Clinical trial NCT02508649
Conditions: Septic Shock
Sponsor: Ferring Pharmaceuticals
Start date: 2015-07-01; Completion date: 2018-02-26
Enrollment: 868 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, randomised, placebo-controlled, two-part adaptive clinical trial. The trial is designed to investigate the efficacy and safety of multiple dosing regimens of selepressin and to confirm the efficacy and safety of one dosing regimen in treatment of adult patients with septic shock requiring vasopressor.

Detailed description:

Arms: arm 1: None arm 2: Starting dose 1.7 ng/kg/min arm 3: Starting dose 2.5 ng/kg/min arm 4: Starting dose 3.5 ng/kg/min arm 5: Starting dose 5.0 ng/kg/min

The highest dosing regimen of selepressin was not investigated in the trial as the desired primary outcome for selepressin 3 arm was not achieved, and the trial was terminated for futility.
Interventions: intervention 1: selepressin intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Protocol 
 
 
Title of trial:  
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 
NCT number: 
NCT02508649 
Sponsor trial code: 
000133  
Date:  
08 Jul 2016 
 
 
 
 
 


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CLINICAL TRIAL PROTOCOL
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 Code: 000133
Note: This is a consolidated protocol including all changes stated in: 

Protocol Amendment 01 (implemented prior to trial start)

Protocol Amendment 02 
EudraCT Number:
2014-003973-41
IND Number:
77246
Investigational Medicinal Products:
Selepressin; concentrate for solution for infusion
Placebo; sterile 0.9% sodium chloride solution
Indication:
Vasopressor-dependent septic shock
Phase:
2b/3
Name and Address of Sponsor:
Ferring Pharmaceuticals A/S
Clinical Research and Development
Kay Fiskers Plads 11
2300 Copenhagen S, Denmark
Telephone number: +45 88 33 88 34
GCP Statement:
This trial will be performed in compliance with GCP
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another company 
within the Ferring Group. It is understood that information in this document shall not be disclosed to any third party, in 
any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or another company 
within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
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
SEPSIS-ACT / Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial
SIGNATORY INVESTIGATORS
 Department of Critical Care Medicine, University of 
Pittsburgh, United States of America.
 Medical-surgical Intensive Care Unit, Saint Luc University Hospital 
at the Université Catholique de Louvain, Brussels, Belgium.
TRIAL SITES
The trial will be conducted predominately across Europe and North America at approximately 60-
100 trial sites in total.
PLANNED TRIAL PERIOD
First visit for the first patient is planned for Q3 2015.
Last visit for the last patient is expected in Q4 2018.
CLINICAL PHASE
2b/3
OBJECTIVES
Primary objective

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 patients with vasopressor-dependent septic shock
Secondary objectives

To determine the efficacy of selepressin on: 
o
Organ dysfunction
o
Morbidity and mortality
o
Fluid balance
o
Health-related quality of life

To determine the safety profile of selepressin

To determine the pharmacokinetics of selepressin

To determine the health economics of selepressin

To further evaluate a range of biomarkers in relation to the mode of action of selepressin


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ENDPOINTS
Primary endpoint 

Vasopressor- and mechanical ventilator-free days (P&VFDs) up to Day 30
This composite endpoint is defined as the number of days (reported to one decimal place
[0.0 to 30.0 days]) from start of treatment with the investigational medicinal product (IMP) 
[selepressin or placebo] to 30.0 days thereafter during which the patient is: 1) alive; 2) free 
of treatment with intravenous vasopressors; and 3) free of any invasive mechanical 
ventilation (see definition below).
Any patient that dies within this 30-day period is assigned zero P&VFDs, even if there is a 
period during which the patient is free of both vasopressor treatment and mechanical 
ventilation. If vasopressors need to be restarted or mechanical ventilation needs to be 
initiated or restarted, and the use of either is greater than 60 minutes within a 24-hour 
period, then the clock is reset and the patient is not considered free of vasopressors and/or 
mechanical ventilation until after those therapies are again finally discontinued. Vasopressor 
use or mechanical ventilation during - and up to three hours after - surgery / procedure 
(including bedside) is exempt from this rule (i.e. does not reset the calculation of P&VFDs). 
The intent is for the endpoint to reflect the speed of recovery from septic shock and 
respiratory failure, with appropriate penalties for recurrent shock, new or recurrent 
respiratory failure, and death.
Vasopressor use is defined as any intravenous dose of norepinephrine/noradrenaline, 
phenylephrine, dopamine, epinephrine/adrenaline, vasopressin, terlipressin, and IMP (i.e. 
selepressin and placebo).
Mechanical ventilation is defined as use of endotracheal or tracheostomy tube assisted 
ventilation (>5 cm H2O continuous positive airway pressure and >5 cm H2O of pressure
support from the ventilator in tracheostomy patients). End of mechanical ventilation is 
defined as: 1) extubation of intubated patients or 2) ≤5 cm H2O continuous positive airway 
pressure and ≤5 cm H2O of pressure support from the ventilator in tracheostomy patients. If 
non-invasive ventilation by mask or bag (>5 cm H2O of pressure support) is deployed to 
avoid (re)intubation, it also counts as mechanical ventilation. However, all other uses of 
non-invasive ventilation such as chronic night-time use of positive airway pressure for 
chronic obstructive pulmonary disease (COPD) or sleep apnea does not count as mechanical 
ventilation (regardless of pressure).
Key secondary endpoints 

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at 
Day 90

Renal replacement therapy (RRT)-free days up to Day 30 (excluding patients on RRT for 
chronic renal failure at time of randomisation)

Intensive care unit (ICU)-free days up to Day 30


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Secondary efficacy endpoints 
Organ dysfunction

Vasopressor-free days up to Day 30

Mechanical ventilator-free days up to Day 30

Duration of septic shock (i.e. vasopressor use) up to Day 30

Duration of mechanical ventilation up to Day 30

Incidence of RRT up to Day 30 (counting patients who die as on RRT and excluding 
patients on RRT for chronic renal failure at time of randomisation)

Duration of RRT up to Day 90 (excluding patients on RRT for chronic renal failure at time 
of randomisation)

Daily overall and individual organ (cardiovascular, respiratory, renal, hepatic, coagulation) 
scores using a modified version of the Sequential Organ Failure Assessment (SOFA) until 
ICU discharge

Incidence of new organ dysfunction and new organ failure (based on the SOFA score) up to 
Days 7 and 30
Morbidity and mortality

ICU length of stay up to Day 30

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at
Days 30 and 180
Fluid balance

Daily and cumulative fluid balance until ICU discharge (for a maximum of 7 days)

Daily and cumulative urine output until ICU discharge (for a maximum of 7 days)
Health-related quality of life

Change in utility, based on the EuroQol group’s 5-dimension 5-level (EQ-5D-5L) 
questionnaire, up to Day 180
Safety endpoints

Incidence of adverse events (type, frequency, and intensity) with specific emphasis on:
o
Ischaemic events (e.g. myocardial, skin, cerebral, mesenteric, and limb ischaemia)

Changes in vital signs and safety laboratory variables, including:
o
Number of clinically significant results assessed as unanticipated in the setting of
septic shock 

Episodes of hypotension (mean arterial pressure <60 mmHg for longer than one hour)
Additional endpoints

Hospital-free days up to Day 90

Hospital length of stay up to Day 90


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
Patient residence at Day 30, Day 60, Day 90, and Day 180

Health economic evaluation - to be reported separately according to a pre-specified health 
economic analytical plan

Mean arterial pressure (MAP), until ICU discharge (for a maximum of 7 days)

Norepinephrine/noradrenaline and other vasopressor doses

Pharmacokinetic response (in a subset of approximately 200 patients) - to be reported 
separately according to a pre-specified pharmacokinetic analysis plan

Creatinine clearance

Ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio)
(in a subset of 100-350 patients)

Extravascular lung water and pulmonary permeability index (in a subset of 100-
350 patients)

Cardiac output (in a subset of 100-350 patients)

Cytokines (in a subset of 100-350 patients)

Angiopoietin-1 and -2 (in a subset of 100-350 patients)
METHODOLOGY
This is a double-blind, randomised, placebo-controlled, two-part adaptive clinical trial. The trial is 
designed to investigate the efficacy and safety of multiple dosing regimens of selepressin and to 
confirm the efficacy and safety of one dosing regimen in treatment of adult patients with septic 
shock requiring vasopressor.
Up to four dosing regimens of selepressin will be investigated:
Treatment
Arm
Starting Dose
(ng/kg/min)
Maximum Dose
(ng/kg/min)
Range
(ng/kg/min)
Arm 1
1.7
2.5
0-2.5
Arm 2
2.5
3.75
0-3.75
Arm 3
3.5
5.25
0-5.25
Arm 4
5.0
7.5
0-7.5
The overall trial design includes two parts (Part 1 – Phase 2b and Part 2 – Phase 3) as illustrated on 
the next page. 


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Part 1 is a dose-finding stage with response-adaptive randomisation to preferentially allocate 
patients to the dosing regimens that appear to have the maximum benefit with respect to the 
primary endpoint. Interim analyses will be conducted regularly in Part 1 to optimise the efficiency 
of selecting the optimal dosing regimen and to allow early termination of the trial for futility. If 
Part 1 results in a decision to run the second part of the trial, Part 2 will be a 1:1 randomised 
comparison of the best-performing dosing regimen of selepressin selected in Part 1 versus placebo 
on top of standard care. All patients will be on norepinephrine/noradrenaline treatment as part of 
standard of care at the time when the IMP (selepressin or placebo) infusion is initiated.
Before administration, selepressin will be diluted to one of four specific concentrations to allow for 
blinded administration using similar infusion rates. The infusion of IMP (selepressin or placebo)
will start as early as possible and no later than 12 hours after initiation of continuous infusion of 
vasopressor treatment for septic shock. To ensure start of IMP treatment without delay, informed 
consent will be obtained, in compliance with local regulations, as early as possible. 
During the course of treatment, the IMP infusion rate will be adjusted within pre-defined infusion 
rates to keep the MAP at the target of 65 mmHg. A different MAP target is acceptable, if it is pre-
specified and if it is appropriate, as judged by the investigator, for the clinical management e.g. 
previous history of hypotension or hypertension (if deemed necessary to maintain adequate organ 
perfusion). A detailed IMP and vasopressor administration guide will be provided to trial sites. If 
the administration of IMP in addition to norepinephrine/noradrenaline increases MAP to above the 
target, norepinephrine/noradrenaline will be weaned first while aiming to keep MAP at the target. 
Norepinephrine/noradrenaline must be completely weaned prior to weaning of IMP. If
norepinephrine/noradrenaline cannot be completely weaned, the infusion rate of IMP is to be 
increased up to the maximum allowed infusion rate in an attempt to use IMP as the sole 
vasopressor. If infusion of IMP alone increases the MAP to above the target, the IMP will be 
weaned step-wise while aiming to keep MAP at the target. If the maximum allowed infusion rate of 
the IMP is not sufficient to maintain MAP at the target, norepinephrine/noradrenaline will be added 
to achieve the targeted MAP. If target MAP cannot be maintained despite maximum allowed 
infusion rate of IMP and ≥1 µg/kg/min norepinephrine/noradrenaline base (or a total catecholamine 
equivalent of 1 µg/kg/min norepinephrine/noradrenaline base), vasopressin may be added.
The IMP infusion will continue as long as blood pressure support is deemed necessary with a 
maximum period of 30 days. After complete weaning, IMP infusion may be re-started during this 
30-day period for treatment of sepsis-induced hypotension if there is no suspicion of mesenteric or 
cardiac ischaemia. Patients who still need vasopressor treatment after 30 days will be switched to 
other vasopressors at the discretion of the investigator.
NUMBER OF PATIENTS
Enough patients will be enrolled in the trial to obtain 1800 evaluable patients in the entire 
programme (including both parts of the trial).


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CRITERIA FOR INCLUSION / EXCLUSION
The intention is to enrol a typical sample of patients presenting with septic shock and commence 
treatment with the IMP during the initial hours of resuscitation, within 12 hours from onset of 
vasopressor treatment, targeting those who do not respond rapidly to fluids and whose vasopressor-
need persists for at least one hour.
Inclusion criteria
1. 18 years of age or older.
2. Proven or suspected infection.
3. Septic shock defined as hypotension (systolic blood pressure less than 90 mmHg OR MAP 
less than 65 mmHg) requiring vasopressor treatment (i.e. any dose of norepinephrine / 
noradrenaline base greater than 5 µg/min) despite adequate fluid resuscitation (at least 
one litre for hypotension). 
4. Informed consent obtained in accordance with local regulations. 
Exclusion criteria
1. Not possible to initiate IMP treatment within 12 hours from onset of vasopressor treatment
for septic shock.
2. Primary cause of hypotension not due to sepsis (e.g. major trauma including traumatic brain 
injury, haemorrhage, burns, or congestive heart failure/cardiogenic shock).
3. Previous severe sepsis with ICU admission within this hospital stay.
4. Known/suspected acute mesenteric ischaemia.
5. Suspicion of concomitant acute coronary syndrome based on clinical symptoms and/or ECG 
during this episode of septic shock. 
6. Chronic mechanical ventilation for any reason OR severe COPD requiring either continuous
daily oxygen use during the preceding 30 days or mechanical ventilation (for acute 
exacerbation of COPD) during the preceding 30 days.
7. Received bone marrow transplant during the preceding 6 months or chemotherapy during 
the preceding 30 days for lymphoma or leukemia.
8. Known to be pregnant.
9. Decision to limit full care taken before obtaining informed consent. 
10. Use of vasopressin in the past 12 hours prior to start of the IMP infusion or use of 
terlipressin within 7 days prior to start of the IMP infusion. 
11. Prior enrolment in the trial.
12. Prior use of an investigational medicinal product within the last month OR planned or 
concurrent participation in a clinical trial for any investigational drug or investigational 
device.


