.7
Proportion of Patients Maintaining Target Mean Arterial Pressure (MAP) (>60 mmHg) With no Open Label NE (Norepinephrine) Day 7 - 168 hrs	62.5 Percentage of patients Interval 24.5 to 91.5	80.0 Percentage of patients Interval 44.4 to 97.5	100.0 Percentage of patients Interval 78.2 to 100.0

PRIMARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Full Analysis Set, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE Day 7 - 168 hrs	62.5 Percentage of patients Interval 24.5 to 91.5	100.0 Percentage of patients Interval 66.4 to 100.0	100.0 Percentage of patients Interval 78.2 to 100.0
Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE Day 1 - 12 hrs	100.0 Percentage of patients Interval 63.1 to 100.0	100.0 Percentage of patients Interval 80.5 to 100.0	94.7 Percentage of patients Interval 74.0 to 99.9
Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE Day 1 - 24 hrs	87.5 Percentage of patients Interval 47.3 to 99.7	100.0 Percentage of patients Interval 78.2 to 100.0	100.0 Percentage of patients Interval 83.2 to 100.0
Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE Day 2 - 48 hrs	100.0 Percentage of patients Interval 66.4 to 100.0	100.0 Percentage of patients Interval 76.8 to 100.0	100.0 Percentage of patients Interval 81.5 to 100.0
Proportion of Patients Maintaining Target MAP (>60) Irrespective of Open Label NE Day 4 - 96 hrs	100.0 Percentage of patients Interval 63.1 to 100.0	100.0 Percentage of patients Interval 63.1 to 100.0	100.0 Percentage of patients Interval 80.5 to 100.0

PRIMARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Full Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Cumulative Dose of Open Label NE. Day 1 - 1 hour	14.3 µg/kg Standard Deviation 11.6	13.1 µg/kg Standard Deviation 12.6	19.2 µg/kg Standard Deviation 14.6
Cumulative Dose of Open Label NE. Day 1 - 3 hours	40.5 µg/kg Standard Deviation 35	30 µg/kg Standard Deviation 33.1	57.2 µg/kg Standard Deviation 44
Cumulative Dose of Open Label NE. Day 1 - 6 hours	75.8 µg/kg Standard Deviation 60.4	46.9 µg/kg Standard Deviation 59.4	110 µg/kg Standard Deviation 84
Cumulative Dose of Open Label NE. Day 1 - 12 hours	130 µg/kg Standard Deviation 96.3	66.5 µg/kg Standard Deviation 102	206 µg/kg Standard Deviation 159
Cumulative Dose of Open Label NE. Day 1 - 24 hours	211 µg/kg Standard Deviation 147	101 µg/kg Standard Deviation 193	360 µg/kg Standard Deviation 270
Cumulative Dose of Open Label NE. Day 2 - 36 hours	282 µg/kg Standard Deviation 206	122 µg/kg Standard Deviation 253	477 µg/kg Standard Deviation 363
Cumulative Dose of Open Label NE. Day 2 - 48 hours	349 µg/kg Standard Deviation 303	138 µg/kg Standard Deviation 297	554 µg/kg Standard Deviation 445
Cumulative Dose of Open Label NE. Day 3 - 60 hours	389 µg/kg Standard Deviation 377	150 µg/kg Standard Deviation 334	606 µg/kg Standard Deviation 509
Cumulative Dose of Open Label NE. Day 3 - 72 hours	420 µg/kg Standard Deviation 432	160 µg/kg Standard Deviation 364	646 µg/kg Standard Deviation 567
Cumulative Dose of Open Label NE. Day 4 - 84 hours	443 µg/kg Standard Deviation 471	169 µg/kg Standard Deviation 395	680 µg/kg Standard Deviation 623
Cumulative Dose of Open Label NE. Day 4 - 96 hours	465 µg/kg Standard Deviation 507	179 µg/kg Standard Deviation 430	707 µg/kg Standard Deviation 674
Cumulative Dose of Open Label NE. Day 5 - 108 hours	349 µg/kg Standard Deviation 342	186 µg/kg Standard Deviation 452	728 µg/kg Standard Deviation 713
Cumulative Dose of Open Label NE. Day 5 - 120 hours	374 µg/kg Standard Deviation 410	193 µg/kg Standard Deviation 467	749 µg/kg Standard Deviation 757
Cumulative Dose of Open Label NE. Day 6 - 132 hours	404 µg/kg Standard Deviation 474	200 µg/kg Standard Deviation 495	767 µg/kg Standard Deviation 793
Cumulative Dose of Open Label NE. Day 6 - 144 hours	421 µg/kg Standard Deviation 519	217 µg/kg Standard Deviation 563	782 µg/kg Standard Deviation 823
Cumulative Dose of Open Label NE. Day 7 - 156 hours	444 µg/kg Standard Deviation 582	236 µg/kg Standard Deviation 643	798 µg/kg Standard Deviation 853
Cumulative Dose of Open Label NE. Day 7 - 168 hours	477 µg/kg Standard Deviation 673	245 µg/kg Standard Deviation 678	824 µg/kg Standard Deviation 897

PRIMARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Infusion Rates of Open Label NE. Day 7 - 168 hours	0.05 µg/kg/min Standard Deviation 0.15	0.02 µg/kg/min Standard Deviation 0.05	0.01 µg/kg/min Standard Deviation 0.03
Infusion Rates of Open Label NE. Day 6 - 144 hours	0.03 µg/kg/min Standard Deviation 0.08	0.03 µg/kg/min Standard Deviation 0.13	0.02 µg/kg/min Standard Deviation 0.06
Infusion Rates of Open Label NE. Day 7 - 156 hours	0.04 µg/kg/min Standard Deviation 0.12	0.02 µg/kg/min Standard Deviation 0.08	0.02 µg/kg/min Standard Deviation 0.06
Infusion Rates of Open Label NE. Day 1 - 1 hour	0.24 µg/kg/min Standard Deviation 0.19	0.22 µg/kg/min Standard Deviation 0.21	0.32 µg/kg/min Standard Deviation 0.24
Infusion Rates of Open Label NE. Day 1 - 3 hours	0.22 µg/kg/min Standard Deviation 0.19	0.11 µg/kg/min Standard Deviation 0.17	0.31 µg/kg/min Standard Deviation 0.24
Infusion Rates of Open Label NE. Day 1 - 6 hours	0.18 µg/kg/min Standard Deviation 0.15	0.09 µg/kg/min Standard Deviation 0.15	0.28 µg/kg/min Standard Deviation 0.22
Infusion Rates of Open Label NE. Day 1 - 12 hours	0.13 µg/kg/min Standard Deviation 0.11	0.06 µg/kg/min Standard Deviation 0.14	0.26 µg/kg/min Standard Deviation 0.20
Infusion Rates of Open Label NE. Day 1 - 24 hours	0.09 µg/kg/min Standard Deviation 0.08	0.04 µg/kg/min Standard Deviation 0.11	0.19 µg/kg/min Standard Deviation 0.17
Infusion Rates of Open Label NE. Day 2 - 36 hours	0.10 µg/kg/min Standard Deviation 0.12	0.02 µg/kg/min Standard Deviation 0.07	0.13 µg/kg/min Standard Deviation 0.14
Infusion Rates of Open Label NE. Day 2 - 48 hours	0.08 µg/kg/min Standard Deviation 0.16	0.02 µg/kg/min Standard Deviation 0.06	0.08 µg/kg/min Standard Deviation 0.13
Infusion Rates of Open Label NE. Day 3 - 60 hours	0.03 µg/kg/min Standard Deviation 0.05	0.02 µg/kg/min Standard Deviation 0.06	0.07 µg/kg/min Standard Deviation 0.11
Infusion Rates of Open Label NE. Day 3 - 72 hours	0.04 µg/kg/min Standard Deviation 0.08	0.01 µg/kg/min Standard Deviation 0.04	0.05 µg/kg/min Standard Deviation 0.10
Infusion Rates of Open Label NE. Day 4 - 84 hours	0.03 µg/kg/min Standard Deviation 0.07	0.02 µg/kg/min Standard Deviation 0.06	0.04 µg/kg/min Standard Deviation 0.11
Infusion Rates of Open Label NE. Day 4 - 96 hours	0.03 µg/kg/min Standard Deviation 0.07	0.01 µg/kg/min Standard Deviation 0.05	0.03 µg/kg/min Standard Deviation 0.10
Infusion Rates of Open Label NE. Day 5 - 108 hours	0.0 µg/kg/min Standard Deviation 0.0	0.01 µg/kg/min Standard Deviation 0.01	0.04 µg/kg/min Standard Deviation 0.08
Infusion Rates of Open Label NE. Day 5 - 120 hours	0.02 µg/kg/min Standard Deviation 0.07	0.01 µg/kg/min Standard Deviation 0.04	0.03 µg/kg/min Standard Deviation 0.07
Infusion Rates of Open Label NE. Day 6 - 132 hours	0.02 µg/kg/min Standard Deviation 0.05	0.01 µg/kg/min Standard Deviation 0.04	0.02 µg/kg/min Standard Deviation 0.06

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Pharmacokinetic (PK) Parameter in Patients : Steady State Concentration	0.50 ng/mL Standard Deviation 0.13	0.99 ng/mL Standard Deviation 0.32	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
PK Parameter in Patients : Time to Steady State	7.6 Hour Standard Deviation 2.8	7.0 Hour Standard Deviation 2.3	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
PK Parameter in Patients : Clearance	10.0 Litre/hour Standard Deviation 2.8	13.1 Litre/hour Standard Deviation 2.9	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
PK Parameter in Patients : Steady State Volume of Distribution	25.5 Litre Standard Deviation 10.6	31.2 Litre Standard Deviation 14.7	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
PK Parameter in Patients : Initial Elimination Half-life	0.18 Hour Standard Deviation 0.09	0.17 Hour Standard Deviation 0.06	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=17 Participants 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.	PLCBO Patients in the arm received an intravenous infusion for up to 7 days of placebo.
PK Parameter in Patients : Terminal Elimination Half-life	2.5 Hour Standard Deviation 1.1	2.7 Hour Standard Deviation 1.2	—

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in C-reactive Protein (CRP) Day 1 (0-24 hours)	9.81 mg/L Standard Deviation 42.2	-4.84 mg/L Standard Deviation 38.5	32.7 mg/L Standard Deviation 63.8
Change From Baseline in C-reactive Protein (CRP) Day 4 (72-96 hours)	-95.8 mg/L Standard Deviation 97.1	-176 mg/L Standard Deviation 208	-71.8 mg/L Standard Deviation 97.5
Change From Baseline in C-reactive Protein (CRP) Day 2 (24-48 hours)	-16.2 mg/L Standard Deviation 89.4	-52.4 mg/L Standard Deviation 70.1	-5.63 mg/L Standard Deviation 118
Change From Baseline in C-reactive Protein (CRP) Day 7 (144-168 hours)	-93.3 mg/L Standard Deviation 58	-211.0 mg/L Standard Deviation 223	-141 mg/L Standard Deviation 221

SECONDARY outcome

Timeframe: At Day 1, Day 2, Day 4, and Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha Day 2 (24-48 hours)	-0.75 ng/L Standard Deviation 2.37	0.0 ng/L Standard Deviation 0.0	0.0 ng/L Standard Deviation 0.0
Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha Day 4 (72-96 hours)	-0.833 ng/L Standard Deviation 2.5	0.75 ng/L Standard Deviation 3.0	-0.125 ng/L Standard Deviation 0.559
Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha Day 1 (0-24 hours)	-0.75 ng/L Standard Deviation 2.37	-0.194 ng/L Standard Deviation 0.825	-0.125 ng/L Standard Deviation 0.559
Change From Baseline in Tumor Necrosis Factor (TNF)-Alpha Day 7 (144-168 hours)	-1.25 ng/L Standard Deviation 3.06	1.14 ng/L Standard Deviation 4.28	0.25 ng/L Standard Deviation 0.845

SECONDARY outcome

Timeframe: At Day 1, Day 2, Day 4, and Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Interleukin-6 (IL-6) Day 1 (0-24 hours)	-329 ng/L Standard Deviation 736	-524 ng/L Standard Deviation 2255	-529 ng/L Standard Deviation 1750
Change From Baseline in Interleukin-6 (IL-6) Day 2 (24-48 hours)	-720 ng/L Standard Deviation 1178	-888 ng/L Standard Deviation 1798	-398 ng/L Standard Deviation 2101
Change From Baseline in Interleukin-6 (IL-6) Day 4 (72-96 hours)	-794 ng/L Standard Deviation 1206	-1209 ng/L Standard Deviation 1844	-1140 ng/L Standard Deviation 1944
Change From Baseline in Interleukin-6 (IL-6) Day 7 (144-168 hours)	-883 ng/L Standard Deviation 1559	-1184 ng/L Standard Deviation 1801	-814 ng/L Standard Deviation 1823

