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Clinical Trial Results:
A Double-blind, Randomised, Placebo-controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients with Vasopressor-dependent Septic Shock

Summary
EudraCT number	2014-003973-41
Trial protocol	BE NL FR DK
Global end of trial date	26 Feb 2018

Results information
Results version number	v1(current)
This version publication date	08 Mar 2019
First version publication date	08 Mar 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

000133

ISRCTN number

US NCT number

NCT02508649

WHO universal trial number (UTN)

Sponsor organisation name

Ferring Pharmaceuticals A/S

Sponsor organisation address

International PharmaScience Center, Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300

Public contact

Global Clinical Compliance, Ferring pharmaceuticals, DK0-Disclosure@ferring.com

Scientific contact

Global Clinical Compliance, Ferring pharmaceuticals, DK0-Disclosure@ferring.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Feb 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

26 Feb 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

To demonstrate superiority of selepressin plus standard care versus placebo plus standard care in the number of vasopressor- and mechanical ventilator-free days (with penalty for mortality) in subjects with vasopressor-dependent septic shock.

Protection of trial subjects

The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial, in compliance with the approved protocol and its amendments, Good Clinical Practice and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Jul 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 21

Country: Number of subjects enrolled

Belgium: 242

Country: Number of subjects enrolled

Denmark: 213

Country: Number of subjects enrolled

France: 335

Country: Number of subjects enrolled

United States: 57

Worldwide total number of subjects

868

EEA total number of subjects

811

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

337

From 65 to 84 years

479

85 years and over

Subject disposition

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Recruitment details

A total of 63 sites were authorised to recruit subjects for the trial between July 2015 and August 2017. Eleven of these sites did not recruit any subjects. The trial sites that randomised subjects to the trial were: 11 in Belgium, 5 in Denmark, 17 in France, 5 in the Netherlands, and 14 in the United States of America.

Screening details

A total of 6377 subjects were screened, of which 868 subjects were randomised (585 subjects were allocated to selepressin [three doses] and 283 subjects were allocated to placebo). Up to four dosing regimens of selepressin were planned to be investigated in the trial. However, the highest dosing regimen was not used.

Period 1 title

Overall Trial Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Sterile 0.9% sodium chloride solution given as an infusion.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Sterile 0.9% sodium chloride solution given as an infusion.

Selepressin 2.5 ng/kg/Min

Arm description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 2.5 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Selepressin 3.75 ng/kg/Min

Arm description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 3.75 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Selepressin 5.25 ng/kg/Min

Arm description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 5.25 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Selepressin Pooled

Arm description

All selepressin arms pooled together and treated as a single arm.

Arm type

Experimental

Investigational medicinal product name

Selepressin Pooled

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

All selepressin arms pooled together and treated as a single arm.

Number of subjects in period 1	Placebo	Selepressin 2.5 ng/kg/Min	Selepressin 3.75 ng/kg/Min	Selepressin 5.25 ng/kg/Min	Selepressin Pooled
Started	283	197	189	199	585
Dosed	266	191	177	194	562
Completed	265	184	174	189	547
Not completed	18	13	15	10	38
Post randomisation screening failure	12	4	9	3	16
Physician decision	1	2	1	-	3
Consent withdrawn by subject	4	6	5	6	17
Lost to follow-up	1	1	-	1	2

Period 2 title

Baseline Period

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

This was a double-blind trial in which the subjects, the investigators and the other trial site staff, the clinical coordinating centres, the trial steering committee, the clinical trial team at Ferring and its representatives were blinded to the treatment assignment.

Are arms mutually exclusive

Placebo

Arm description

Sterile 0.9% sodium chloride solution given as an infusion.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Sterile 0.9% sodium chloride solution given as an infusion.

Selepressin 2.5 ng/kg/Min

Arm description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 2.5 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Selepressin 3.75 ng/kg/Min

Arm description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 3.75 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Selepressin 5.25 ng/kg/Min

Arm description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Arm type

Experimental

Investigational medicinal product name

Selepressin 5.25 ng/kg/Min

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Selepressin Pooled

Arm description

All selepressin arms pooled together and treated as a single arm.