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Eligibility criteria – post-randomisation / before start of IMP infusion
In addition, the following criteria must be met at start of IMP infusion:
1. Received a minimum of 30 mL/kg fluid in total from the onset of hypotension (or less if 
evidence of fluid replete/overload).
2. Received a continuous infusion of norepinephrine/noradrenaline base greater than 5 µg/min 
for at least one hour and is still receiving at least 5 µg/min norepinephrine/noradrenaline
base.
3. Less than 12 hours since onset of vasopressor treatment for septic shock.
INVESTIGATIONAL MEDICINAL PRODUCTS

Selepressin 0.3 mg/mL (10 mM acetate buffer, pH 4). Selepressin is provided as a stock 
solution which will be diluted with sterile 0.9% sodium chloride solution prior to infusion 
according to a specific dilution protocol.

Placebo: sterile 0.9% sodium chloride solution.
DURATION OF TREATMENT
All patients will receive IMP (selepressin or placebo) as an intravenous infusion until recovery 
from the need of vasopressor treatment or for 30 days, whichever comes first. If the need of 
vasopressor treatment subsides and recurs due to sepsis-induced hypotension within the 30-day 
treatment period, IMP should be used when possible if there is no suspicion of mesenteric or 
cardiac ischaemia.
STATISTICAL METHODS
The trial is powered to demonstrate superiority of selepressin plus standard care versus placebo plus 
standard care in the number of P&VFDs in patients with vasopressor-dependent septic shock.
Primary analysis
If Part 2 of the trial is run, the primary endpoint, P&VFDs, will be analysed using a van Elteren 
test. The primary analysis will compare all patients on all selepressin arms from both parts of the 
trial (pooled together and treated as a single arm) to all patients on the placebo arm from both parts 
of the trial. 
The primary analysis will be a test of superiority using a two-sided 5% significance level test. This 
test, within the trial, controls the type 1 error at a two-sided 5% level. 
The analysis will be based on both the full analysis set (FAS) and the per protocol (PP) analysis set, 
with the FAS being considered the primary analysis to judge statistical significance and the PP 
analysis considered as supportive. The FAS comprises all randomised (as planned) patients who 
have received IMP treatment. 
Power
The overall power for obtaining statistical significance based on combined evidence from Part 1 
and Part 2 is 91% in situations where all 4 arms have a true underlying 1.5% lower mortality rate 


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and a 1.5-day higher expected number of P&VFDs for survivors (corresponding to an overall 
treatment effect of 1.5 P&VFDs) as compared to placebo. If the effect sizes are 2% on mortality 
and 2 days for P&VFDs in survivors for all 4 arms (corresponding to an overall treatment effect of 
2 P&VFDs) then the overall power is 98%. In this latter case the probability of engaging into Part 2 
is ~99%.
Secondary analyses
The secondary endpoints are aimed at supporting primary efficacy by further demonstrating 
treatment effect accompanied by an acceptable safety profile. 
Endpoints defined as ‘-free days’ will be defined and analysed in a similar manner as the primary 
endpoint. Endpoints addressing SOFA score, fluid balance, and health-related quality of life as well 
as all endpoints measuring duration and split in survivors/non-survivors will be analysed by 
analysis of covariance (ANCOVA) methods and presented graphically. Mortality, incidence of new 
organ dysfunction, and new organ failure will be analysed by logistic regression. Mortality will be 
presented graphically by a Kaplan-Meier plot. All secondary endpoints will be analysed using both 
the FAS and the PP analysis set. 
For the purpose of a possible label inclusion, the Hochberg procedure for adjustment on 
multiplicity will be implemented to selected secondary endpoints. Only if the primary efficacy 
analysis leads to a statistically significant result at the (one-sided) 2.5% level, then the Hochberg 
procedure, which is described below, will be applied to selected secondary analyses. If the primary 
efficacy analysis does not result in statistical significance at the (one-sided) 2.5% level, then 
statistical significance (for the purpose of a possible label inclusion only) will not be declared for 
any of the secondary analyses, regardless of their p-values. 
The selected key secondary endpoints aimed at further demonstrating treatment effect are: 

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at 
Day 90

RRT-free days up to Day 30 (excluding patients on RRT for chronic renal failure at time of 
randomisation)

ICU-free days up to Day 30
In this application of the Hochberg procedure there are three hypothesis tests of superiority for each 
of the selected secondary endpoints. The target alpha level is (one-sided) 2.5%. The Hochberg 
procedure is as follows:

Order the p-values from the smallest to the largest value, p(1) < p(2) < p(3), with 
corresponding null hypothesis H(1), H(2), and H(3).

Start with the highest p-value. If p(3) < 2.5% (one-sided), then stop and declare all 
three comparisons significant at the 2.5% (one-sided) level (i.e. reject H(1), H(2), and H(3)). 
Otherwise, accept H(3) for the endpoint related to p(3), and go to p(2) the second highest p-
value.

If p(2) < 2.5/2 = 1.25% (one-sided), then stop and declare significance for H(1) and H(2). 


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Otherwise, accept H(2), for the endpoint related to p(2), and go to p(1) the lowest p-value.

If p(1) < 2.5/3 = 0.833% (one-sided), then stop and declare significance for H(1). Otherwise, 
accept H(1), for the endpoint related to p(1).
Regardless of the statistical significance declared according to the Hochberg procedure, all analysis 
will be included and presented in the statistical report.
The safety profile, including adverse events, vital signs, and safety laboratory variables, will be 
summarised descriptively. The safety analyses will be performed using the safety analysis set. The 
safety analysis set comprises all IMP-treated patients and are analysed according to the actual 
treatment received.


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 16
LIST OF FIGURES...................................................................................................................................... 16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 17
1
INTRODUCTION ............................................................................................................................. 20
1.1
Background............................................................................................................................. 20
1.2
Scientific Justification for Conducting the Trial..................................................................... 20
1.3
Benefit / Risk Aspects............................................................................................................. 21
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 24
2.1
Objectives ............................................................................................................................... 24
2.2
Endpoints ................................................................................................................................ 25
3
INVESTIGATIONAL PLAN ........................................................................................................... 28
3.1
Overall Trial Design................................................................................................................ 28
3.1.1
Trial Design Diagram................................................................................................. 28
3.1.2
Overall Design and Control Methods ........................................................................ 30
3.1.3
Trial Schedule............................................................................................................ 30
3.2
Planned Number of Trial Sites and Patients ........................................................................... 31
3.3
Interim Analysis...................................................................................................................... 31
3.4
Data and Safety Monitoring Board ......................................................................................... 31
3.5
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 31
3.5.1
Trial Design ............................................................................................................... 31
3.5.2
Selection of Endpoints ............................................................................................... 32
3.5.3
Choice of Control Group............................................................................................ 33
3.5.4
Selection of Doses in the Trial................................................................................... 33
3.5.5
Selection and Timing of Dose for Each Patient......................................................... 34
4
SELECTION OF TRIAL POPULATION ...................................................................................... 36
4.1
Trial Population....................................................................................................................... 36
4.1.1
Inclusion Criteria ....................................................................................................... 36
4.1.2
Exclusion Criteria ...................................................................................................... 37
4.1.3
Eligibility Criteria – Post-randomisation / Before Start of IMP Infusion.................. 38
4.2
Method of Assigning Patients to Treatment Groups............................................................... 39
4.2.1
Recruitment................................................................................................................ 39
4.2.2
Randomisation ........................................................................................................... 39
4.3
Restrictions ............................................................................................................................. 40
4.3.1
Prior and Concomitant Medications/Procedures........................................................ 40
4.3.2
Prohibited Medications/Procedures ........................................................................... 40
4.4
Discontinuation and Withdrawal............................................................................................. 40
5
TREATMENTS ................................................................................................................................. 42
5.1
Treatments Administered........................................................................................................ 42
5.1.1
Investigational Medicinal Product (IMP)................................................................... 42
5.1.2
Norepinephrine/Noradrenaline................................................................................... 42
5.2
Characteristics and Source of the IMPs .................................................................................. 42
5.3
Packaging and Labelling......................................................................................................... 42


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5.4
Conditions for Storage and Use .............................................................................................. 43
5.5
Blinding / Unblinding ............................................................................................................. 43
5.5.1
Blinding...................................................................................................................... 43
5.5.2
Unblinding of Individual Patient Treatment .............................................................. 45
5.6
Treatment Compliance............................................................................................................ 45
5.7
Return and Destruction of IMP............................................................................................... 45
6
TRIAL PROCEDURES .................................................................................................................... 46
6.1
Trial Flow Chart...................................................................................................................... 47
7
TRIAL ASSESSMENTS ................................................................................................................... 48
7.1
Assessments Related to Endpoints.......................................................................................... 48
7.1.1
Vasopressors .............................................................................................................. 48
7.1.2
Mechanical Ventilation.............................................................................................. 48
7.1.3
Renal Replacement Therapy (RRT) and Renal Function .......................................... 49
7.1.4
Modified Sequential Organ Failure Assessment (SOFA) Score................................ 49
7.1.5
Mortality Rate and Hospitalisation ............................................................................ 49
7.1.6
Health-related Quality of Life.................................................................................... 50
7.1.7
Fluid balance, Fluids, and Urine Output.................................................................... 50
7.1.8
Adverse Events .......................................................................................................... 51
7.1.9
Safety Laboratory Variables (Clinical Chemistry, Haematology, and Coagulation). 51
7.1.10 Diastolic and Systolic Blood Pressure, Heart Rate, Respiratory Rate, and Body 
Temperature............................................................................................................... 52
7.1.11 Mean Arterial Pressure............................................................................................... 52
7.1.12 PaO2/FiO2 Ratio......................................................................................................... 53
7.1.13 Extravascular Lung Water and Pulmonary Permeability Index................................. 53
7.1.14 Cardiac Output........................................................................................................... 54
7.2
Trial-specific Blood Sampling................................................................................................ 54
7.2.1
Copeptin Levels ......................................................................................................... 54
7.2.2
Pharmacokinetics....................................................................................................... 54
7.2.3
Cytokines ................................................................................................................... 54
7.2.4
Angiopoietins............................................................................................................. 55
7.3
Other Assessments.................................................................................................................. 55
7.3.1
Central Venous Pressure............................................................................................ 55
7.3.2
Central Venous Oxygen Saturation............................................................................ 55
7.3.3
Arterial Blood Gases and Lactate Levels................................................................... 55
7.4
Demographics and Other Baseline Assessments .................................................................... 56
7.4.1
Demographics ............................................................................................................ 56
7.4.2
Septic Shock Characteristics...................................................................................... 56
7.4.3
APACHE II................................................................................................................ 56
7.4.4
Electrocardiography................................................................................................... 56
7.4.5
Body Weight and Height............................................................................................ 56
7.4.6
Medical History ......................................................................................................... 56
7.4.7
Prior and Concomitant Medication/Procedure........................................................... 56
7.4.8
Pregnancy Test........................................................................................................... 57
7.5
Handling of Biological Samples ............................................................................................. 57
8
ADVERSE EVENTS ......................................................................................................................... 58
8.1
Adverse Event Definition........................................................................................................ 58


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8.2
Collection and Recording of Adverse Events......................................................................... 58
8.2.1
Collection of Adverse Events .................................................................................... 58
8.2.2
Recording of Adverse Events .................................................................................... 58
8.3
Adverse Events of Special Interest ......................................................................................... 61
8.4
Pregnancy................................................................................................................................ 61
8.5
Serious Adverse Events .......................................................................................................... 62
8.5.1
Serious Adverse Event Definition.............................................................................. 62
8.5.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 63
8.6
Follow-up of Adverse Events and Serious Adverse Events.................................................... 64
8.6.1
Follow-up of Adverse Events with Onset during the Trial........................................ 64
8.6.2
Collection of Serious Adverse Events with Onset after End of Trial ........................ 64
9
STATISTICAL METHODS ............................................................................................................. 65
9.1
Determination of Sample Size ................................................................................................ 65
9.2
Patient Disposition.................................................................................................................. 65
9.3
Protocol Deviations................................................................................................................. 66
9.4
Analysis Sets........................................................................................................................... 66
9.4.1
Intention-to-Treat Analysis Dataset........................................................................... 66
9.4.2
Full Analysis Set........................................................................................................ 66
9.4.3
Per Protocol Dataset................................................................................................... 66
9.4.4
Safety Dataset ............................................................................................................ 66
9.5
Trial Population....................................................................................................................... 66
9.5.1
Demographics and other Baseline Characteristics..................................................... 66
9.5.2
Medical History and Prior/Concomitant Medication................................................. 67
9.6
Endpoint Assessments............................................................................................................. 67
9.6.1
General Considerations.............................................................................................. 67
9.6.2
Primary Endpoint....................................................................................................... 67
9.6.2.1
Sensitivity Analyses of the Primary Endpoint .........................................................70
9.6.2.2
Additional Analyses.................................................................................................72
9.6.3
Secondary Endpoints ................................................................................................. 72
9.6.4
Other Efficacy Endpoints........................................................................................... 78
9.7
Extent of Exposure and Treatment Compliance ..................................................................... 79
9.8
Safety ...................................................................................................................................... 79
9.8.1
General Considerations.............................................................................................. 79
9.8.2
Adverse Events .......................................................................................................... 79
9.8.3
Safety Laboratory Variables ...................................................................................... 81
9.8.4
Vital Signs and Central Venous Pressure .................................................................. 82
9.8.5
Episodes of Hypotension ........................................................................................... 82
9.9
Interim Analyses ..................................................................................................................... 82
10
DATA HANDLING ........................................................................................................................... 84
10.1
Source Data and Source Documents....................................................................................... 84
10.2
Electronic Case Report Form (eCRF)..................................................................................... 85
10.3
Data Management ................................................................................................................... 86
10.4
Provision of Additional Information....................................................................................... 86
11
MONITORING PROCEDURES ..................................................................................................... 87
11.1
Periodic Monitoring................................................................................................................ 87
11.2
Audit and Inspection............................................................................................................... 87