SECONDARY outcome

Timeframe: At Day 1, Day 2, Day 4, and Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Interleukin-10 (IL-10) Day 1 (0-24 hours)	-19.2 ng/L Standard Deviation 54.6	-58.3 ng/L Standard Deviation 179	-25.8 ng/L Standard Deviation 51.7
Change From Baseline in Interleukin-10 (IL-10) Day 2 (24-48 hours)	-34 ng/L Standard Deviation 70.4	-78.9 ng/L Standard Deviation 189	-43 ng/L Standard Deviation 76.1
Change From Baseline in Interleukin-10 (IL-10) Day 4 (72-96 hours)	-31.9 ng/L Standard Deviation 95.2	-92.3 ng/L Standard Deviation 213	-56.6 ng/L Standard Deviation 84.5
Change From Baseline in Interleukin-10 (IL-10) Day 7 (144-168 hours)	8 ng/L Standard Deviation 24.3	-91.7 ng/L Standard Deviation 220	-52.8 ng/L Standard Deviation 97.1

SECONDARY outcome

Timeframe: At Day 1, Day 2, Day 4, and Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist Day 1 (0-24 hours)	0.763 µg/L Standard Deviation 5.39	-3.71 µg/L Standard Deviation 7.61	-3.28 µg/L Standard Deviation 5.79
Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist Day 2 (24-48 hours)	-3.65 µg/L Standard Deviation 9.89	-4.77 µg/L Standard Deviation 10.7	-3.84 µg/L Standard Deviation 7.86
Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist Day 4 (72-96 hours)	-6.38 µg/L Standard Deviation 12	-6.44 µg/L Standard Deviation 12	-4.51 µg/L Standard Deviation 8.63
Change From Baseline in Interleukin-1 Receptor (IL-1R) Antagonist Day 7 (144-168 hours)	-3.5 µg/L Standard Deviation 5.72	-5.3 µg/L Standard Deviation 10.4	-3.9 µg/L Standard Deviation 8.35