Arm type

Experimental

Investigational medicinal product name

Selepressin Pooled

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

All selepressin arms pooled together and treated as a single arm.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 included all subjects that were enrolled in the trial whereas Period 2 included all subjects that were dosed in the trial. Baseline data, efficacy, and safety outcomes are presented for all the dosed subjects.

Number of subjects in period 2	Placebo	Selepressin 2.5 ng/kg/Min	Selepressin 3.75 ng/kg/Min	Selepressin 5.25 ng/kg/Min	Selepressin Pooled
Started	266	191	177	194	562
Completed	263	184	172	187	543
Not completed	3	7	5	7	19
Consent withdrawn by subject	2	6	5	6	17
Lost to follow-up	1	1	-	1	2

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Sterile 0.9% sodium chloride solution given as an infusion.

Reporting group title

Selepressin 2.5 ng/kg/Min

Reporting group description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 3.75 ng/kg/Min

Reporting group description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 5.25 ng/kg/Min

Reporting group description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin Pooled

Reporting group description

All selepressin arms pooled together and treated as a single arm.

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: Period 1 included all subjects that were enrolled in the trial whereas Period 2 included all subjects that were dosed in the trial. Baseline data, efficacy, and safety outcomes are presented for all the dosed subjects.

Reporting group values	Placebo	Selepressin 2.5 ng/kg/Min	Selepressin 3.75 ng/kg/Min	Selepressin 5.25 ng/kg/Min	Selepressin Pooled	Total
Number of subjects	266	191	177	194	562
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
geometric mean (standard deviation)	65.7 ± 14.56	66.0 ± 12.76	67.2 ± 13.13	66.8 ± 12.47	66.6 ± 12.76	-
Gender categorical
Units: Subjects
Female	121	80	70	70	220	341
Male	145	111	107	124	342	487
Ethinicity
Units: Subjects
Hispanic or Latino	4	3	1	4	8	12
Not Hispanic or Latino	262	188	176	190	554	816
Unknown or Not Reported	0	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	1	0	0	0	0	1
Asian	1	2	5	4	11	12
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	4	3	11	7	21	25
White	260	186	161	183	530	790

End points

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Reporting group title

Placebo

Reporting group description

Sterile 0.9% sodium chloride solution given as an infusion.

Reporting group title

Selepressin 2.5 ng/kg/Min

Reporting group description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 3.75 ng/kg/Min

Reporting group description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 5.25 ng/kg/Min

Reporting group description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin Pooled

Reporting group description

All selepressin arms pooled together and treated as a single arm.

Reporting group title

Placebo

Reporting group description

Sterile 0.9% sodium chloride solution given as an infusion.

Reporting group title

Selepressin 2.5 ng/kg/Min

Reporting group description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 3.75 ng/kg/Min

Reporting group description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 5.25 ng/kg/Min

Reporting group description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin Pooled

Reporting group description

All selepressin arms pooled together and treated as a single arm.

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

The FAS comprised of all the subjects who were enrolled (i.e. randomised [as planned]) and dosed.

Subject analysis set title

Selepressin Pooled

Subject analysis set type

Full analysis

Subject analysis set description

All selepressin arms pooled together and treated as a single arm.

Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

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End point title

Vasopressor- and Mechanical Ventilator-free Days (PVFDs) ^[1]

End point description

Composite endpoint defined as number of days from start of treatment to 30 days thereafter during which subject is: 1. Alive. However, if patient dies within these 30-days then PVFDs will be zero even if there is a period during which subject is alive and free of both vasopressor treatment and mechanical ventilation; 2. Free of treatment with vasopressors: Less than 60 min during any contiguous 24-h period. If a patient requires vasopressors longer than 60 min in total during any 24-h period, the intervening intervals during which they are free of vasopressors will not be included in the determination of PVFDs; 3. Free of any mechanical ventilation: Less than 60 min during any contiguous 24-h period. If a patient requires mechanical ventilation longer than 60 min in total during any 24-h period, the intervening intervals during which they are not receiving mechanical ventilation will not be included in the period free of mechanical ventilation in the determination of PVFDs.