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11.3
Confidentiality of Patient Data ............................................................................................... 87
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 88
12.1
Protocol Amendments............................................................................................................. 88
12.2
Deviations from the Protocol .................................................................................................. 88
12.3
Premature Trial Termination................................................................................................... 88
13
REPORTING AND PUBLICATION .............................................................................................. 89
13.1
Clinical Trial Report ............................................................................................................... 89
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 89
13.3
Publications and Public Disclosure......................................................................................... 89
13.3.1 Publication Policy...................................................................................................... 89
13.3.2 Public Disclosure Policy............................................................................................ 90
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 91
14.1
Independent Ethics Committees or Institutional Review Boards............................................ 91
14.2
Regulatory Authorities Authorisation / Approval / Notification ............................................ 91
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 91
14.4
Ethical Conduct of the Trial.................................................................................................... 91
14.5
Patient Information and Consent............................................................................................. 91
14.6
Patient Information Card......................................................................................................... 92
14.7
Compliance Reference Documents......................................................................................... 92
15
LIABILITIES AND INSURANCE .................................................................................................. 93
15.1
ICH-GCP Responsibilities...................................................................................................... 93
15.2
Liabilities and Insurance......................................................................................................... 93
16
ARCHIVING...................................................................................................................................... 94
16.1
Investigator File ...................................................................................................................... 94
16.2
Trial Master File...................................................................................................................... 94
17
REFERENCES................................................................................................................................... 95


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LIST OF TABLES 
Table 1
Dosing Regimens ............................................................................................................28
Table 2
Safety Laboratory Variables ...........................................................................................52
LIST OF FIGURES
Figure 1
Trial Design.....................................................................................................................29
Figure 2
Safeguards to Maintain Blinding during Trial Conduct..................................................44
Figure 3
Risk-based Heterogeneity of the Treatment Effect on P&VFDs over the Risk of 
Dying (an example).........................................................................................................70
Figure 4
Tipping Point Analysis of P&VFDs (an example) .........................................................72


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical (Classification System)
CCC
Clinical Coordinating Centre
CCL
CC Chemokine Ligand
COPD
Chronic Obstructive Pulmonary Disease
CSF
Colony-stimulating Factor
CVP
Central Venous Pressure
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
EQ-5D-5L
EuroQoL group’s 5-dimension 5-level Questionnaire 
EudraCT
European Union Clinical Trial Database
EVLW
Extravascular Lung Water
FAS
Full Analysis Set
FiO2
Fraction of Inspired Oxygen
FPFV
First Patient First Visit
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCO3
Bicarbonate
ICMJE
the International Committee of Medicinal Journal Editors
ICH
International Conference on Harmonisation
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IL
Interleukin
IMP
Investigational Medicinal Product
IND
Investigational New Drug


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IRB
Institutional Review Board
ITT
Intention-to-Treat
KM
Kaplan Meier
LOCF 
Last Observation Carried Forward
LPLV
Last Patient Last Visit
LTA
Lymphotoxin Alpha
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
P&VFD
Vasopressor- and Mechanical Ventilator-free Day
PaCO2
Arterial Carbon Dioxide Partial Pressure
PaO2
Arterial Oxygen Partial Pressure
PK
Pharmacokinetic
PP
Per Protocol
PPI
Pulmonary Permeability Index
PT
Preferred Term
QALY 
Quality-adjusted Life Years
RRT
Renal Replacement Therapy
SaO2
Arterial Oxygen Saturation
ScvO2
Central Venous Oxygen Saturation
SOC
System Organ Class
SOFA
Sequential Organ Failure Assessment
SUSAR
Suspected Unexpected Serious Adverse Reaction
TSC
Trial Steering Committee
VEGFA
Vascular Endothelial Growth Factor


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Definition of Terms
Audit
A systematic and independent examination of trial-related activities and 
documents to determine whether the evaluated trial-related activities were 
conducted, and the data were recorded, analysed, and accurately reported 
according to the protocol, sponsor's standard operating procedures, good 
clinical practice, and the applicable regulatory requirement(s).
Clinical Coordinating 
Center
A third party contracted by Ferring to provide support to the trial sites for 
certain aspects of conduct of the trial, such as assessment of eligibility and 
medical support.
Compliance
Adherence to all the trial-related requirements, good clinical practice 
requirements, and the applicable regulatory requirements.
Evaluable Patient
A patient who has been treated with the investigational medicinal product
(IMP) and 30 days have passed since initiation of IMP infusion.
Good Clinical Practice
A standard for the design, conduct, performance, monitoring, auditing, 
recording, analyses, and reporting of clinical trials that provides assurance 
that the data and reported results are credible and accurate, and that the 
rights, integrity, and confidentiality of trial participants are protected.
Investigator
The person responsible for the conduct of the clinical trial at a trial site. If 
a trial is conducted by a team of individuals at a trial site, the investigator 
is the responsible leader of the team and may be called the principal 
investigator.
Legal Representative
An individual or juridical or other body authorised under applicable law 
to consent, on behalf of a prospective patient, to the patient’s participation 
in the clinical trial.
Treated Patient
A patient who has been treated with the IMP.
Trial Entry Terms
Screening
The act of determining if an individual meets requirements for 
participation in the clinical trial.
Enter (=Consent)
The act of obtaining informed consent for participation in the clinical trial 
from patients deemed eligible or potentially eligible to participate in the 
clinical trial. Patients who have entered into a trial are those who sign the 
informed consent document directly or through their legally acceptable 
representatives.
Enrolment (=Randomisation)
The act of assigning a patient to a treatment. Patients who are enrolled in 
the trial are those who have been assigned to a treatment.


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1
INTRODUCTION
1.1
Background
Ferring Pharmaceuticals A/S (hereinafter called Ferring) is currently developing selepressin, a 
novel vasoconstrictor agent for treatment of patients with vasopressor-dependent septic shock. 
Patients suffering from septic shock, defined by the need for vasopressor treatment despite adequate 
fluid resuscitation, represent an extremely ill patient population with a common need for prolonged 
intensive care, frequent multisystem organ failure, and a high mortality. Septic shock is one of the 
most common causes of death in intensive care units (ICUs) and its incidence is rising. The 
growing incidence is most likely due to increased use of invasive devices and immunosuppressive 
therapies, higher numbers of immunocompromised patients, more antibiotic resistance, and an 
aging population.
Selepressin is a cyclic nonapeptide vasopressin analogue with high affinity and selectivity for the 
human vasopressin V1a-receptor versus the V1b-, V2-, and oxytocin receptors and no known affinity 
to other receptors, ion-channels, and transporters (Laporte R et al, 2011). The lack of V1b and V2
activity is the main differentiator of selepressin from existing vasopressin analogues such as 
arginine vasopressin. 
In addition to its vasopressor activity, one of the key characteristic of selepressin is its apparent
anti-leakage properties (Maybauer et al., 2014; Rehberg et al., 2012(a); Rehberg et al., 2011; Su et 
al., 2012). The ability to limit vascular leakage is a clinically relevant and very important feature of 
selepressin. While fluid therapy is fundamental to the acute resuscitation of critically ill patients, in 
those with sepsis accompanied by increased capillary permeability from microvascular injury, it 
can contribute to tissue oedema and eventually organ dysfunction. 
Thus, selepressin may serve a dual role of providing haemodynamic benefit while reducing the 
leakage of intravascular fluid into the extracellular space. It is believed that these unique 
characteristics could help address the unmet need in the treatment of vasopressor-dependent septic 
shock and provide significant benefit for the patients.
Moreover, due to the lack of V2 activity, selepressin does not cause V2-mediated antidiuresis and 
release of coagulation factors (Rehberg et al, 2012(b)), important safety consideration in septic 
shock patients that often have a positive fluid balance and coagulation disturbances.
1.2
Scientific Justification for Conducting the Trial
Septic shock is characterised by hypotension and decreased tissue perfusion due to vasodilation and 
capillary leakage. In this setting, vasopressors such as norepinephrine / noradrenaline, epinephrine / 
adrenaline, and dopamine are considered to be critical life-support necessary to quickly restore 
perfusion pressure. However, at the same time these drugs may cause serious adverse effects such 
as arrhythmias, myocardial, mesenteric, cerebral, or digital ischaemia/infarction, and acute kidney 


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injury. Such complications may prevent or prolong the recovery from septic shock and may cause 
long-term sequelae. Therefore, interventions that decrease the duration of the need for vasopressors
are expected to result in reduced risk of complications and possibly improved patient outcome.
In the first clinical trial with selepressin in septic shock patients (FE 202158 CS02), selepressin 
reduced the need for norepinephrine/noradrenaline in a dose-dependent manner 
(Ferring report, CS02). Furthermore, selepressin significantly reduced the duration of mechanical 
ventilation compared to placebo during the first 7 days. Also, cumulative fluid balance and fluid 
overload tended to be reduced compared to placebo. However, the FE 202158 CS02 trial was not 
powered to assess clinical outcomes and therefore, a large pivotal trial is needed to fully assess the 
effects and clinical outcomes associated with the use of selepressin. 
The present trial (trial code: 000133) is an adequately powered Phase 2b/3 clinical trial designed to 
assess and confirm the efficacy and safety of selepressin as a treatment for patients with 
vasopressor-dependent septic shock. The trial design has been reviewed by both the United States 
Food and Drug Administration and the European Medicines Agency.
1.3
Benefit / Risk Aspects
Selepressin is a potent vasoconstrictor and expected pharmacological effects include correction of 
hypotension which makes treatment potentially beneficial to the septic shock patients participating 
in the trial. The vasoconstrictor effect of selepressin has been investigated in a number of studies in 
vitro and in vivo in healthy animals, in sheep models of severe sepsis and septic shock, in isolated 
human resistance arteries, and in septic shock patients. In animal models of severe sepsis and septic 
shock, selepressin was shown to limit fluid accumulation and pulmonary oedema formation 
(Maybauer et al, 2014; Su et al, 2012). In patients with septic shock, this may provide clinical 
benefit by reducing mortality and/or the total duration of time that the patient requires life support 
with vasopressors and mechanical ventilation, speeding up the recovery, and reducing the risk of 
short- and long-term sequelae from organ dysfunction. 
In healthy adult men and women, the safety profile of selepressin was consistent with the 
pharmacological effects of a V1a agonist, mainly related to its vasoconstrictor properties, and did 
not cause any safety concerns (Ferring report, FE 202158 CS01). The dose-limiting effect was 
reduction in cardiac output. The infusion of selepressin was interrupted in 7 out of 10 subjects in 
the highest dose group (13.1 µg/h [i.e. 3.1 ng/kg/min assuming 70 kg body weight]) due to a 
decrease in cardiac output by more than 25%, which was a pre-defined criterion for termination of 
infusion. No negative renal or hepatic effects were observed. Some subjects reported signs of 
gastrointestinal discomfort, pallor, and feeling of body temperature change (i.e. signs of effects on 
the peripheral blood flow). The ECG, blood gases, lactate, and the other safety laboratory 
parameters were not affected to any measurable extent by the infusion of selepressin. QTcF values 
of >450 msec, or an increase of >30 msec, were sporadically observed in all dose groups at all time-
points, including 7 subjects that received placebo. V1a-induced mesenteric vasoconstriction is a 
general safety concern. However, no signs of mesenteric or myocardial ischaemia were observed in 
the healthy subjects. The lack of signs of myocardial ischaemia is consistent with previous findings 


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that selepressin did not demonstrate specific coronary vasoconstrictive properties in anaesthetised 
dogs. 
Two clinical trials in septic shock patients have been conducted. In the first trial (trial code: 
FE 202158 CS02), selepressin was safe and well tolerated up to an infusion rate of 2.5 ng/kg/min.
Too few patients were enrolled in the highest dose group (i.e. 3.75 ng/kg/min), and hence it was not 
possible to conclude on the safety of this dose level. In approximately 50% of the patients receiving 
2.5 ng/kg/min of selepressin, norepinephrine/noradrenaline could be completely weaned within 
12 hours whereas all patients receiving 1.25 ng/kg/min required norepinephrine/noradrenaline at 
12 hours (Ferring report, FE 202158 CS02). There were neither apparent differences between 
treatment with selepressin and placebo with respect to adverse event reporting nor apparent shifts or 
trends in the means of the ECG parameters during the treatment period that could be attributed to 
the treatment. A number of patients in all treatment groups, including >75% of the placebo patients, 
had occasional QTcF values >450 ms, several of whom already had this finding at baseline, or an 
increase of >30 ms. These observations were regarded as caused by the underlying disease.
The second trial in septic shock patients (trial code: 000025) investigated the dose-range from 2.5-
7.5 ng/kg/min and allowed free up- as well as down-titration of selepressin within a certain range. 
Data from this trial showed that: 1) it was possible to wean norepinephrine/noradrenaline
completely within few hours in most of the patients when the selepressin dose was increased to 5-
7.5 ng/kg/min, 2) it was possible to maintain mean arterial pressure (MAP) within a target range by 
adjusting the dose, and 3) in the majority of patients, doses above 3.75 ng/kg/min were only needed 
during the first 6 hours. Five patients reported a total of eight treatment-emergent serious adverse 
events which were regarded as related to the treatment. Four of these events occurred in the same 
patient including one with fatal outcome. Although it cannot be ruled out that the infusion of 
selepressin, which was stopped after 9.5 hours, approximately 17 hours before the fatal outcome, 
contributed to the development of the adverse event, it should be recognised that the condition of 
the patient at enrolment was very serious with a very high baseline infusion rate of noradrenaline
(1 μg/kg/min) and a high lactate level (5.4 mmol/L).
The pharmacokinetic profile of selepressin in septic shock patients is based on data from the
FE 202158 CS02 and the 000025 trials. As the infusion rate of selepressin was adjusted according
to the need of the patient, the pharmacokinetic parameters were calculated by means of population
pharmacokinetic modelling. Clearance was on average estimated to 11.28 L/h in a typical patient 
with a body weight of 70 kg, with inter-individual variability of 22 (CV%). The time to steady state
concentration was approximately 7 hours and the steady-state concentrations were proportional to
the initial infusion rate. The terminal half-life was approximately 1.4 hours irrespective of dose.
However, the initial distribution phase half-life was short, approximately 10 minutes.
The evaluation of benefits and risks indicate that participation in this trial is associated with a 
favourable benefit-risk ratio. The trial is justified by the potential clinical benefit of a selective V1a
receptor agonist treatment in patients with vasopressor-dependent septic shock and the risk posed to 
the patients participating in the trial is deemed low as the standard septic shock treatment will be in 


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line with the Surviving Sepsis Campaign guidelines (Dellinger et al, 2013). Patients participating in 
this trial will be closely monitored and they will have either the same or more frequent contacts 
with treating clinicians compared to routine treatment, depending on local clinical practice. 
For further information regarding selepressin, please refer to the current investigator’s brochure.