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Safety Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Heart Rate Day 1 - 3 hours	-5.7 Beats per minute Standard Deviation 8.06	-11.0 Beats per minute Standard Deviation 14.1	-4.9 Beats per minute Standard Deviation 14.3
Change From Baseline in Heart Rate Day 1 - 6 hours	-4.9 Beats per minute Standard Deviation 6.06	-11.9 Beats per minute Standard Deviation 14.9	-6.55 Beats per minute Standard Deviation 13.1
Change From Baseline in Heart Rate Day 1 - 9 hours	-7.2 Beats per minute Standard Deviation 7.02	-11.6 Beats per minute Standard Deviation 17.3	-5.35 Beats per minute Standard Deviation 17.7
Change From Baseline in Heart Rate Day 1 - 12 hours	-7.6 Beats per minute Standard Deviation 10.4	-11.5 Beats per minute Standard Deviation 13.8	-8.45 Beats per minute Standard Deviation 16.3
Change From Baseline in Heart Rate Day 1 - 15 hours	-8.6 Beats per minute Standard Deviation 7.76	-13.2 Beats per minute Standard Deviation 15.5	-4.5 Beats per minute Standard Deviation 18.5
Change From Baseline in Heart Rate Day 1 - 18 hours	-7.22 Beats per minute Standard Deviation 9.58	-6.26 Beats per minute Standard Deviation 19.1	-6.95 Beats per minute Standard Deviation 18.8
Change From Baseline in Heart Rate Day 1 - 21 hours	-10 Beats per minute Standard Deviation 9.31	-9.79 Beats per minute Standard Deviation 14.8	-3.2 Beats per minute Standard Deviation 22.9
Change From Baseline in Heart Rate Day 1 - 24 hours	-7.44 Beats per minute Standard Deviation 17.9	-2.95 Beats per minute Standard Deviation 25.1	-2.37 Beats per minute Standard Deviation 29.4
Change From Baseline in Heart Rate Day 2 - 27 hours	-7.6 Beats per minute Standard Deviation 14.5	-9.16 Beats per minute Standard Deviation 19.3	-5.4 Beats per minute Standard Deviation 27.9
Change From Baseline in Heart Rate Day 2 - 30 hours	-10.3 Beats per minute Standard Deviation 14.4	-13.1 Beats per minute Standard Deviation 17.4	-7.35 Beats per minute Standard Deviation 22.9
Change From Baseline in Heart Rate Day 2 - 33 hours	-9.3 Beats per minute Standard Deviation 13.9	-11.1 Beats per minute Standard Deviation 15	-10.5 Beats per minute Standard Deviation 22.2
Change From Baseline in Heart Rate Day 2 - 36 hours	-6.9 Beats per minute Standard Deviation 15.5	-9.47 Beats per minute Standard Deviation 16.0	-9.05 Beats per minute Standard Deviation 26.7
Change From Baseline in Heart Rate Day 2 - 39 hours	-6.7 Beats per minute Standard Deviation 12.8	-9.21 Beats per minute Standard Deviation 18.4	-7.2 Beats per minute Standard Deviation 25.7
Change From Baseline in Heart Rate Day 2 - 42 hours	-6 Beats per minute Standard Deviation 12.4	-11.3 Beats per minute Standard Deviation 16.5	-9.5 Beats per minute Standard Deviation 24.4
Change From Baseline in Heart Rate Day 2 - 45 hours	-1.9 Beats per minute Standard Deviation 8.91	-9.11 Beats per minute Standard Deviation 14.1	-6.5 Beats per minute Standard Deviation 28.1
Change From Baseline in Heart Rate Day 2 - 48 hours	-9.9 Beats per minute Standard Deviation 13.8	-7.39 Beats per minute Standard Deviation 13	-8.9 Beats per minute Standard Deviation 25
Change From Baseline in Heart Rate Day 3 - 51 hours	-10.2 Beats per minute Standard Deviation 8.53	-8.06 Beats per minute Standard Deviation 16.7	-9.11 Beats per minute Standard Deviation 27.9
Change From Baseline in Heart Rate Day 3 - 54 hours	-6.11 Beats per minute Standard Deviation 10.1	-10.5 Beats per minute Standard Deviation 18.1	-9.94 Beats per minute Standard Deviation 27
Change From Baseline in Heart Rate Day 3 - 57 hours	-3.67 Beats per minute Standard Deviation 10.4	-6.87 Beats per minute Standard Deviation 21.8	-7.94 Beats per minute Standard Deviation 28.6
Change From Baseline in Heart Rate Day 3 - 60 hours	-1.6 Beats per minute Standard Deviation 7.96	-8.25 Beats per minute Standard Deviation 22.3	-9.4 Beats per minute Standard Deviation 25.5
Change From Baseline in Heart Rate Day 3 - 63 hours	-6.78 Beats per minute Standard Deviation 10.6	-10.3 Beats per minute Standard Deviation 22.6	-10.6 Beats per minute Standard Deviation 24.7
Change From Baseline in Heart Rate Day 3 - 66 hours	-5.11 Beats per minute Standard Deviation 10.9	-9.63 Beats per minute Standard Deviation 19.4	-10.9 Beats per minute Standard Deviation 25
Change From Baseline in Heart Rate Day 3 - 69 hours	-9.44 Beats per minute Standard Deviation 11.9	-4.64 Beats per minute Standard Deviation 24.6	-8.35 Beats per minute Standard Deviation 26.2
Change From Baseline in Heart Rate Day 3 - 72 hours	-11.9 Beats per minute Standard Deviation 10.5	-10.7 Beats per minute Standard Deviation 19.8	-8.41 Beats per minute Standard Deviation 28.7
Change From Baseline in Heart Rate Day 4 - 78 hours	-2.11 Beats per minute Standard Deviation 20.9	-10.1 Beats per minute Standard Deviation 18.9	-7.06 Beats per minute Standard Deviation 29.7
Change From Baseline in Heart Rate Day 4 - 84 hours	-2.4 Beats per minute Standard Deviation 16.8	-12.5 Beats per minute Standard Deviation 17.6	-9.5 Beats per minute Standard Deviation 27
Change From Baseline in Heart Rate Day 4 - 90 hours	-7.38 Beats per minute Standard Deviation 15.3	-10.6 Beats per minute Standard Deviation 19.2	-4.18 Beats per minute Standard Deviation 31.0
Change From Baseline in Heart Rate Day 4 - 96 hours	-2.56 Beats per minute Standard Deviation 22.3	-12.2 Beats per minute Standard Deviation 16.1	-7.78 Beats per minute Standard Deviation 28
Change From Baseline in Heart Rate Day 5 - 102 hours	4.63 Beats per minute Standard Deviation 23.2	-9.38 Beats per minute Standard Deviation 19.8	-9.65 Beats per minute Standard Deviation 28.4
Change From Baseline in Heart Rate Day 5 - 108 hours	2.11 Beats per minute Standard Deviation 15.7	-10.5 Beats per minute Standard Deviation 15.9	-6.05 Beats per minute Standard Deviation 27.8
Change From Baseline in Heart Rate Day 5 - 114 hours	1.25 Beats per minute Standard Deviation 18.9	-10.3 Beats per minute Standard Deviation 16.7	-6.12 Beats per minute Standard Deviation 30.3
Change From Baseline in Heart Rate Day 5 - 120 hours	4.11 Beats per minute Standard Deviation 18.1	-7.15 Beats per minute Standard Deviation 17.4	-5.06 Beats per minute Standard Deviation 28.1
Change From Baseline in Heart Rate Day 6 - 126 hours	-0.714 Beats per minute Standard Deviation 13	-5.79 Beats per minute Standard Deviation 20.2	-4.19 Beats per minute Standard Deviation 24.4
Change From Baseline in Heart Rate Day 6 - 132 hours	1.13 Beats per minute Standard Deviation 14.8	-9.93 Beats per minute Standard Deviation 16.7	-4.22 Beats per minute Standard Deviation 24.7
Change From Baseline in Heart Rate Day 6 - 138 hours	-3 Beats per minute Standard Deviation 9.92	-10.6 Beats per minute Standard Deviation 14.6	-6.4 Beats per minute Standard Deviation 23.6
Change From Baseline in Heart Rate Day 6 - 144 hours	1.38 Beats per minute Standard Deviation 8.19	-10.7 Beats per minute Standard Deviation 17.3	1.28 Beats per minute Standard Deviation 18.6
Change From Baseline in Heart Rate Day 7 - 150 hours	0.2 Beats per minute Standard Deviation 13.4	-6 Beats per minute Standard Deviation 22.3	-1.88 Beats per minute Standard Deviation 28.2
Change From Baseline in Heart Rate Day 7 - 156 hours	6 Beats per minute Standard Deviation 20.2	-4.58 Beats per minute Standard Deviation 19.9	-8.83 Beats per minute Standard Deviation 15.2
Change From Baseline in Heart Rate Day 7 - 162 hours	6.33 Beats per minute Standard Deviation 22	-3.5 Beats per minute Standard Deviation 19.1	-11.5 Beats per minute Standard Deviation 15.9
Change From Baseline in Heart Rate Day 7 - 168 hours	8.17 Beats per minute Standard Deviation 13.7	-6.27 Beats per minute Standard Deviation 21.3	-6.94 Beats per minute Standard Deviation 15.6