End point type

Primary

End point timeframe

Up to Day 30

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.

End point values	Placebo	Selepressin Pooled
Number of subjects analysed	266	562
Units: days
least squares mean (confidence interval 95%)	14.45 (12.82 to 16.09)	15.00 (13.77 to 16.23)

Placebo, Selepressin Pooled

Statistical analysis description

The primary endpoint was analysed using a van Elteren test. The analysis included a test of superiority using a two-sided 5% significance level.

Comparison groups

Placebo v Selepressin Pooled

Number of subjects included in analysis

828

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3015

Method

van Elteren test

Parameter type

Treatment difference

Point estimate

0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-1.34

upper limit

2.43

Secondary: All-cause Mortality

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End point title

All-cause Mortality ^[2]

End point description

Defined as the fraction of subjects that have died, regardless of cause.

End point type

Secondary

End point timeframe

At Day 90

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.

End point values	Placebo	Selepressin Pooled
Number of subjects analysed	257	526
Units: percent
number (not applicable)	39.44	40.59

Placebo, Selepressin Pooled

Statistical analysis description

Mortality was analysed using a logistic regression model with the individual sequential organ failure assessment (SOFA) scores and age as covariates and treatment arm as factor.

Comparison groups

Placebo v Selepressin Pooled

Number of subjects included in analysis

783

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.7694

Method

Logistic regression

Parameter type

Odds ratio (OR)

Point estimate

1.049

Confidence interval

level

95%

sides

2-sided

lower limit

0.762

upper limit

1.445

Notes
[3] - An odds ratio < 1 in proportion of subjects dying indicates lower mortality in the selepressin group.

Secondary: Renal Replacement Therapy (RRT)-free Days

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End point title

Renal Replacement Therapy (RRT)-free Days ^[4]

End point description

RRT-free days was defined as the number of days a subject is free of treatment with any form of RRT (continuous RRT, intermittent haemodialysis or peritoneal dialysis) and the intermittent periods were not included. RRT-free days was analysed excluding subjects on RRT for chronic renal failure at time of randomisation.

End point type

Secondary

End point timeframe

Up to Day 30

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.

End point values	Placebo	Selepressin Pooled
Number of subjects analysed	261	550
Units: days
least squares mean (confidence interval 95%)	18.21 (16.14 to 20.29)	18.50 (17.03 to 19.98)

Placebo, Selepressin Pooled

Statistical analysis description

This endpoint was analysed using a van Elteren test. The analysis was a test of superiority using a two-sided 5% significance level.

Comparison groups

Placebo v Selepressin Pooled

Number of subjects included in analysis

811

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8458

Method

van Elteren test

Parameter type

Treatment difference

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-2.07

upper limit

2.65

Secondary: Intensive Care Unit (ICU)-free Days

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End point title

Intensive Care Unit (ICU)-free Days ^[5]

End point description

The ICU free days, as for the PVFDs, reflect the time from last discharge of the ICU to Day 30 with an absolute penalty for mortality, i.e., any subject that died within this 30-day period was assigned zero value).

End point type

Secondary

End point timeframe

Up to Day 30

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.

End point values	Placebo	Selepressin Pooled
Number of subjects analysed	266	562
Units: days
least squares mean (confidence interval 95%)	12.15 (10.66 to 13.64)	12.64 (11.51 to 13.76)

Placebo, Selepressin Pooled

Statistical analysis description

This endpoint was analysed using a van Elteren test. The analysis was a test of superiority using a two-sided 5% significance level.

Comparison groups

Placebo v Selepressin Pooled

Number of subjects included in analysis

828

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4124

Method

van Elteren test

Parameter type

Treatment difference

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.22

upper limit

2.19

Adverse events

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Timeframe for reporting adverse events

Treatment-emergent adverse events (TEAEs) occurring after the investigational medicinal product (IMP) infusion to within 12 hours after the IMP infusion was stopped.