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

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 patients with vasopressor-dependent septic shock
Secondary Objectives

To determine the efficacy of selepressin on: 
o
Organ dysfunction
o
Morbidity and mortality
o
Fluid balance
o
Health-related quality of life

To determine the safety profile of selepressin

To determine the pharmacokinetics of selepressin

To determine the health economics of selepressin

To further evaluate a range of biomarkers in relation to the mode of action of selepressin


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2.2
Endpoints
Primary Endpoint

Vasopressor- and mechanical ventilator-free days (P&VFDs) up to Day 30
This composite endpoint is defined as the number of days (reported to one decimal place [0.0 to 
30.0 days]) from start of treatment with the investigational medicinal product (IMP) 
[selepressin or placebo] to 30.0 days thereafter during which the patient is: 1) alive; 2) free of 
treatment with intravenous vasopressors; and 3) free of any invasive mechanical ventilation (see 
definition below). 
Any patient that dies within this 30-day period is assigned zero P&VFDs, even if there is a 
period during which the patient is free of both vasopressor treatment and mechanical 
ventilation. If vasopressors need to be restarted or mechanical ventilation needs to be initiated 
or restarted, and the use of either is greater than 60 minutes within a 24-hour period, then the 
clock is reset and the patient is not considered free of vasopressors and/or mechanical 
ventilation until after those therapies are again finally discontinued. Vasopressor use or 
mechanical ventilation during - and up to three hours after - surgery / procedure (including 
bedside) is exempt from this rule (i.e. does not reset the calculation of P&VFDs). The intent is 
for the endpoint to reflect the speed of recovery from septic shock and respiratory failure, with 
appropriate penalties for recurrent shock, new or recurrent respiratory failure, and death.
Vasopressor use is defined as any intravenous dose of norepinephrine/noradrenaline, 
phenylephrine, dopamine, epinephrine/adrenaline, vasopressin, terlipressin, and IMP (i.e. 
selepressin and placebo).
Mechanical ventilation is defined as use of endotracheal or tracheostomy tube assisted 
ventilation (>5 cm H2O continuous positive airway pressure and >5 cm H2O of pressure support 
from the ventilator in tracheostomy patients). End of mechanical ventilation is defined as: 
1) extubation of intubated patients or 2) ≤5 cm H2O continuous positive airway pressure and 
≤5 cm H2O of pressure support from the ventilator in tracheostomy patients. If non-invasive 
ventilation by mask or bag (>5 cm H2O of pressure support) is deployed to avoid (re)intubation, 
it also counts as mechanical ventilation. However, all other uses of non-invasive ventilation 
such as chronic night-time use of positive airway pressure for chronic obstructive pulmonary 
disease (COPD) or sleep apnea does not count as mechanical ventilation (regardless of 
pressure). 
Key Secondary Endpoints
The following key secondary endpoints have been selected for the purpose of a possible label 
inclusion (see Section 9.6.3).

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at 
Day 90

Renal replacement therapy (RRT)-free days up to Day 30 (excluding patients on RRT for 
chronic renal failure at time of randomisation)


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
Intensive care unit (ICU)-free days up to Day 30
Secondary Efficacy Endpoints
Other secondary endpoints are listed below. All ssessments related to the endpoints are described in 
Section 7.1. 
Organ dysfunction

Vasopressor-free days up to Day 30

Mechanical ventilator-free days up to Day 30

Duration of septic shock (i.e. vasopressor use) up to Day 30

Duration of mechanical ventilation up to Day 30

Incidence of RRT up to Day 30 (counting patients who die as on RRT and excluding 
patients on RRT for chronic renal failure at time of randomisation) 

Duration of RRT up to Day 90 (excluding patients on RRT for chronic failure at time of 
randomisation)

Daily overall and individual organ (cardiovascular, respiratory, renal, hepatic, coagulation) 
scores using a modified version of the Sequential Organ Failure Assessment (SOFA) until 
ICU discharge

Incidence of new organ dysfunction and new organ failure (based on the SOFA score) up to 
Days 7 and 30
Morbidity and mortality

ICU length of stay up to Day 30

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at 
Days 30 and 180
Fluid balance

Daily and cumulative fluid balance until ICU discharge (for a maximum of 7 days)

Daily and cumulative urine output until ICU discharge (for a maximum of 7 days)
Health-related quality of life

Change in utility, based on the EuroQol group’s 5-dimension 5-level (EQ-5D-5L) 
questionnaire, up to Day 180
Safety Endpoints

Incidence of adverse events (type, frequency, and intensity) with specific emphasis on:
o
Ischaemic events (e.g. myocardial, skin, cerebral, mesenteric, and limb ischaemia)

Changes in vital signs and safety laboratory variables, including:
o
Number of clinically significant results assessed as unanticipated in the setting of 
septic shock

Episodes of hypotension (MAP <60 mmHg for longer than one hour)


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Additional Endpoints

Hospital-free days up to Day 90

Hospital length of stay up to Day 90

Patient residence at Day 30, Day 60, Day 90, and Day 180

Health economic evaluation - to be reported separately according to a pre-specified health 
economic analytical plan

Mean arterial pressure (MAP), until ICU discharge (for a maximum of 7 days)

Norepinephrine/noradrenaline and other vasopressor doses

Pharmacokinetic response (in a subset of approximately 200 patients) - to be reported
separately according to a pre-specified pharmacokinetic analysis plan

Creatinine clearance

Ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio)
(in a subset of 100-350 patients)

Extravascular lung water and pulmonary permeability index (in a subset of 100-
350 patients)

Cardiac output (in a subset of 100-350 patients)

Cytokines (in a subset of 100-350 patients)

Angiopoietin-1 and -2 (in a subset of 100-350 patients)


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
The overall trial design is a multi-centre, double-blind, randomised, placebo-controlled, two-part 
adaptive clinical trial. The trial is designed to investigate the efficacy and safety of multiple dosing 
regimens of selepressin and to confirm the efficacy and safety of one dosing regimen in treatment 
of adult patients with septic shock requiring vasopressor treatment. 
Up to four dosing regimens of selepressin, as described in Table 1, will be investigated in the first 
part of the trial and the best-performing dosing regimen will be selected for the second part of the 
trial.
Table 1
Dosing Regimens
Starting Dose
(ng/kg/min)
Maximum Dose
(ng/kg/min)
Range
(ng/kg/min)
Arm 1
1.7
2.5
0-2.5
Arm 2
2.5
3.75
0-3.75
Arm 3
3.5
5.25
0-5.25
Arm 4
5.0
7.5
0-7.5
3.1.1
Trial Design Diagram
The overall trial design is illustrated in Figure 1. The entire trial duration for an individual patient is 
up to 6 months (see Section 6).


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Figure 1
Trial Design


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3.1.2
Overall Design and Control Methods
This is a Phase 2b/3 adaptive clinical trial with two parts: Part 1 - Phase 2b and Part 2 - Phase 3 
(Figure 1). The entire trial, combining both parts, represents an adequate and well-controlled 
comparison of selepressin versus placebo. Part 1 comprises 300 evaluable – 800 treated patients. 
The size of Part 2 will include enough patients to bring the total number of patients in Part 1 and 
Part 2 to 1800 evaluable patients, ensuring a minimum sample size of 1000 patients in Part 2. The 
final analysis uses all patients from both parts of the trial.
Part 1 will begin with a 200-patient ‘burn-in’ period during which fixed randomisation across 
Arms 1, 2, and 3 will be used (the arms are described in Table 1) with: 

One-third of the patients randomised to placebo 

Two-third of the patients randomised to selepressin (two-ninths of the patients to each of the 
Arms 1, 2, and 3). 
After completion of the ‘burn-in’ period, Part 1 will utilise response-adaptive randomisation to 
preferentially allocate patients to the treatment arms that appear to have the maximum benefit with 
respect to the primary endpoint (i.e. vasopressor- and mechanical ventilator-free days [P&VFD]). A 
fixed fraction (one-third) of patients will be randomised to placebo throughout Part 1 to ensure 
contemporaneous control patients are enrolled throughout the trial. Arm 4 will only be opened 
between 200 evaluable and 600 treated patients and if there is at least a 50% posterior probability 
that Arm 3 has a higher expected P&VFD than Arm 2 and data from the lower dosing regimens do 
not suggest any significant safety concerns.
If Part 1 results in the decision to run Part 2, Part 2 will utilise a fixed 1:1 randomisation proportion 
between placebo and the best-performing dosing regimen of selepressin. The best-performing 
dosing regimen will be identified at the end of Part 1. 
Pre-defined interim analyses will be conducted as described in Section 3.3 and Section 9.9. Patient 
enrolment will continue without any stop at the interim analyses and a seamless transition to Part 2 
can occur after any interim analysis after 300 evaluable - 800 treated patients in Part 1.
3.1.3
Trial Schedule
The estimated timelines are:

First patient first visit (FPFV): 
Q3 2015

Last patient at Day 30 (primary database lock):
Q2 2018

Last patient last visit (LPLV) / end-of-trial:
Q4 2018
It is expected that all patients will be recruited within a period of up to 3 years. Hence, the duration 
of the entire trial is expected to be no longer than 3.5 years. 
The primary database will be locked when all ongoing patients have passed Day 30.


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3.2
Planned Number of Trial Sites and Patients
Enough patients will be randomised to bring the total number of evaluable patients up to 1800 in
the entire trial programme (including both parts of the trial). Patient recruitment will be competitive 
between trial sites. To achieve the requested number of patients within the given timelines in 
Section 3.1.3, approximately 60 - 100 trial sites will actively participate in the trial, with additional 
sites identified as ‘back-up’ sites to replace non-performing sites.
3.3
Interim Analysis
There will be no interim analyses with the potential to stop the trial early for success. The trial will 
either stop for futility or run to 1800 evaluable patients.
Once the ‘burn-in’ period in Part 1 is completed, interim analyses will be conducted regularly
during Part 1 to improve the efficiency of dosing regimen selection and to allow early termination 
for futility or for successful dosing regimen selection.
During Part 2, regular interim analyses for futility will be performed until 1600 patients have been 
treated.
The interim analyses reports will be prepared by an external company who is not otherwise 
involved in the conduct of the trial, and who will not divulge these data to Ferring personnel. The 
measures taken to protect the overall blinding during the interim analyses are illustrated in Figure 2
in Section 5.5.1.
The statistical considerations of the interim analyses are further described in Section 9.9.
3.4
Data and Safety Monitoring Board
A data and safety monitoring board (DSMB) will be established for this trial. The DSMB will be an 
independent group of critical care and emergency medicine experts not otherwise involved in the 
trial and a statistician with expertise in adaptive designs. The DSMB will oversee safety and ensure 
appropriate trial conduct, which includes overseeing that the adaptive design is implemented and 
performing as intended. 
The DSMB will have access to unblinded interim efficacy and safety data as well as recruitment
data so that they are able to monitor the enrolment of the intended patient population. The DSMB 
will keep the interim results confidential from any individuals involved in the trial conduct. A trial-
specific DSMB charter specifies the composition of the DSMB and its responsibilities and working 
procedures.
3.5
Discussion of Overall Trial Design and Choice of Control Groups
3.5.1
Trial Design
This is a multi-centre, randomised, placebo-controlled, double-blind Phase 2b/3 adaptive clinical 
trial, which will be conducted in accordance with the protocol, good clinical practice, and 
applicable regulatory requirements. 