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Fluid Balance Day 2 - 24-30 hours	-3.49 mL/hour/kg Standard Deviation 5.56	-1.75 mL/hour/kg Standard Deviation 3.1	-0.905 mL/hour/kg Standard Deviation 2.68
Change From Baseline in Fluid Balance Day 2 - 30-36 hours	-3.42 mL/hour/kg Standard Deviation 5.63	-0.963 mL/hour/kg Standard Deviation 3.82	-1.47 mL/hour/kg Standard Deviation 3.04
Change From Baseline in Fluid Balance Day 2 - 36-42 hours	-3.34 mL/hour/kg Standard Deviation 6.09	-1.82 mL/hour/kg Standard Deviation 3.36	-2.54 mL/hour/kg Standard Deviation 3.48
Change From Baseline in Fluid Balance Day 2 - 42-48 hours	-3.82 mL/hour/kg Standard Deviation 6.66	-2.18 mL/hour/kg Standard Deviation 3.51	-2.01 mL/hour/kg Standard Deviation 3.52
Change From Baseline in Fluid Balance Day 3 - 48-54 hours	-3.2 mL/hour/kg Standard Deviation 6.26	-1.97 mL/hour/kg Standard Deviation 3.68	-1.93 mL/hour/kg Standard Deviation 2.59
Change From Baseline in Fluid Balance Day 3 - 54-60 hours	-4.42 mL/hour/kg Standard Deviation 7.6	-2.85 mL/hour/kg Standard Deviation 3.52	-2.91 mL/hour/kg Standard Deviation 2.55
Change From Baseline in Fluid Balance Day 3 - 60-66 hours	-4.31 mL/hour/kg Standard Deviation 6.68	-2.86 mL/hour/kg Standard Deviation 3.33	-2.21 mL/hour/kg Standard Deviation 2.54
Change From Baseline in Fluid Balance Day 3 - 66-72 hours	-4.64 mL/hour/kg Standard Deviation 6.71	-2.75 mL/hour/kg Standard Deviation 3.76	-2.54 mL/hour/kg Standard Deviation 2.79
Change From Baseline in Fluid Balance Day 4 - 72-84 hours	-4.82 mL/hour/kg Standard Deviation 6.47	-2.52 mL/hour/kg Standard Deviation 3.36	-2.35 mL/hour/kg Standard Deviation 3.28
Change From Baseline in Fluid Balance Day 6 - 120-132 hours	-4.17 mL/hour/kg Standard Deviation 6.19	-3.04 mL/hour/kg Standard Deviation 3.86	-2.67 mL/hour/kg Standard Deviation 3.45
Change From Baseline in Fluid Balance Day 1 - 0-6 hours	-2.11 mL/hour/kg Standard Deviation 6.99	-0.0513 mL/hour/kg Standard Deviation 3.08	-0.477 mL/hour/kg Standard Deviation 2.03
Change From Baseline in Fluid Balance Day 1 - 0-12 hours	-3.56 mL/hour/kg Standard Deviation 6.34	-0.889 mL/hour/kg Standard Deviation 3.29	-0.578 mL/hour/kg Standard Deviation 2.2
Change From Baseline in Fluid Balance Day 1 - 12-18 hours	-3.66 mL/hour/kg Standard Deviation 6.68	-1.41 mL/hour/kg Standard Deviation 3.11	-0.98 mL/hour/kg Standard Deviation 2.42
Change From Baseline in Fluid Balance Day 1 - 18-24 hours	-3.49 mL/hour/kg Standard Deviation 6.78	-1.47 mL/hour/kg Standard Deviation 3.45	-0.119 mL/hour/kg Standard Deviation 2.95
Change From Baseline in Fluid Balance Day 4 - 84-96 hours	-4.01 mL/hour/kg Standard Deviation 6.08	-2.4 mL/hour/kg Standard Deviation 3.55	-2.67 mL/hour/kg Standard Deviation 3.58
Change From Baseline in Fluid Balance Day 5 - 96-108 hours	-4.3 mL/hour/kg Standard Deviation 6.08	-2.84 mL/hour/kg Standard Deviation 4.08	-2.62 mL/hour/kg Standard Deviation 3.2
Change From Baseline in Fluid Balance Day 5 - 108-120 hours	-4.12 mL/hour/kg Standard Deviation 5.99	-3.3 mL/hour/kg Standard Deviation 3.84	-2.22 mL/hour/kg Standard Deviation 2.78
Change From Baseline in Fluid Balance Day 6 - 132-144 hours	-5.41 mL/hour/kg Standard Deviation 6.62	-2.99 mL/hour/kg Standard Deviation 3.17	-2.87 mL/hour/kg Standard Deviation 3.19
Change From Baseline in Fluid Balance Day 7 - 144-156 hours	-5.56 mL/hour/kg Standard Deviation 6.34	-2.37 mL/hour/kg Standard Deviation 3.1	-2.8 mL/hour/kg Standard Deviation 2.69
Change From Baseline in Fluid Balance Day 7 - 156-168 hours	-5.38 mL/hour/kg Standard Deviation 6.09	-2.85 mL/hour/kg Standard Deviation 3.13	-2.6 mL/hour/kg Standard Deviation 2.46

SECONDARY outcome

Timeframe: Day 1 up to Day 7, Day 14 and Day 29

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
SOFA Score Day 2 (24-48 hours)	8.0 Score on a scale Standard Deviation 3.5	8.68 Score on a scale Standard Deviation 3.07	9.0 Score on a scale Standard Deviation 2.83
SOFA Score Day 3 (48-72 hours)	7.6 Score on a scale Standard Deviation 3.53	8.32 Score on a scale Standard Deviation 3.64	8.2 Score on a scale Standard Deviation 2.57
SOFA Score Day 4 (72-96 hours)	6.8 Score on a scale Standard Deviation 3.91	7.5 Score on a scale Standard Deviation 3.91	8.05 Score on a scale Standard Deviation 2.82
SOFA Score Day 5 (96-120 hours)	6.6 Score on a scale Standard Deviation 4.2	7.06 Score on a scale Standard Deviation 3.49	7.44 Score on a scale Standard Deviation 2.77
SOFA Score Day 6 (120-144 hours)	5.22 Score on a scale Standard Deviation 3.35	6.63 Score on a scale Standard Deviation 3.32	7.06 Score on a scale Standard Deviation 3.02
SOFA Score Day 7 (144-168 hours)	4.63 Score on a scale Standard Deviation 3.7	5.93 Score on a scale Standard Deviation 3.65	7.18 Score on a scale Standard Deviation 2.65
SOFA Score Day 28	1.75 Score on a scale Standard Deviation 2.36	2.7 Score on a scale Standard Deviation 2.63	2.11 Score on a scale Standard Deviation 0.93
SOFA Score Day 1 (0-24 hours)	8.7 Score on a scale Standard Deviation 2.45	11.9 Score on a scale Standard Deviation 3.43	10.5 Score on a scale Standard Deviation 3.22
SOFA Score Day 14	5.0 Score on a scale Standard Deviation 4.36	4.27 Score on a scale Standard Deviation 3.82	3.53 Score on a scale Standard Deviation 1.81