Adverse event reporting additional description

TEAEs were defined as adverse events that occurred after the IMP infusion to within 12 hours after the IMP infusion was stopped. All treated subjects were included in the safety analysis set and were analysed according to the actual treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Placebo

Reporting group description

Sterile 0.9% sodium chloride solution given as an infusion.

Reporting group title

Selepressin 2.5 ng/kg/Min

Reporting group description

Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 3.75 ng/kg/Min

Reporting group description

Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

Reporting group title

Selepressin 5.25 ng/kg/Min

Reporting group description

Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

Serious adverse events	Placebo	Selepressin 2.5 ng/kg/Min	Selepressin 3.75 ng/kg/Min	Selepressin 5.25 ng/kg/Min
Total subjects affected by serious adverse events
subjects affected / exposed	85 / 266 (31.95%)	57 / 191 (29.84%)	65 / 177 (36.72%)	57 / 194 (29.38%)
number of deaths (all causes)	58	43	40	42
number of deaths resulting from adverse events	58	43	40	42
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Metastatic carcinoma of the bladder
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Distributive shock
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Hypertension
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
Ischaemia
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Poor peripheral circulation
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	4 / 266 (1.50%)	1 / 191 (0.52%)	1 / 177 (0.56%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	0 / 4	0 / 1	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 4	0 / 1	1 / 1	0 / 3
Shock haemorrhagic
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Thrombosis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasoconstriction
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	4 / 177 (2.26%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	1 / 1	1 / 1	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
General disorders and administration site conditions
Catheter site haemorrhage
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	24 / 266 (9.02%)	10 / 191 (5.24%)	17 / 177 (9.60%)	12 / 194 (6.19%)
occurrences causally related to treatment / all	0 / 24	0 / 10	0 / 17	0 / 12
deaths causally related to treatment / all	0 / 24	0 / 10	0 / 17	0 / 12
Organ failure
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	4 / 266 (1.50%)	3 / 191 (1.57%)	3 / 177 (1.69%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	2 / 177 (1.13%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
Mediastinal mass
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 266 (1.13%)	0 / 191 (0.00%)	1 / 177 (0.56%)	5 / 194 (2.58%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 3
Investigations
Cardiac output decreased
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Troponin I increased
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anastomotic leak
subjects affected / exposed	0 / 266 (0.00%)	2 / 191 (1.05%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endotracheal intubation complication
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Traumatic haemothorax
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 266 (0.00%)	2 / 191 (1.05%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 266 (1.13%)	5 / 191 (2.62%)	5 / 177 (2.82%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	1 / 3	4 / 7	0 / 6	0 / 1
deaths causally related to treatment / all	1 / 2	1 / 2	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiogenic shock
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Cyanosis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Defect conduction intraventricular
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Myocardial depression
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	4 / 177 (2.26%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial stunning
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	2 / 177 (1.13%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Right ventricular failure
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cerebral ischaemia
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	2 / 266 (0.75%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Vasculitis cerebral
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Haemolysis
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic necrosis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal compartment syndrome
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Colitis ischaemic
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colonic fistula
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal ischaemia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Intestinal ischaemia
subjects affected / exposed	3 / 266 (1.13%)	4 / 191 (2.09%)	1 / 177 (0.56%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	2 / 3	3 / 4	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 1	2 / 3	1 / 1	1 / 2
Large intestine perforation
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Chronic hepatic failure
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Gallbladder disorder
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic hepatitis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin discolouration
subjects affected / exposed	1 / 266 (0.38%)	2 / 191 (1.05%)	2 / 177 (1.13%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	1 / 1	2 / 2	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	5 / 266 (1.88%)	0 / 191 (0.00%)	2 / 177 (1.13%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 266 (0.38%)	1 / 191 (0.52%)	0 / 177 (0.00%)	2 / 194 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fasciitis
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Arthritis infective
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Device related sepsis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	1 / 177 (0.56%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Extradural abscess
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Klebsiella sepsis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising fasciitis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	0 / 177 (0.00%)	1 / 194 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Peritonitis bacterial
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 266 (1.50%)	2 / 191 (1.05%)	2 / 177 (1.13%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	1 / 177 (0.56%)	3 / 194 (1.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
Septic shock
subjects affected / exposed	15 / 266 (5.64%)	10 / 191 (5.24%)	12 / 177 (6.78%)	8 / 194 (4.12%)
occurrences causally related to treatment / all	1 / 15	0 / 10	0 / 12	0 / 8
deaths causally related to treatment / all	1 / 14	0 / 9	0 / 9	0 / 7
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	1 / 266 (0.38%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hyperlactacidaemia
subjects affected / exposed	0 / 266 (0.00%)	1 / 191 (0.52%)	0 / 177 (0.00%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 266 (0.00%)	0 / 191 (0.00%)	1 / 177 (0.56%)	0 / 194 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Selepressin 2.5 ng/kg/Min	Selepressin 3.75 ng/kg/Min	Selepressin 5.25 ng/kg/Min
Total subjects affected by non serious adverse events
subjects affected / exposed	94 / 266 (35.34%)	54 / 191 (28.27%)	63 / 177 (35.59%)	60 / 194 (30.93%)
Injury, poisoning and procedural complications
Expired product administered
subjects affected / exposed	50 / 266 (18.80%)	26 / 191 (13.61%)	29 / 177 (16.38%)	31 / 194 (15.98%)
occurrences all number	94	48	47	62
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	30 / 266 (11.28%)	22 / 191 (11.52%)	24 / 177 (13.56%)	22 / 194 (11.34%)
occurrences all number	43	23	27	29
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	24 / 266 (9.02%)	12 / 191 (6.28%)	6 / 177 (3.39%)	7 / 194 (3.61%)
occurrences all number	25	13	6	7
Thrombocytopenia
subjects affected / exposed	12 / 266 (4.51%)	9 / 191 (4.71%)	10 / 177 (5.65%)	11 / 194 (5.67%)
occurrences all number	13	9	10	11
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	4 / 266 (1.50%)	5 / 191 (2.62%)	9 / 177 (5.08%)	4 / 194 (2.06%)
occurrences all number	4	5	9	4