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The trial will be conducted at multiple trial sites predominantly across Europe and North America. 
High-quality trial sites with shared standards of practice and values will be selected; all trial sites 
follow the globally accepted Surviving Sepsis Campaign guidelines (Dellinger et al, 2013) which 
provides recommendations for the best care of patients with severe sepsis and septic shock. 
Patients will be enrolled in the trial and the IMP infusion will be initiated as early as possible. To 
ensure, as far as possible, that only eligible patients enter the trial (see Section 4.1), all potential 
patients will be discussed with one of the assigned clinical coordinating centres (CCCs) prior to 
randomisation. The CCCs will be available 24 hours a day throughout the trial to answer 
investigators’ medical questions (such as assessment of eligibility and medical support). 
As described in Section 3.4, the trial will be overseen by an independent DSMB. In addition, a trial 
steering committee (TSC) will oversee the overall conduct of the trial in a blinded manner. The 
TSC includes representatives of Ferring and the CCCs, trial investigators, and experts in the fields 
of critical care, emergency medicine and clinical trial methodology. The TSC will make 
recommendations to Ferring regarding all trial-related decisions including those based on 
recommendations from the DSMB. A TSC charter specifies the composition of the TSC and its 
responsibilities and working procedures.
The trial design is robust with clear, prospectively determined clinical and statistical analytic 
criteria. The design achieves control of type 1 error through analytical means. While the trial can 
stop early for futility, a successful Phase 3 trial can only be achieved with at least 1800 evaluable 
patients. At the end of the trial, a single test statistic will be calculated to compare two populations 
that are defined before the trial begins, namely patients allocated to placebo compared to patients 
allocated to any dosing regimen of selepressin. 
3.5.2
Selection of Endpoints
Mortality is indisputably a critical endpoint to consider in septic shock patients; however, as more 
and more patients survive septic shock it becomes increasingly important to focus on patient-
centred outcomes in survivors such as improving the speed of recovery, the ability to limit the need 
for life support, and long-term sequelae of septic shock. Therefore in this trial, we will not only 
assess mortality, but also compare survival free of both vasopressor and mechanical ventilation –
the two primary forms of life-support provided to septic shock patients in the ICUs. The primary 
endpoint is constructed to capture selepressin’s ability to hasten the resolution of septic shock and 
to reduce the time the patient is dependent on life-support. A faster resolution of septic shock is 
expected to lead to a reduction in irreversible morbidities and serious outcomes resulting from fluid 
overload and ischaemic damage to organs. 
The primary endpoint is a composite endpoint capturing the need for vasopressor, the need for 
mechanical ventilation, and mortality. All three components on their own represent important 
beneficial effects for septic shock patients and will also be captured separately as secondary 
endpoints. This combined endpoint (vasopressor- and mechanical ventilator-free days [P&VFDs]) 


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is well aligned with the currently understood beneficial actions of selepressin and supported by the 
effects of selepressin found in previous non-clinical and clinical trials as discussed in Section 1. 
Septic shock is associated with a wide array of serious and troublesome sequelae that may impact 
long-term outcomes. The secondary efficacy and safety endpoints (as listed in Section 2.2) were 
selected to focus on key effects related to the primary mode of action of selepressin (i.e. 
vasopressor and anti-leakage effects) and at the same time to capture other clinically meaningful 
outcomes such as incidence of organ dysfunction, mortality, quality of life, and general safety of 
selepressin. Hence, the secondary endpoints will capture both efficacy and safety aspects of the 
treatment. Furthermore, the length of stay at the ICU as well as health-related quality of life 
represent society and life impact focused endpoints. 
Patients with septic shock represent a notoriously heterogeneous patient population. To account for 
potential differences in outcome based on baseline characteristics, patients will be randomised in a 
stratified manner as described in Section 4.2.2.
3.5.3
Choice of Control Group
In this trial, selepressin plus standard of care will be compared to placebo plus standard of care with 
norepinephrine/noradrenaline as primary vasopressor. Use of placebo allows provision of usual 
standard of care in both the selepressin-treated group and the placebo-treated group. The 
investigators can continue the use of norepinephrine/noradrenaline, continue to add (or not) 
antibiotics, fluids, inotropic agents (such as dobutamine), oxygen, mechanical ventilation, 
corticosteroids, feeding, and other supportive care in accordance with standard clinical practice 
following the Surviving Sepsis Campaign guidelines (Dellinger et al, 2013). Thus, this background 
of ethical usual clinical care would occur in both the selepressin-treated group and the placebo-
treated group.
3.5.4
Selection of Doses in the Trial
Four dosing regimens of selepressin ranging from 1.7 ng/kg/min to 7.5 ng/kg/min (as detailed in 
Table 1) have been selected for this trial. These dosing regimens are chosen to cover the relevant 
dose range based on dosing experience from the previous clinical trials (i.e. FE 202158 CS02 and 
000025).
In FE 202158 CS02, which was the first clinical trial in septic shock patients, selepressin was safe 
and well tolerated up to 2.5 ng/kg/min. In approximately 50% of the patients receiving 
2.5 ng/kg/min of selepressin, norepinephrine/noradrenaline could be completely weaned within 
12 hours whereas all patients receiving 1.25 ng/kg/min of selepressin required norepinephrine/
noradrenaline at 12 hours (Ferring report FE 202158 CS02). This suggests that some patients may 
require more than 2.5 ng/kg/min of selepressin in order to wean norepinephrine/noradrenaline 
completely. 
The second clinical trial (000025) was initiated to assess whether use of higher doses of selepressin 
would allow for a faster and more complete weaning of norepinephrine/noradrenaline. In that trial, 


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the dose-range from 2.5 to 7.5 ng/kg/min with free up- and down-titration of selepressin within a 
certain range was investigated. The flexible dose-adjusting was designed to mimic the current 
clinical practice for the use of vasopressors. The 000025 trial showed that it was possible to wean 
norepinephrine/noradrenaline completely within a few hours in most of the patients when the 
selepressin dose was increased to 5 to 7.5 ng/kg/min. Despite the pharmacokinetic characteristics of 
selepressin (i.e. approximately 7 hours to reach steady state plasma levels and a half-life of 
approximately 1.4 hours), it was possible to maintain MAP within the target range by adjusting the 
dose. In the majority of patients, doses above 3.75 ng/kg/min were only needed in the first 
24 hours. However, as the 000025 trial was not designed (or powered) to provide data on efficacy 
and safety, it is not known whether allowing the use of higher doses of selepressin is associated 
with an increased benefit or safety risk; hence, four dosing regimens (see Table 1) have been 
selected for investigation in the 000133 trial.
The lowest dosing regimen selected for the 000133 trial is expected to allow partial weaning of 
norepinephrine/noradrenaline and will address the question whether low doses of selepressin or co-
treatment of selepressin and norepinephrine/noradrenaline is superior to full substitution of 
norepinephrine/noradrenaline with selepressin. The higher dosing regimens will allow 
progressively faster and more complete weaning of norepinephrine/noradrenaline and will answer 
the question whether higher doses of selepressin are associated with increased clinical benefit. The 
high granularity in the dose-selection is chosen to increase the ability to detect the dosing regimen 
that provides the optimal risk-benefit ratio.
3.5.5
Selection and Timing of Dose for Each Patient
Treatment with the IMP (selepressin or placebo) has to start as early as possible following 
fulfilment of the eligibility criteria and no later than 12 hours after initiation of the required 
continuous infusion of vasopressor treatment for septic shock. All patients will be on 
norepinephrine/noradrenaline treatment as part of standard of care at the time when the IMP 
infusion is initiated.
During the course of treatment, the IMP will be continuously administered and adjusted within pre-
defined infusion rates. An administration guide will be provided with recommendations on how to 
adjust the IMP infusion rate. 
As the vasopressor-need varies significantly from patient to patient and over time in any given 
patient, it is necessary to allow dose-adjustments. A lower starting infusion rate of the IMP has 
been included to minimise the risk of overshooting when IMP is added on top of the 
norepinephrine/noradrenaline infusion the patient is receiving to maintain the target MAP. The 
infusion rate of the IMP will be increased if the starting rate is insufficient to wean norepinephrine/
noradrenaline completely. If the MAP is increased above the target, norepinephrine/noradrenaline 
will be weaned first while aiming to keep MAP at the target. Norepinephrine/noradrenaline must be 
completely weaned prior to weaning of the IMP. If the IMP alone increases the MAP above the 
target, the IMP will be weaned step-wise while aiming to keep MAP at the target. If the maximum 
allowed infusion rate of the IMP is not sufficient to maintain the MAP at the target, norepinephrine/


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noradrenaline will be added to achieve the targeted MAP. If target MAP cannot be maintained 
despite maximum allowed infusion rate of IMP and ≥1 µg/kg/min norepinephrine/noradrenaline
base (or a total catecholamine equivalent of 1 µg/kg/min norepinephrine/noradrenaline base), 
vasopressin may be added.
The IMP infusion will continue as long as blood pressure support is deemed necessary with a 
maximum of 30 days. After complete weaning, IMP infusion may be re-started during this 30-day 
period for treatment of sepsis-induced hypotension if there is no suspicion of mesenteric or cardiac 
ischaemia. Patients who still need vasopressor treatment after 30 days will be switched to other 
vasopressors at the discretion of the investigator.


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
The intention is to enrol a typical sample of patients presenting with septic shock and commence 
treatment with the IMP during the initial hours of resuscitation, within 12 hours from the onset of 
vasopressor treatment, targeting those who do not respond rapidly to fluids and whose vasopressor-
need persists for at least one hour.
4.1.1
Inclusion Criteria
1. 18 years of age or older.
2. Proven or suspected infection.
3. Septic shock defined as hypotension (systolic blood pressure less than 90 mmHg OR MAP 
less than 65 mmHg) requiring vasopressor treatment (i.e. any dose of norepinephrine / 
noradrenaline base greater than 5 µg/min) despite adequate fluid resuscitation (at least 
one litre for hypotension). 
The MAP threshold for inclusion in the trial is a MAP below 65 mmHg before vasopressor 
support is started. However, it is not a requirement that patients are under the target MAP 
during vasopressor treatment with norepinephrine/noradrenaline. The patients must require 
vasopressor treatment to stay on the target MAP i.e. a patient can be at the target of 
65 mmHg or higher while on at least 5 µg/min of norepinephrine/noradrenaline base at 
least for one hour before inclusion and when IMP is started.
A patient can also be included based on systolic blood pressure less than 90 mmHg even if 
the MAP is above 65 mmHg if the patient is judged in need of vasopressor treatment based 
on evidence of poor organ perfusion.
The requirement of at least one litre of fluid for hypotension to start the randomisation 
process balances the need to ensure that patients have been properly fluid resuscitated 
while still allowing for early enrolment before there is marked endothelial injury and 
increased permeability so that the proposed permeability-protection of selepressin can be 
assessed. Fluid resuscitation should continue according to the recommendations in the 
Surviving Sepsis Campaign guidelines (Dellinger et al, 2013) and therefore the patients 
should have received the recommended 30 mL/kg fluid from the onset of hypotension and to
the time IMP infusion is started (unless evidence of fluid replete/overload) (see 
Section 4.1.3).
4. Informed consent obtained in accordance with local regulations. 


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4.1.2
Exclusion Criteria
1. Not possible to initiate IMP treatment within 12 hours from onset of vasopressor treatment
for septic shock.
Patients will be excluded if IMP infusion cannot be started within 12 hours from onset of 
vasopressor treatment. This time limit exclusion is added to ensure that patients are 
included early in the septic shock state. If the inclusion is left too late, then there is often 
irreparable organ dysfunction and endothelial injury with increased permeability in septic 
shock. Thus, even an effective intervention could fail if applied later when there is 
irreversible injury.
2. Primary cause of hypotension not due to sepsis (e.g. major trauma including traumatic brain 
injury, haemorrhage, burns, or congestive heart failure/cardiogenic shock).
3. Previous severe sepsis with ICU admission within this hospital stay.
Patients who have had a prior episode of severe sepsis have a poorer prognosis and may 
still be recovering from the associated organ dysfunction so patients with previous severe 
sepsis within this hospital stay are not eligible.
4. Known/suspected acute mesenteric ischaemia.
Selepressin is a potent V1a agonist and V1a-induced mesenteric vasoconstriction is a safety 
concern so patients with known or suspected acute mesenteric ischaemia are not allowed 
for safety reasons.
5. Suspicion of concomitant acute coronary syndrome based on clinical symptoms and/or ECG 
during this episode of septic shock. 
V1a agonism could also induce coronary vasoconstriction and so, for safety reasons, 
patients are not allowed in the trial if the investigator believes the ECG and clinical 
symptoms suggest a concomitant acute coronary syndrome.
6. Chronic mechanical ventilation for any reason OR severe COPD requiring either continuous 
daily oxygen use during the preceding 30 days or mechanical ventilation (for acute 
exacerbation of COPD) during the preceding 30 days.
A potential confounder to interpretation of the efficacy of selepressin on ventilator-free days 
would be inclusion of patients who have severe COPD requiring chronic oxygen use or 
mechanical ventilation. Such patients may recover from the acute pulmonary effects of 
septic shock (such as acute respiratory distress syndrome) because of the proposed 
beneficial effects of selepressin but then prove difficult and slow to wean from mechanical 
ventilation because of their significant underlying disease. Accordingly such patients are
not allowed in the trial. However, patients with less severe COPD are allowed.


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7. Received bone marrow transplant during the preceding 6 months or chemotherapy during 
the preceding 30 days for lymphoma or leukemia.
Patients who have had bone marrow transplant during the preceding 6 months or 
chemotherapy during the preceding 30 days for lymphoma or leukemia are excluded 
because these patients can have a significantly worse prognosis compared to the average 
septic shock patient due to their impaired immunity and other effects of their underlying 
disease and its treatment. Depending on the state of immune dysfunction, the mortality rate 
of these patients when they get septic shock - even with aggressive intensive care, 
resuscitation, and appropriate intravenous broad spectrum antibiotics - can exceed 90%. 
Furthermore, many of these patients have thrombocytopenia secondary to their disease or 
their therapies and this underlying thrombocytopenia increases the risks of worsening to 
profound thrombocytopenia during septic shock because septic shock induces 
thrombocytopenia directly and independent of prior chemotherapy. Finally, many of these 
patients have other mortality risk factors such as anemia, hepatic and renal dysfunction, all 
of which would be worsened during septic shock.
8. Known to be pregnant.
9. Decision to limit full care taken before obtaining informed consent. 
10. Use of vasopressin in the past 12 hours prior to start of the IMP infusion or use of 
terlipressin within 7 days prior to start of the IMP infusion. 
11. Prior enrolment in the trial.
12. Prior use of an investigational medicinal product within the last month OR planned or 
concurrent participation in a clinical trial for any investigational drug or investigational 
device.
In order to be able to assess the safety and efficacy of selepressin without confounding 
factors from the use of other investigational drugs or devices, co-enrolment in trials 
involving investigational products are not allowed. Co-enrolment in a non-investigational 
trial requires preapproval of the TSC and will be assessed on a case by case basis. In 
principle, co-enrolment is allowed unless it is expected to impact the outcome of this clinical 
trial. 
4.1.3
Eligibility Criteria – Post-randomisation / Before Start of IMP Infusion
In addition, the following criteria must be met at start of IMP infusion:
1. Received a minimum of 30 mL/kg fluid in total from the onset of hypotension (or less if 
evidence of fluid replete/overload).
2. Received a continuous infusion of norepinephrine/noradrenaline base greater than 5 µg/min 
for at least one hour and is still receiving at least 5 µg/min norepinephrine/noradrenaline
base.