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Safety Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 1 - 6 hours	-1.7 Ratio Standard Deviation 80.3	1.35 Ratio Standard Deviation 85.2	-7.06 Ratio Standard Deviation 99.9
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 1 - 12 hours	22.8 Ratio Standard Deviation 95.3	-11.9 Ratio Standard Deviation 61.9	7.32 Ratio Standard Deviation 72.3
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 1 - 18 hours	12.1 Ratio Standard Deviation 86.7	-17.6 Ratio Standard Deviation 94	9.21 Ratio Standard Deviation 88.5
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 1 - 24 hours	-4.22 Ratio Standard Deviation 84.4	34.8 Ratio Standard Deviation 144	-3.68 Ratio Standard Deviation 92.8
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 2 - 30 hours	54.3 Ratio Standard Deviation 142	-16.5 Ratio Standard Deviation 116	12.4 Ratio Standard Deviation 96.1
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 2 - 36 hours	15.8 Ratio Standard Deviation 112	6.89 Ratio Standard Deviation 115	39.8 Ratio Standard Deviation 100
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 2 - 42 hours	28.6 Ratio Standard Deviation 137	-1.27 Ratio Standard Deviation 118	14.6 Ratio Standard Deviation 123
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 2 - 48 hours	16.2 Ratio Standard Deviation 74.3	10.3 Ratio Standard Deviation 105	8.24 Ratio Standard Deviation 135
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 3 - 72 hours	51.7 Ratio Standard Deviation 120	74.2 Ratio Standard Deviation 89.8	21.8 Ratio Standard Deviation 119
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 4 - 84 hours	61.4 Ratio Standard Deviation 115	7.54 Ratio Standard Deviation 85.4	44.1 Ratio Standard Deviation 97.9
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 6 - 144 hours	42.8 Ratio Standard Deviation 69.3	30.2 Ratio Standard Deviation 83.7	-19.6 Ratio Standard Deviation 114
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 7 - 156 hours	37.6 Ratio Standard Deviation 68.3	40.9 Ratio Standard Deviation 83.8	-19.1 Ratio Standard Deviation 151
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 7 - 168 hours	117 Ratio Standard Deviation 255	59 Ratio Standard Deviation 68.1	-30.2 Ratio Standard Deviation 105
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 3 - 54 hours	24.8 Ratio Standard Deviation 137	49.5 Ratio Standard Deviation 81.1	19.4 Ratio Standard Deviation 129
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 3 - 60 hours	118 Ratio Standard Deviation 172	9.8 Ratio Standard Deviation 106	50 Ratio Standard Deviation 108
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 3 - 66 hours	64.7 Ratio Standard Deviation 131	6.38 Ratio Standard Deviation 70.1	17.7 Ratio Standard Deviation 120
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 4 - 96 hours	96.1 Ratio Standard Deviation 97.2	65.5 Ratio Standard Deviation 112	22.9 Ratio Standard Deviation 128
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 5 - 108 hours	123 Ratio Standard Deviation 233	30.1 Ratio Standard Deviation 49.3	38.4 Ratio Standard Deviation 115
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 5 - 120 hours	63.7 Ratio Standard Deviation 130	5.89 Ratio Standard Deviation 58.3	51.8 Ratio Standard Deviation 132
Pulmonary Function : Change From Baseline in PaO2/FiO2 Day 6 - 132 hours	123 Ratio Standard Deviation 154	7.17 Ratio Standard Deviation 89.6	40.3 Ratio Standard Deviation 133

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Safety Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Pulmonary Function : Change From Baseline in Tidal Volume Day 1 - 6 hours	-0.533 mL/kg Standard Deviation 0.666	0.196 mL/kg Standard Deviation 0.736	-0.0189 mL/kg Standard Deviation 1.91
Pulmonary Function : Change From Baseline in Tidal Volume Day 1 - 12 hours	-0.208 mL/kg Standard Deviation 0.708	0.256 mL/kg Standard Deviation 0.794	-0.24 mL/kg Standard Deviation 1.37
Pulmonary Function : Change From Baseline in Tidal Volume Day 1 - 18 hours	0.171 mL/kg Standard Deviation 0.957	0.141 mL/kg Standard Deviation 0.539	-0.26 mL/kg Standard Deviation 1.17
Pulmonary Function : Change From Baseline in Tidal Volume Day 1 - 24 hours	-1.1 mL/kg Standard Deviation 1.16	0.285 mL/kg Standard Deviation 1.02	0 mL/kg Standard Deviation 1.64
Pulmonary Function : Change From Baseline in Tidal Volume Day 3 - 72 hours	-0.23 mL/kg Standard Deviation 1.49	1.48 mL/kg Standard Deviation 3.19	-0.348 mL/kg Standard Deviation 1.78
Pulmonary Function : Change From Baseline in Tidal Volume Day 4 - 84 hours	0.966 mL/kg Standard Deviation 2.44	0.466 mL/kg Standard Deviation 1.89	-0.844 mL/kg Standard Deviation 2.03
Pulmonary Function : Change From Baseline in Tidal Volume Day 2 - 30 hours	-0.81 mL/kg Standard Deviation 1.15	0.34 mL/kg Standard Deviation 1.46	-0.0259 mL/kg Standard Deviation 2.11
Pulmonary Function : Change From Baseline in Tidal Volume Day 2 - 36 hours	-0.208 mL/kg Standard Deviation 1.24	0.145 mL/kg Standard Deviation 0.734	-0.223 mL/kg Standard Deviation 1.64
Pulmonary Function : Change From Baseline in Tidal Volume Day 2 - 42 hours	-0.478 mL/kg Standard Deviation 1.13	0.298 mL/kg Standard Deviation 1.21	-1.19 mL/kg Standard Deviation 1.33
Pulmonary Function : Change From Baseline in Tidal Volume Day 2 - 48 hours	-0.604 mL/kg Standard Deviation 1.52	0.532 mL/kg Standard Deviation 1.31	-0.538 mL/kg Standard Deviation 2.02
Pulmonary Function : Change From Baseline in Tidal Volume Day 3 - 54 hours	-0.118 mL/kg Standard Deviation 1.86	0.163 mL/kg Standard Deviation 1.19	-0.859 mL/kg Standard Deviation 1.84
Pulmonary Function : Change From Baseline in Tidal Volume Day 3 - 60 hours	-0.214 mL/kg Standard Deviation 1.1	0.62 mL/kg Standard Deviation 1.69	-0.951 mL/kg Standard Deviation 1.57
Pulmonary Function : Change From Baseline in Tidal Volume Day 3 - 66 hours	-0.01 mL/kg Standard Deviation 1.37	0.628 mL/kg Standard Deviation 1.25	-0.592 mL/kg Standard Deviation 1.98
Pulmonary Function : Change From Baseline in Tidal Volume Day 4 - 96 hours	-0.528 mL/kg Standard Deviation 1.62	-0.313 mL/kg Standard Deviation 0.864	-1.16 mL/kg Standard Deviation 2.44
Pulmonary Function : Change From Baseline in Tidal Volume Day 5 - 108 hours	0.633 mL/kg Standard Deviation 1.93	0.207 mL/kg Standard Deviation 1.39	-0.723 mL/kg Standard Deviation 2.14
Pulmonary Function : Change From Baseline in Tidal Volume Day 5 - 120 hours	-0.338 mL/kg Standard Deviation 2.24	-0.412 mL/kg Standard Deviation 0.709	-0.613 mL/kg Standard Deviation 1.73
Pulmonary Function : Change From Baseline in Tidal Volume Day 6 - 132 hours	-0.298 mL/kg Standard Deviation 1.41	0.462 mL/kg Standard Deviation 1.86	-0.746 mL/kg Standard Deviation 1.41
Pulmonary Function : Change From Baseline in Tidal Volume Day 6 - 144 hours	-0.458 mL/kg Standard Deviation 1.09	0.292 mL/kg Standard Deviation 2.69	-0.823 mL/kg Standard Deviation 1.71
Pulmonary Function : Change From Baseline in Tidal Volume Day 7 - 156 hours	0.483 mL/kg Standard Deviation 1.13	-0.733 mL/kg Standard Deviation 1.32	-2.14 mL/kg Standard Deviation 2.53
Pulmonary Function : Change From Baseline in Tidal Volume Day 7 - 168 hours	-0.0667 mL/kg Standard Deviation 1.1	-0.438 mL/kg Standard Deviation 1.37	-2.19 mL/kg Standard Deviation 2.93