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Were there any global substantial amendments to the protocol? Yes

08 Jul 2016

This was a substantial amendment, which was implemented during the conduct of the trial. The main reasons for this protocol amendment were to implement the following changes to the protocol: • To allow use of infusion pumps for administration of the investigational medicinal product. • To allow for calcium (free or total), creatinine (plasma or serum), and troponin (I or T) measurements according to local clinical practice. Uric acid was not routinely measured in clinical practice and therefore, uric acid was no longer required to be collected. • To introduce the recording of the highest lactate level obtained in accordance with local clinical practice in the pre-IMP treatment period following start of vasopressor treatment and to clarify that venous lactate could be recorded if arterial lactate had not been measured.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Double-blind, Randomised, Placebo-controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients with Vasopressor-dependent Septic Shock

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

Secondary: All-cause Mortality

Secondary: All-cause Mortality

Secondary: Renal Replacement Therapy (RRT)-free Days

Secondary: Renal Replacement Therapy (RRT)-free Days

Secondary: Intensive Care Unit (ICU)-free Days

Secondary: Intensive Care Unit (ICU)-free Days

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: A Double-blind, Randomised, Placebo-controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients with Vasopressor-dependent Septic Shock

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

Secondary: All-cause Mortality

Secondary: All-cause Mortality

Secondary: Renal Replacement Therapy (RRT)-free Days

Secondary: Renal Replacement Therapy (RRT)-free Days

Secondary: Intensive Care Unit (ICU)-free Days

Secondary: Intensive Care Unit (ICU)-free Days

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Double-blind, Randomised, Placebo-controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients with Vasopressor-dependent Septic Shock