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The requirement of at least one hour duration of vasopressor support is intended to ensure a 
certain severity of the septic shock while balancing the need to recruit patients early during 
the initial hours of resuscitation.
3. Less than 12 hours since onset of vasopressor treatment for septic shock.
4.2
Method of Assigning Patients to Treatment Groups
4.2.1
Recruitment
Both emergency departments (EDs) and ICUs will recruit patients. Each patient considered for the 
trial will receive a unique screening number. The screening number will be allocated sequentially
within each trial site in the order in which the patients are screened. The screening number and the 
result of each screening will be recorded.
A screening log with patient identification details for consecutive patients with septic shock must 
be maintained at each trial site to capture how many patients that were screened to include the 
1800 evaluable patients in the trial. The main reason for exclusion will be described.
4.2.2
Randomisation
A computer-generated randomisation list will be prepared prior to enrolment of the first patient into 
the trial and updated during the trial via the response-adaptive randomisation procedure. 
To minimise the risk of imbalance between the treatment arms, the randomisation will be stratified 
by: 1) trial site, 2) need for mechanical ventilation (‘Yes’ or ‘No’), 3) norepinephrine/noradrenaline 
requirement (< or ≥30 µg/min), and 4) plasma/serum creatinine (< or ≥150 µmol/L).
The patient-specific randomisation number will be allocated in the order at which the patients are 
being randomised into the trial. The actual patient randomisation number will be added on the 
screening log. No patient can be enrolled twice.
The first 200 patients will be randomised to treatment in a fixed manner. The randomisation is 
3:2:2:2:0 for placebo and active treatment arms 1, 2, 3, and 4, respectively. After the first 
200 patients and throughout the rest of Part 1, the patients will be randomised with one-third 
probability to placebo and the remaining probability allocated to active treatment arms in a 
response-adaptive randomisation manner. A pre-defined algorithm will be used to determine the 
relative randomisation to each of the treatment arms. Interim analyses will be conducted regularly 
in Part 1 to adjust the adaptive randomisation probabilities for the active treatment arms. The 
enrolment of patients will continue without any stop at the interim analyses.
During Part 2, a minimum of 1000 patients will be randomised in a 1:1 fashion to placebo and the 
active treatment arm selected from Part 1 in order to get the 1800 evaluable patients needed for the
final analysis.


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4.3
Restrictions
4.3.1
Prior and Concomitant Medications/Procedures
Medicinal products may be administered and concomitant procedures may be conducted for the 
well-being of the patients at the discretion of the investigators. 
Use of vasopressors, mechanical ventilation, RRTs, and fluids must be documented thoroughly as 
these are related to the endpoints of the trial (see Section 2.2). Concomitant medications/procedures 
that are likely to influence the outcome from septic shock have to be detailed.
4.3.2
Prohibited Medications/Procedures
The following medications/procedures are prohibited:

Vasopressin in the past 12 hours prior to start of IMP infusion and during IMP infusion 
unless the patient remains hypotensive despite the maxium allowed infusion rate of IMP and 
≥1 µg/kg/min norepinephrine/noradrenaline base (or a total catecholamine equivalent of 
1 µg/kg/min norepinephrine/noradrenaline base).

Terlipressin (from 7 days prior to start of IMP infusion to end of ICU stay).

Another investigational medicinal product (from 1 month prior to trial enrolment to 30 days 
after initiation of IMP infusion).

Participation in another clinical trial for an investigational drug or investigational device
or co-enrolment in a non-investigational trial that is not pre-approved by the TSC (from 
1 month prior to trial enrolment to 30 days after initiation of IMP infusion). 
4.4
Discontinuation and Withdrawal
For all discontinuations and withdrawals, the investigator will document the date of the termination 
and the main reason.
Premature discontinuation of IMP infusion
The IMP infusion will continue as long as blood pressure support is deemed necessary (up to a 
maximum of 30 days). Premature discontinuation of IMP infusion is defined as termination of IMP 
infusion even though continued intravenous vasopressor treatment for blood pressure support is 
needed. A premature discontinuation of IMP infusion may occur if the investigator decides that 
IMP infusion should be discontinued or if the patient, the patient’s legal representative, or attending 
physician requests that IMP infusion be discontinued. If the IMP infusion is prematurely paused or 
discontinued due to a serious adverse event, an additional blood sample will be collected (see 
Section 7.2.2).
Patients whose IMP infusion is prematurely discontinued, regardless of reason, are not discontinued 
from the trial. These patients will continue in the trial and undergo the trial assessments following 
the trial protocol in order to provide the data needed for the analyses and to determine their survival 
status.


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If a patient who does not meet the eligibility criteria is inadvertently enrolled and the IMP infusion 
has been started, the investigator will consult with the CCC regarding termination or continuation 
of the IMP infusion.
Withdrawal from the trial
A patient has the right to withdraw from the trial at any time for any reason, without the need to 
justify the decision. 
In the event that the patient (or the patient’s legal representative) withdraws consent or the 
investigator or Ferring, for any reason, prematurely stops the patient’s participation in the trial, the 
IMP infusion and all scheduled trial-related assessments and laboratory testings will be stopped. 
Data collected up to withdrawal will remain in the database but data obtained after the patient has 
withdrawn his/her consent will not be entered into the database. However, results from assessments 
and blood samples collected prior to the withdrawal of the consent but not analysed at the time of 
the withdrawal will be entered into the database unless the patient refuses. The patient can request 
destruction of samples which would otherwise have been kept in storage.
Refer to Section 12.3 for information regarding premature trial termination.


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Product (IMP)
The IMP (selepressin and placebo) will be administered through a central venous catheter as a 
continuous intravenous infusion at a controlled flow rate using a syringe pump or an infusion pump
suited for vasopressor administration. The administration is discussed in Section 3.5.5. A detailed 
IMP and vasopressor administration guide will be provided to the trial sites.
5.1.2
Norepinephrine/Noradrenaline
In order to be eligible for the trial, all patients will be on norepinephrine/noradrenaline treatment as 
part of standard of care (see Section 4.1.1). During the trial, the norepinephrine/noradrenaline 
treatment will continue as deemed necessary. Norepinephrine/noradrenaline will be from the 
commercial batches that the trial sites are using as part of usual clinical care and no modification to 
their commercial state will be made.
5.2
Characteristics and Source of the IMPs
Selepressin
Selepressin 0.3 mg/mL is a concentrate for solution for infusion. It has been manufactured in 
accordance with the principles of Good Manufacturing Practice (GMP) and will be provided by 
Ferring in vials in which the drug substance has been dissolved in an isotonic 10 mM acetate buffer 
of pH 4.0.
The concentrate will be diluted with sterile 0.9% sodium chloride solution to one of four different 
concentrations as detailed in a dilution protocol. Sterile 0.9% sodium chloride solution will be 
provided together with the vial with selepressin concentrate. The dilution will be prepared by 
dedicated and trained personnel at the hospital pharmacy or at another approved facility at the 
hospital. A dilution log will be provided in which the dilution will be documented.
Placebo
Sterile 0.9% sodium chloride solution will be used as the placebo. It will be provided by Ferring 
from commercial batches and no modification to their commercial state will be made.
5.3
Packaging and Labelling
Packaging and labelling of the IMPs (selepressin and placebo) will be performed under the 
responsibility of the IMP department at Ferring in accordance with GMP and national regulatory 
requirements.
The IMPs (selepressin and placebo) will be labelled with trial-specific labels and the content on the 
labels will be in accordance with Annex 13, EudraLex, volume 4 and national requirements. The 
labels will contain a self-adhesive tear-off portion to be affixed to the dispensing log maintained at 
the trial site.


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5.4
Conditions for Storage and Use
The IMPs will be stored in accordance with the label. 
The investigator will ensure that the IMPs will be stored in appropriate conditions in a secure 
location with controlled access. The storage compartment shall be monitored regularly and the 
temperature shall be documented. Deviations in storage temperature must be reported to Ferring 
without delay and the IMPs must not be used until further instructions are received. 
Diluted IMP dosing solutions must be used within 26 hours after the preparation if prepared in 
controlled and validated aseptic conditions, otherwise within 24 hours after the preparation.
5.5
Blinding / Unblinding
5.5.1
Blinding
This is a double-blind, placebo-controlled trial in which patients, investigators and other trial site 
staff, the CCCs, the TSC, the clinical trial team at Ferring and its representatives will be blinded to 
the treatment assignment. As discussed in Section 3.4, the DSMB will have access to unblinded 
data during the trial. The personnel preparing the IMPs and the drug accountability monitors will 
also be unblinded. Figure 2 illustrates the applicable safeguards to maintain the overall blinding 
during conduct of trial. Three independent parties will be involved in forming the safeguard during 
the adaptive portion of the trial. One part (the randomisation company) will provide the expertise to 
run the adaptive algorithm. The second part (the statistical consulting company) will provide 
expertise in producing the DSMB reports and provide statistical and project management support 
for the DSMB. The third part (the adaptive design company) will provide expertise in adaptive 
clinical trial design to oversee the performance of the adaptive algorithm and provide statistical 
support for the DSMB in relation to the adaptive trial design.
Adequate blinding of the treating investigators and nurses is important to ensure the integrity of the 
results. Use of placebo will ensure effective blinding due to the significant individual variability in 
the vasopressor need from patient to patient. Thus, in some patients the vasopressor need declines 
quickly and it will not be possible to tell whether fast weaning of norepinephrine/noradrenaline is 
due to the fact that the patient receives active treatment or whether it is just because the patient is 
improving. Also, the potential side effects of selepressin are similar to side effects that can be seen 
with norepinephrine/noradrenaline or that may be caused by worsening of septic shock so there are 
no obvious effects of selepressin that will lead to unblinding.
The IMPs will be prepared in accordance with the trial-specific computer-generated randomisation 
numbers. The randomisation will be securely kept without access for personnel involved in the 
conduct of the trial with exception of the personnel preparing the IMPs until the trial database is 
declared clean and released to the trial team statistician. The prepared IMPs (i.e. the four diluted 
selepressin dosing solutions and the placebo) will be indistinguishable i.e. identical appearance and 
smell and will be administered using similar infusion rates.


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Figure 2
Safeguards to Maintain Blinding during Trial Conduct
DSMB+Futility Flow
Adaptive Randomisation Flow
IMP flow
Lab flow
Drug
Accountability 
Monitor
Site Monitor
Randomisation 
Company
Contract 
Research Labs
Statistical 
Consulting 
Company
Pharmacy
(or approved facility)
Trial Site
Ferring Biometrics
DSMB
9) Randomisation Company uploads randomisation lists: 
fixed list for the ’burn-in’ period, adapted lists during Part 1, 
and fixed list for Part 2
3) Pharmacy 
retrieves 
unblinded 
treatment
information
from eCRF
4) Pharmacy provides 
blinded IMP to Trial Site
Trial Site 
sends blood
samples to 
Central Lab
Contract Research Labs 
analyses and uploads results
7) Ferring Biometrics 
retrieves blinded raw data from eCRF
8a) Randomisation Company 
receives blinded primary
endpoint data from Ferring
11b) DSMB receives all unblinded
interim analysis reports and 
other DSMB-related reports
from the Statistical 
Consulting Company 
◄2) Trial Site records stratification data in eCRF
◄6) Trial Site records ongoing trial data in eCRF
Trial Site retrieves patient-specific 
randomisation number from eCRF►
CCC confirms eligibility
Randomisation Company 
receives software for
adaptive randomisation from 
the Adaptive Design Company
Unblinded
Blinded
13) Ferring/TSC receives blinded 
recommendation from 
DSMB
10) Statistical Consulting Company receives adaptive design 
interim reports+randomisation list from the Randomisation Company
Central Lab
(Logistics)
Central Lab sends 
blood samples to 
Contract Research Labs
Site Local Lab
Trial Site 
sends blood
samples to 
Local Lab▲
Local Lab 
sends results 
to Trial Site▼
Ferring/TSC
8b) Statistical Consulting Company 
receives access to blinded
analysis data from Ferring
IMP Warehouse -
Europe
eCRF 
Trial data base
Pharmacy requests IMP ►
◄Warehouse provides IMP
to Pharmacy
Patient
◄1) Patient 
enters 
Trial Site
5) Patient 
receives 
IMP ►
Site Monitor 
performs SDV
and remote 
monitoring on
data entered
in eCRF
Drug Accountability 
Monitor performs 
drug accountability
IMP Warehouse -
North America
CCC – Europe 
CCC – North America
After Clean File + Code Break:
- Randomisation Company sends randomisation lists to Ferring
- Contract Research Lab uploads actual results to trial database/eCRF
- eCRF allows download of unblinded data
CCC
= Clinical Coordinating Center
DSMB = Data and Safety Monitoring Board
eCRF = Electronic Case Report Form
IMP
= Investigational Medicinal Product (selepressin or placebo)
SDV = Source Data Verification
TSC
= Trial Steering Committee
Adaptive Design 
Company
12) DSMB may receive support 
during the adaptive portion of the 
trial from the Adaptive Design Company
11a) Adaptive Design Company receives 
unblinded adaptive design interim reports from 
the Statistical Consulting Company