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Safety Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Change From Baseline in Arterial Blood Gas (Lactate) Day 5 - 120 hours	-0.6 mmol/L Standard Deviation 1	-1.06 mmol/L Standard Deviation 1.89	-1.38 mmol/L Standard Deviation 1.5
Change From Baseline in Arterial Blood Gas (Lactate) Day 7 - 156 hours	-0.56 mmol/L Standard Deviation 0.783	-2.17 mmol/L Standard Deviation 3.44	-1.3 mmol/L Standard Deviation 1.36
Change From Baseline in Arterial Blood Gas (Lactate) Day 7 - 168 hours	-0.533 mmol/L Standard Deviation 2.2	-1.6 mmol/L Standard Deviation 1.92	-1.34 mmol/L Standard Deviation 1.62
Change From Baseline in Arterial Blood Gas (Lactate) Day 1 - 24 hours	-0.9 mmol/L Standard Deviation 1.06	-1.01 mmol/L Standard Deviation 1.93	-0.533 mmol/L Standard Deviation 1.13
Change From Baseline in Arterial Blood Gas (Lactate) Day 2 - 30 hours	-0.975 mmol/L Standard Deviation 1.09	-1.33 mmol/L Standard Deviation 2.5	-0.647 mmol/L Standard Deviation 1.12
Change From Baseline in Arterial Blood Gas (Lactate) Day 4 - 96 hours	-0.671 mmol/L Standard Deviation 0.948	-0.52 mmol/L Standard Deviation 0.902	-1.34 mmol/L Standard Deviation 1.47
Change From Baseline in Arterial Blood Gas (Lactate) Day 5 - 108 hours	-0.633 mmol/L Standard Deviation 0.963	-1.37 mmol/L Standard Deviation 2.07	-1.21 mmol/L Standard Deviation 1.51
Change From Baseline in Arterial Blood Gas (Lactate) Day 6 - 144 hours	-1.03 mmol/L Standard Deviation 1.01	-1.28 mmol/L Standard Deviation 1.84	-1.12 mmol/L Standard Deviation 0.946
Change From Baseline in Arterial Blood Gas (Lactate) Day 1 - 6 hours	0 mmol/L Standard Deviation 0.482	-0.367 mmol/L Standard Deviation 1.03	-0.0278 mmol/L Standard Deviation 0.647
Change From Baseline in Arterial Blood Gas (Lactate) Day 1 - 12 hours	-0.489 mmol/L Standard Deviation 0.857	-0.833 mmol/L Standard Deviation 1.53	-0.0444 mmol/L Standard Deviation 0.912
Change From Baseline in Arterial Blood Gas (Lactate) Day 1 - 18 hours	-0.525 mmol/L Standard Deviation 0.932	-1.01 mmol/L Standard Deviation 1.66	-0.3 mmol/L Standard Deviation 0.974
Change From Baseline in Arterial Blood Gas (Lactate) Day 2 - 36 hours	-0.744 mmol/L Standard Deviation 1.01	-1.45 mmol/L Standard Deviation 2.57	-0.683 mmol/L Standard Deviation 1.19
Change From Baseline in Arterial Blood Gas (Lactate) Day 2 - 42 hours	-0.844 mmol/L Standard Deviation 0.958	-1.57 mmol/L Standard Deviation 2.84	-0.917 mmol/L Standard Deviation 1.11
Change From Baseline in Arterial Blood Gas (Lactate) Day 2 - 48 hours	-0.722 mmol/L Standard Deviation 1.11	-1.68 mmol/L Standard Deviation 2.84	-0.888 mmol/L Standard Deviation 1.29
Change From Baseline in Arterial Blood Gas (Lactate) Day 3 - 54 hours	-0.788 mmol/L Standard Deviation 1.22	-1.6 mmol/L Standard Deviation 1.99	-1.11 mmol/L Standard Deviation 1.33
Change From Baseline in Arterial Blood Gas (Lactate) Day 3 - 60 hours	-0.163 mmol/L Standard Deviation 1.13	-1.15 mmol/L Standard Deviation 1.65	-0.925 mmol/L Standard Deviation 1.4
Change From Baseline in Arterial Blood Gas (Lactate) Day 3 - 66 hours	-0.371 mmol/L Standard Deviation 1.08	-1.01 mmol/L Standard Deviation 1.84	-1.15 mmol/L Standard Deviation 1.39
Change From Baseline in Arterial Blood Gas (Lactate) Day 3 - 72 hours	-0.643 mmol/L Standard Deviation 1.03	-1.27 mmol/L Standard Deviation 1.92	-0.879 mmol/L Standard Deviation 1.45
Change From Baseline in Arterial Blood Gas (Lactate) Day 4 - 84 hours	-0.5 mmol/L Standard Deviation 1.07	-0.975 mmol/L Standard Deviation 1.76	-1.12 mmol/L Standard Deviation 1.36
Change From Baseline in Arterial Blood Gas (Lactate) Day 6 - 132 hours	-0.717 mmol/L Standard Deviation 0.768	-1.26 mmol/L Standard Deviation 1.87	-1.23 mmol/L Standard Deviation 1.27

SECONDARY outcome

Timeframe: At Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Days Alive and Free of Any Organ Dysfunction at Day 7	5.38 Percentage of days Standard Deviation 10.7	3.8 Percentage of days Standard Deviation 11.4	0.0 Percentage of days Standard Deviation 0.0