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5.5.2
Unblinding of Individual Patient Treatment
An emergency decoding possibility (via the eCRF) will be available to the investigator and 
designated persons at Ferring. Breaking of the blind for individual patients in emergency situations 
is an investigator responsibility. As far as the emergency permits, the need to break the blind will 
be discussed with the CCC and communicated to Ferring. 
The unblinding in emergency situations is only permitted in case of a suspected unexpected serious 
adverse reaction (SUSAR) or in case of an important adverse event where the knowledge of the 
medicinal product in question is required for therapeutic decisions for the management of the 
patient. It will be documented in the eCRF that the code is broken, when, and by whom. The 
investigator must record the event of unblinding in the patient’s medical record, including the 
reason for unblinding, but not the treatment allocation if this can be avoided.
In case of accidental unblinding, the same documentation as for emergency unblinding must be 
obtained.
It may be necessary to unblind an individual patient’s treatment for the purposes of expedited 
reporting to the authorities and/or independent ethics committees (IECs) / institutional review 
boards (IRBs). In that situation, every effort will be made to maintain blinding of personnel 
involved in data analysis and interpretation. Other personnel may be unblinded for SUSARs, 
including trial site staff as well as staff acting on behalf of Ferring.
Information on whether the blind has been broken for any patients must be collected before the 
database is declared clean and released to the trial team statistician.
5.6
Treatment Compliance
The IMPs will only be administered by authorised staff at the trial sites to patients who meet the 
eligibility criteria and are randomised to a treatment in the trial. The investigator (or his/her 
designated personnel, e.g. trial nurse) will maintain a drug dispensing log detailing the dates and 
quantities of IMP administered to, and used by, each patient, as well as the unique batch identifier
used in the trial. 
The tear-off portion of the labels will be affixed to the drug accountability form. The monitors will 
verify the drug accountability during the trial.
5.7
Return and Destruction of IMP
All used IMP will be destructed at the trial site in accordance with local requirements after the drug 
accountability has been finalised, verified by the monitor, and signed off by the investigator. Any 
material used for preparation of the infusion solution and for the infusion will be destroyed at the 
trial site immediately after usage according to standard procedures at the trial site. 
All unused IMP will be accounted for and must be destructed in a certified way in accordance with 
trial-specific instructions.


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6
TRIAL PROCEDURES
Participating sites should consider all septic shock patients for inclusion in the trial; the main reason 
for not being eligible will be documented. Refer to Section 4.1 for inclusion, exclusion, and 
eligibility criteria. One of the assigned CCCs must be contacted to confirm the eligibility of each 
patient.
The trial consists of a pre-IMP treatment period, an IMP treatment period, and a follow-up period 
(see Section 6.1).
The pre-IMP treatment period is defined as the time from sepsis-induced hypotension to the start of 
IMP infusion. To ensure start of IMP treatment without delay, informed consent will be obtained, in 
compliance with local regulations, as early as possible. During this period, baseline evaluations will 
be made.
The IMP treatment period begins with Day 0 (which is defined as time from onset of IMP infusion 
to midnight of that day). The infusion of the IMP (selepressin or placebo) will be started as early as 
possible following randomisation and no later than 12 hours after initiation of continuous infusion 
of vasopressor treatment for septic shock. During the course of treatment, the IMP infusion rate will 
be adjusted as within pre-defined infusion rates to keep the MAP at the target. The IMP 
administration is described in Section 3.5.5 and the target MAP is defined in Section 7.1.11. A 
detailed IMP and vasopressor administration guideline will be provided to trial sites. The IMP 
infusion will continue as long as blood pressure support is deemed necessary with a maximum 
period of 30 days. A confirmation of the septic shock characteristics recorded at time of enrolment
will be recorded in the eCRF at ICU discharge.
The follow-up period includes Days 30, 60, 90, and 180. If a patient has been discharged from the 
trial hospital, trial site personnel will contact the patient, the patient’s legal representative, or the 
patient’s health care professional to collect required trial information.
All assessments to be performed and all data to be collected during the trial are summarised in 
Section 6.1 and further described in Section 7. The majority of the assessments are widely and 
routinely used clinically and generally regarded as reliable, accurate, and relevant. Collection of 
data requiring invasive equipment or mechanical ventilation is applicable only if it is measured as 
part of local clinical practice. Samples collected and assessments performed for clinical purposes in 
accordance with standard of care after start of fluid resuscitation for hypotension and before start of 
IMP may be used as baseline values if deemed appropriate. In case several values of the same 
assessment are available, the recordings obtained closest to the start of IMP treatment will be used
as baseline and the recordings obtained closest to a given time-point will be used as post-baseline 
values (if not otherwise specified).
At pre-selected trial sites, additional data collection will be performed to further evaluate the effect
of selepressin.


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6.1
Trial Flow Chart


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7
TRIAL ASSESSMENTS
7.1
Assessments Related to Endpoints
Vasopressor treatment, mechanical ventilation, and mortality are all part of the primary endpoint 
and it is extremely important to document these variables thoroughly and without delay. If a patient 
has been discharged from the trial hospital before Day 30, trial site personnel will contact the 
patient, the patient’s legal representative, or the patient’s health care professional to collect required 
information. If the trial site personnel are unable to collect the required information, Ferring should 
be notified. Completeness of data collection for the primary endpoint will be closely monitored 
during the conduct of the trial and issues of missing data collection will result in re-training (or 
termination) of trial sites.
7.1.1
Vasopressors
The integrity of the primary endpoint depends on accurate start and stop times of vasopressor 
treatment and therefore start and stop time of all vasopressor periods must be recorded in the eCRF. 
It is key to ensure that vasopressor treatment is neither prolonged longer than necessary nor 
prematurely stopped leading to episodes of hypotension.
All vasopressor treatment (any intravenous dose of norepinephrine/noradrenaline, phenylephrine, 
dopamine, epinephrine/adrenaline, vasopressin, terlipressin, and IMP [selepressin and placebo]) 
must be thoroughly documented up to Day 30. The infusion rate of IMP will be recorded at baseline 
and at 1, 3, 6, 12, and 24 hours after start of IMP infusion. After 24 hours, the infusion rate of IMP
will be recorded twice daily (around 8:00 a.m. and 8:00 p.m. when the MAP is recorded) until end 
of IMP treatment. In addition, the IMP infusion rate at the time of pharmacokinetic blood sampling 
will be recorded in the eCRF. In approximately 200 patients at pre-selected trial sites, the IMP 
infusion rate at 30 minutes after start IMP infusion will also be recorded (see Section 7.2.2).
Furthermore, the total volume of infused IMP within the following time periods will be recorded: 0-
12 hours, 12-24 hours, and from 24 hours to regular schedule according to clinical practice at each 
trial site. Thereafter, daily according to local clinical practice. For all other vasopressors, the dose 
of each vasopressor will be recorded at baseline and at 1, 3, 6, 12, and 24 hours after start of IMP
infusion. After 24 hours, the dose of the individual vasopressors will be recorded twice daily 
(around 8:00 a.m. and 8:00 p.m. when the MAP is recorded) until end of vasopressor treatment.
7.1.2
Mechanical Ventilation
Respiratory failure, requiring mechanical ventilation, is a common complication of septic shock. In 
septic shock patients, it is a key goal of management of ventilation to minimise the duration of 
ventilation because increased duration of mechanical ventilation increases the risk of nosocomial 
pneumonia, neuromuscular weakness, and death. 
The use of mechanical ventilation (as defined in Section 2.2) must be thoroughly documented up to 
Day 30. Start and stop time of all mechanical ventilation periods must be recorded in the eCRF.


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The weaning of mechanical ventilation will be based on daily spontaneous breathing trials as 
described in a trial-specific weaning guide. The time and outcome (i.e. success or failure) of each 
spontaneous breathing trial will be documented in patient’s medical records to monitor if a 
successful spontaneous breathing trial is followed by extubation.
7.1.3
Renal Replacement Therapy (RRT) and Renal Function
Acute kidney injury is a common complication of septic shock. Treatment of acute kidney injury is 
primarily supportive including RRT (continuous RRT, intermittent haemodialysis, or peritoneal 
dialysis). The decision to initiate RRT in a patient enrolled in this trial will be based on local 
clinical practice. The use of RRT must be thoroughly documented up to Day 90. The reason for and 
type of RRT as well as start and stop time will be recorded in the eCRF. If a patient is shifted from 
continuous RRT to intermittent haemodialysis, the patient is still on RRT until the last hemodialysis 
has been performed.
Renal function will be assessed, using urine output, plasma/serum creatinine, and creatinine 
clearance, at baseline and the first 3 days after initiation of IMP infusion and up to 7 days if 
collected for clinical purposes [or until ICU discharge if the patient leaves the ICU before Day 7]).
Creatinine clearance will be determined by estimated glomerular filtration rate (using plasma/serum 
creatinine, age, and gender as per Cockcroft-Gault equation). 
7.1.4
Modified Sequential Organ Failure Assessment (SOFA) Score
SOFA is a scoring system used to track the patient’s organ function status during episodes of 
critical illness (Vincent et al, 1996). 
In this trial, a modified version of the SOFA will be used (i.e. SOFA except the Glasgow Coma 
Scale). As many patients are sedated due to mechanical ventilation a meaningful assessment of the 
neurological function using the Glasgow Coma Scale cannot be performed. In addition, any dose of 
IMP, vasopressin, terlipressin, or phenylephrine will attribute 3 points on the cardiovascular scale, 
and any dose of the positive inotropes milrinone and levosimendan will attribute 2 points on the 
cardiovascular scale.
The worst value for each individual organ system (i.e. respiratory, cardiovascular, renal, 
coagulation, and hepatic) components within the past 24 hours (at baseline and once daily until ICU 
discharge) will be recorded in the eCRF and the eCRF will calculate the overall modified SOFA 
score.
7.1.5
Mortality Rate and Hospitalisation
The actual date and time for ED, ICU, and hospital admission and discharge as well as time of
death (if applicable) will be recorded. Trial site personnel will visit or contact each patient who is 
still hospitalised and contact each patient or healthcare professional for patients who has left the 
hospital to determine survival status and current residence. 


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Functional status and residence of each patient before the infection leading to this episode of septic 
shock (baseline) as well as functional/survival status and residence throughout the trial will be 
recorded by using one of the following alternatives:

Home, receiving no support

Home, receiving paid professional support

Home, receiving unpaid support

Rehabilitation site/skilled (or unskilled) nursing facility

Other acute care hospital (including long-term acute care)

Still in (or readmitted to) trial hospital

Unknown

Dead
7.1.6
Health-related Quality of Life
The EuroQoL-5-Dimensions (EQ-5D™) will be used to assess patient’s overall health. EQ-5D™ is 
a standardised instrument in two parts for use as a measure of health outcome; it provides a simple, 
generic measure of health for clinical and economic appraisal (The EuroQol Group; 
http://www.euroqol.org). The first part includes five dimensions where the patient will indicate 
which given statements best describe the health state on the day of questionnaire completion. The 
second part contains a visual analogue scale (VAS) where the patient will indicate how good or bad 
his or her own health is on the day of questionnaire completion. The VAS scores range from 0 
(worst health state) to 100 (best health state).
The five level version of the instrument will be used in this trial (i.e. EQ-5D-5L). 
The baseline value refers to a recall of the time before the infection leading to the septic shock 
episode and the EQ-5D-5L will be completed as soon as possible after the shock state. A telephone
interview will be adequate at Days 30, 60, 90, and 180 if the patient has been discharged. The 
responses will be entered into the eCRF.
The investigator and/or delegated personnel will receive training and instruction in completion of 
the questionnaire before enrolment of patients. 
Each patient must receive proper training and instruction before use. The investigator or a delegated 
trial team member will instruct the patient to respond to each question without influence from trial 
team members or accompanying family or friends and explain that there are no right or wrong 
answers. Nobody will be allowed to answer or interpret questions for the patient. 
7.1.7
Fluid balance, Fluids, and Urine Output
In order to investigate selepressin’s effect on fluid balance, it is important to document all fluid 
administered during this episode of severe sepsis/septic shock including the time (i.e. up to 
18 hours) before initiation of the IMP infusion (baseline) and during the first 7 days after initiation 


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of IMP infusion [or until ICU discharge if the patient leaves the ICU before Day 7]). The period of 
Day 0 is from the start of IMP infusion to the time of the first regular daily fluid recording 
according to local clinical practice. Thereafter, daily fluid recordings according to local clinical 
practice.  
The fluid balance (as calculated in accordance with local clinical practice) and the total amount of 
intravenous fluid and urine output will be recorded in the eCRF. Urine output will be used for 
assessing renal function (see Section 7.1.3).
7.1.8
Adverse Events
The procedure for collecting and reporting adverse events is described in Section 8.
7.1.9
Safety Laboratory Variables (Clinical Chemistry, Haematology, and Coagulation)
Standard safety laboratory variables will be analysed using standard equipment in accordance with 
local clinical practice. Accreditation/certification of the laboratories and reference ranges of the 
laboratory variables will be kept in the trial files. The investigator must document their review of 
the laboratory results. Any laboratory abnormality should be assessed by the investigator as to 
whether it constitutes an adverse event (see Section 8.1). 
The baseline levels and the results, of the variables as listed in Table 2, obtained 1 and 3 days after 
initiation of the IMP infusion will be recorded. The results obtained at Days 7, 14, 30 will also be 
recorded if the patient is still in trial hospital.
Daily creatinine, bilirubin, and platelets values will be used for the SOFA scores (see 
Section 7.1.4). Creatinine level will also be used for assessing renal function and calculation of 
creatinine clearance (see Section 7.1.3).