SECONDARY outcome

Timeframe: At Day 7, Day 14 and Day 28

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Percentage of Patients Alive and Free of All Vasopressors Day 7	60.0 Percentage of patients	57.9 Percentage of patients	73.7 Percentage of patients
Percentage of Patients Alive and Free of All Vasopressors Day 14	40.0 Percentage of patients	89.5 Percentage of patients	94.7 Percentage of patients
Percentage of Patients Alive and Free of All Vasopressors Day 28	50.0 Percentage of patients	82.4 Percentage of patients	83.3 Percentage of patients

SECONDARY outcome

Timeframe: At Day 7, Day 14 and Day 28

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Percentage of Days Alive and Free of Dialysis Day 7	53.9 Percentage of days Standard Deviation 43.4	79.7 Percentage of days Standard Deviation 36.4	83.2 Percentage of days Standard Deviation 24.1
Percentage of Days Alive and Free of Dialysis Day 14	55.1 Percentage of days Standard Deviation 45.0	80.1 Percentage of days Standard Deviation 33.4	87.6 Percentage of days Standard Deviation 16.9
Percentage of Days Alive and Free of Dialysis Day 28	50.5 Percentage of days Standard Deviation 43.9	78.5 Percentage of days Standard Deviation 35.4	88.6 Percentage of days Standard Deviation 19.8

SECONDARY outcome

Timeframe: At Day 7

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Percentage of Days Alive and Free of Ventilation	31.3 Percentage of days Standard Deviation 37.5	53.8 Percentage of days Standard Deviation 38.9	23.1 Percentage of days Standard Deviation 34.8

SECONDARY outcome

Timeframe: At Day 1, 7, 14, and 28

Population: The analysis population consist of FAS, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Mortality At Day 1	0.0 Percentage of patients	0.0 Percentage of patients	0.0 Percentage of patients
Mortality At Day 7	20.0 Percentage of patients	0.0 Percentage of patients	0.0 Percentage of patients
Mortality At Day 14	40.0 Percentage of patients	0.0 Percentage of patients	0.0 Percentage of patients
Mortality At Day 28	50.0 Percentage of patients	5.3 Percentage of patients	21.1 Percentage of patients

SECONDARY outcome

Timeframe: Day 1 up to Day 7

Population: The analysis population consist of Safety Analysis Set, which comprised of all patients who were dosed.

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.

Outcome measures

Outcome measures
Measure	FE 202158 1.25 n=10 Participants 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.	FE 202158 2.5 n=19 Participants 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.	PLCBO n=21 Participants Patients in the arm received an intravenous infusion for up to 7 days of placebo.
Incidence of Abnormal Changes in ECG Heart rate <=50 beats per minute	0 Number of patients	1 Number of patients	4 Number of patients
Incidence of Abnormal Changes in ECG Heart rate >=100 beats per minute	5 Number of patients	11 Number of patients	8 Number of patients
Incidence of Abnormal Changes in ECG PQ interval <=120 msec	1 Number of patients	6 Number of patients	5 Number of patients
Incidence of Abnormal Changes in ECG PQ interval >=220 msec	0 Number of patients	0 Number of patients	1 Number of patients
Incidence of Abnormal Changes in ECG QRS interval >=120 msec	2 Number of patients	2 Number of patients	4 Number of patients
Incidence of Abnormal Changes in ECG QT interval >=450 msec	3 Number of patients	4 Number of patients	8 Number of patients
Incidence of Abnormal Changes in ECG QT interval >=480 msec	1 Number of patients	2 Number of patients	6 Number of patients
Incidence of Abnormal Changes in ECG QT interval >=500 msec	0 Number of patients	2 Number of patients	3 Number of patients
Incidence of Abnormal Changes in ECG QT interval >=30 msec increase from Baseline	7 Number of patients	15 Number of patients	14 Number of patients
Incidence of Abnormal Changes in ECG QT interval >=60 msec increase from Baseline	5 Number of patients	13 Number of patients	12 Number of patients
Incidence of Abnormal Changes in ECG QTcF >=450 msec	1 Number of patients	9 Number of patients	10 Number of patients
Incidence of Abnormal Changes in ECG QTcF >=480 msec	0 Number of patients	3 Number of patients	7 Number of patients
Incidence of Abnormal Changes in ECG QTcF >=30 msec increase from Baseline	3 Number of patients	14 Number of patients	11 Number of patients
Incidence of Abnormal Changes in ECG QTcF >=60 msec increase from Baseline	2 Number of patients	9 Number of patients	9 Number of patients
Incidence of Abnormal Changes in ECG QTcF >=500 msec	0 Number of patients	2 Number of patients	6 Number of patients

Adverse Events

FE 202158 1.25

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

FE 202158 2.5

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

FE 202158 3.75

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

PLCBO

Serious events: 6 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Development Support

Ferring Pharmaceuticals

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.
Publication restrictions are in place

Restriction type: OTHER

Measure	FE 202158 1.25 n=10 participants at risk Patients in the arm received a continuous intravenous infusion of FE 202158 1.25 ng/kg/min up to seven consecutive days. 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.	FE 202158 2.5 n=19 participants at risk Patients in the arm received a continuous intravenous infusion of FE 202158 2.5 ng/kg/min up to seven consecutive days. 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.	FE 202158 3.75 n=2 participants at risk Patients in the arm received a continuous intravenous infusion of FE 202158 3.75 ng/kg/min up to seven consecutive days. 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.	PLCBO n=21 participants at risk Patients in the arm received a continuous intravenous infusion of isotonic saline up to seven consecutive days.
Blood and lymphatic system disorders Disseminated intravascular coagulation	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	50.0% 1/2 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Cardiac disorders Atrial fibrillation	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Cardiac disorders Myocarditis	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	5.3% 1/19 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Gastrointestinal disorders Gastrointestinal ischaemia	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Infections and infestations Haematoma infection	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Metabolism and nutrition disorders Hyperkalaemia	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Metabolism and nutrition disorders Metabolic acidosis	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Nervous system disorders Cerebral haemorrhage	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Renal and urinary disorders Oliguria	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	10.0% 1/10 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	5.3% 1/19 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	5.3% 1/19 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Vascular disorders Peripheral ischaemia	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	5.3% 1/19 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/2 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	4.8% 1/21 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.
Cardiac disorders Myocardial ischaemia	0.00% 0/10 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/19 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	50.0% 1/2 • Number of events 1 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.	0.00% 0/21 • 28 days AE information was collected throughout the trial from the time of obtaining informed consent until the end of follow-up.