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Table 2
Safety Laboratory Variables
Clinical Chemistry
Haematology
Coagulation
Alanine aminotransferase
Haematocrit
Activated partial 
thromboplastin time 
Albumin
Haemoglobin
Alkaline phosphatase
Platelet count 
Prothrombin time / 
international normalised 
ratio
Aspartate aminotransferase
Red blood cell count
Calcium (free or total)
White blood cell count
Chloride
C-reactive protein
Creatine phosphokinase
Creatinine (plasma or serum)
Lactate dehydrogenase
Phosphate
Potassium
Sodium
Total bilirubin
Troponin (I or T)
Urea (blood urea nitrogen or 
blood urea)
7.1.10
Diastolic and Systolic Blood Pressure, Heart Rate, Respiratory Rate, and Body
Temperature
Diastolic and systolic blood pressure, heart rate, respiratory rate, and body temperature will be 
monitored up to Day 7 (or until ICU discharge if the patient leaves the ICU before Day 7) using 
standard equipment in accordance with local clinical practice. The baseline values, the values 
measured every 6 hours after initiation of IMP infusion up to midnight of Day 1 and twice daily 
(around 8:00 a.m. and 8:00 p.m.) the following days will be recorded in the eCRF. Any abnormality 
should be assessed by the investigator as to whether it constitutes an adverse event (see 
Section 8.1).
7.1.11
Mean Arterial Pressure
The MAP will be measured intra-arterially (or non-invasively if an arterial line is not available)
using standard equipment in accordance with local clinical practice. The method (intra-arterially or 
non-invasively) used will be documented in the eCRF.
The infusion rate of the IMP will be adjusted to keep the MAP at the target of 65 mmHg. However, 
a different target MAP will be accepted, if pre-specified in the eCRF and if appropriate, as judged 
by the investigator, for the clinical management e.g. in patients with previous hypotension or 
hypertension (if deemed necessary to maintain adequate organ perfusion). In such case, the target 
MAP and the reason for why a different target MAP has been chosen will be recorded in the eCRF.


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The following MAP values will be recorded in the eCRF:

Baseline.

Every 30 minutes during the first 3 hours after initiation of IMP infusion.

Every hour the following 3 hours.

Thereafter, every 6 hours up to midnight of Day 1. 

Twice daily (around 8:00 a.m. and 8:00 p.m.) until Day 7 or longer if IMP infusion is 
ongoing (until end of IMP infusion). 

Every hour for 6 hours following discontinuation of the IMP infusion.
In order to assess that vasopressor treatment is not prematurely stopped leading to episodes of 
hypotension, the MAP will be recorded hourly for the first 6 hours after complete weaning of IMP 
and episodes of clinically relevant hypotension (i.e. any period recorded in the hospital/medical 
source records through routine clinical care where the MAP drops below 60 mmHg for more than 
one hour) will be recorded in the eCRF detailing the total duration of the episode, the lowest MAP 
measured during the episode, and the actions taken to correct the hypotension.
MAP is also needed for the SOFA score (see Section 7.1.4). 
In addition, in the first patients at each trial site, the MAP should be noted in the patient’s medical 
record at the time when the infusion rate of the IMP or the norepinephrine/noradrenaline is adjusted
in order to monitor compliance with the IMP and vasopressor administration guide.
7.1.12
PaO2/FiO2 Ratio
PaO2/FiO2 ratio will be monitored up to Day 7 (or until ICU discharge if the patient leaves the ICU 
before Day 7) in accordance with local clinical practice. The baseline value, the values measured 
every 6 hours after initiation of IMP infusion up to midnight of Day 1 and daily (around 8:00 a.m.) 
the following days will be recorded in the eCRF.
The PaO2 and FiO2 are also needed for the SOFA score (see Section 7.1.4).
7.1.13
Extravascular Lung Water and Pulmonary Permeability Index 
The extravascular lung water (EVLW) is the amount of water that is contained in the lungs outside 
the pulmonary vasculature, that is, in the interstitial and alveolar spaces (Jozwiak et al, 2013). The 
ratio between the EVLW and the pulmonary blood volume is called the pulmonary permeability 
index (PPI) which is believed to reflect the permeability of the alveolo-capillary barrier 
(Monnet et al, 2007). Both EVLW and PPI are useful tools to characterise pulmonary oedema.
EVLW and PPI will be collected at pre-selected trial sites who measure these variables as part of 
clinical practice. The baseline values and the daily (around 8:00 a.m.) values for the first 7 days 
after initiation of IMP infusion (or until ICU discharge if the patient leaves the ICU before Day 7), 
as measured using standard equipment in accordance with local clinical practice, will be recorded if 
available.


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7.1.14
Cardiac Output
Cardiac output will be monitored up to Day 7 (or until ICU discharge if the patient leaves the ICU 
before Day 7) at pre-selected trial sites who measure cardiac output as part of clinical practice. The 
baseline value and the values obtained twice daily (around 8:00 a.m. and 8:00 p.m.) for the first 
2 days after initiation of IMP infusion and daily (around 8:00 a.m.) for the following days, as 
measured using standard equipment in accordance with local clinical practice, will be recorded if 
available.
7.2
Trial-specific Blood Sampling
7.2.1
Copeptin Levels
In patients at pre-selected trial sites, a blood sample will be collected before initiation of the IMP 
infusion for measurement of baseline levels of copeptin.
7.2.2
Pharmacokinetics
One blood sample for measurement of maximal plasma concentration of selepressin will be 
collected from all patients at one of the following time points (the one that occurs first): 1) right 
before first attempt to wean the IMP infusion, 2) after at least 7 hours of IMP infusion at maximal 
infusion rate, 3) at time of first pause of IMP, or 4) at time of IMP discontinuation.
Moreover, if the IMP infusion is prematurely paused or discontinued due to a serious adverse event, 
an additional blood sample will be collected at the time of IMP discontinuation or pause for 
measurement of plasma concentration of selepressin.
The IMP infusion rate at the time of the blood sampling will be recorded in the eCRF.
In approximately 200 patients at pre-selected trial sites, additional blood sampling for analysis of 
pharmacokinetic parameters will be conducted twice during the initiation of the IMP infusion (at
approximately 1-3 hours and 6-9 hours after start of infusion) and twice during the weaning of the 
IMP infusion (at approximately 1-2 hours and 2-3 hours after stop of infusion). If these patients are 
on RRT, additional blood sampling will also be performed before and after the RRT. The IMP 
infusion rate at 30 minutes after start of IMP infusion will be recorded in the eCRF.
7.2.3
Cytokines
The development of septic shock is associated with elevated levels of proinflammatory cytokines 
(Fjell et al, 2013). Exposure to inflammatory mediators and interaction with leukocytes causes 
endothelial activation and damage (Aird et al, 2003). Vasopressin has effects on immunity 
(Russell et al, 2010) and decreases cytokines more than does norepinephrine/noradrenaline 
(Russell et al, 2013). Selepressin is a potent V1a agonist that could also have effects on cytokines. 
Furthermore, cytokine levels in the blood may be predictive of the response to selepressin 
compared to placebo in septic shock.


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In patients at pre-selected trial sites, a blood sample will be collected at baseline (before initiation 
of IMP infusion) and at the first 3 days after initiation of IMP infusion for analysis of several 
cytokines e.g. VEGFA (vascular endothelial growth factor), interleukin (IL)-6, IL-2, CCL (CC 
chemokine ligand)-22, CCL11, LTA (lymphotoxin alpha), CSF (colony-stimulating factor)-2.
7.2.4
Angiopoietins
Angiopoietin-1 and angiopoietin-2 are circulating proteins with opposing roles on the vascular 
endothelium, i.e. angiopoietin-1 protects against vascular leakage whereas angiopoietin-2 promotes 
increased vascular permeability.
In patients at pre-selected trial sites, a blood sample will be collected at baseline (before initiation 
of IMP infusion) and at the first 3 days after initiation of IMP infusion for measurement of 
angiopoietin-1 and -2 levels.
7.3
Other Assessments
7.3.1
Central Venous Pressure
If central venous pressure (CVP) is measured for clinical purposes (via a central venous catheter 
using standard equipment in accordance with local clinical practice), the baseline value and the 
values measured every 6 hours after initiation of IMP infusion up to midnight of Day 1 and a daily 
(around 8:00 a.m.) value the following days until Day 7 (or until ICU discharge if the patient leaves 
the ICU before Day 7) will be recorded, if available. 
7.3.2
Central Venous Oxygen Saturation
If central venous oxygen saturation (ScvO2) is measured for clinical purposes (via a central venous 
catheter using standard equipment in accordance with local clinical practice), the baseline value  
and the values measured every 6 hours after initiation of IMP infusion up to midnight of Day 1 and 
a daily (around 8:00 a.m.) value the following days until Day 7 (or until ICU discharge if the 
patient leaves the ICU before Day 7) will be recorded, if available.
7.3.3
Arterial Blood Gases and Lactate Levels
If arterial blood gases and acid/base status (arterial oxygen partial pressure (PaO2), arterial carbon 
dioxide partial pressure (PaCO2), arterial oxygen saturation (SaO2), arterial pH, bicarbonate 
(HCO3), base excess) and lactate levels are available, as measured using standard equipment in 
accordance with local clinical practice, the baseline values and the values measured every 6 hours 
after initiation of IMP infusion up to midnight of Day 1 and a daily (around 8:00 am) result the 
following days until Day 7 (or until ICU discharge if the patient leaves the ICU before Day 7) will 
be recorded. In addition, the highest lactate level obtained after start of vasopressor treatment but 
before start of IMP will be recorded. If arterial lactate level has not been measured, the venous 
value can be recorded if available.
PaO2 will be used for the SOFA (see Section 7.1.4) and the PaO2/FiO2 ratio (see Section 7.1.12).


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7.4
Demographics and Other Baseline Assessments
7.4.1
Demographics
Demographic data including date of birth, race, and ethnic origin will be recorded.
7.4.2
Septic Shock Characteristics
Baseline septic shock characteristics (including site of infection, cause of infection, and whether the 
infection was proven or suspected) will be recorded. In addition, a confirmation of the septic shock 
characteristics recorded at time of enrolment and whether initial antibiotic treatment and source 
control was adequate will be recorded at ICU discharge.
7.4.3
APACHE II
APACHE II is a classification system which uses a point score based upon initial values of routine 
physiologic measurements, age, and previous health status to provide a general measure of severity 
of disease (Knaus et al, 1985). In this trial, the baseline (within the preceding 24 hours before 
initiation of the IMP infusion) APACHE II score will be recorded to assess the similarity of illness 
severity at baseline between treatment arms. 
7.4.4
Electrocardiography
A 12-lead baseline ECG obtained prior to start of IMP infusion must be available. ECGs obtained 
for clinical purposes within 48 hours of starting IMP may be used as baseline ECG, provided there 
is no indication of any change in the cardiac condition. If there is any reason to suspect a change in
cardiac condition, a new 12-lead ECG should be obtained prior to initiation of IMP. The purpose of 
the baseline ECG is to have a status at entry to which later ECGs may be compared, should this 
become relevant. The ECG should be obtained in accordance with local clinical practice and ECG 
recordings should capture at least four QRS complexes, i.e. three evaluable RR intervals. 
Continuous ECG monitoring will be performed as medically required in accordance with local 
clinical practice.
7.4.5
Body Weight and Height
The baseline (usual) body weight and height will be assessed in accordance with local clinical 
practice. The baseline weight will be used for calculation of the infusion rate of IMP and the 
norepinephrine/noradrenaline dosing. 
7.4.6
Medical History
Information about relevant medical history will be collected. The Charlson Comorbidity Index will 
be used.
7.4.7
Prior and Concomitant Medication/Procedure
Information about relevant concomitant medications/procedures will be collected (see Section 4.3). 


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7.4.8
Pregnancy Test
Women of child bearing potential will be tested for pregnancy (in accordance with local clinical 
practice) before initiation of IMP infusion. Urine dipstick pregnancy tests will be provided to the 
trial sites.
7.5
Handling of Biological Samples
Copeptin, cytokines, angiopoietin-1, angiopoietin-2, and selepressin levels will be measured by 
contract research laboratories. A detailed description of the sample collection and shipment 
procedures will be included in a trial-specific laboratory manual. These blood samples will be 
maintained in storage after the end of the trial. Destruction will take place within one year after last 
visit/trial-related contact with the last ongoing patient. Bio bank/data protection will be handled in 
compliance with the national/local regulations.
Handling of all other biological samples will be in accordance with local clinical practice.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An adverse event is any untoward medical occurrence in a patient participating in a clinical trial. It 
includes:

Any unfavourable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP.

Adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the IMP.

Any laboratory abnormality, vital sign, or finding from physical examination assessed as 
clinically significant and unanticipated in a setting of septic shock by the investigator. 
Findings from assessments and examinations done during screening are not adverse events, 
but are recorded as medical history.

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures.

Overdoses and medication errors with and without clinical consequences.
8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The investigator must monitor the condition of the patient throughout the trial from the time of 
obtaining informed consent until the last visit/trial-related contact.
The sources of adverse events cover:

Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities which are unanticipated in the setting of 
septic shock.

The patient’s response to questions about his/her health (a standard non-leading question 
such as "How have you been feeling since your last visit?" is asked at each visit).

Symptoms spontaneously reported by the patient.

Other information relating to the patient’s health becoming known to the investigator (e.g. 
hospitalisation in the follow-up period).
8.2.2
Recording of Adverse Events
The investigator must record all adverse events in the adverse event log provided in each patient's 
eCRF with information about:

Adverse event


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
Date and time of onset (time can be omitted, if applicable)

Intensity

Causal relationship to the IMP

Action taken to the IMP

Other action taken

Date and time of outcome (time can be omitted, if applicable)

Outcome

Seriousness
Each of the items in the adverse event log is described in detail in the following sections.
Adverse Event
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record.
If a patient suffers from the same adverse event more than once and the patient recovers in between 
the events, the adverse events should be recorded separately. 
If an adverse event changes (decreases or increases) in intensity, a worst-case approach should be 
used when recording the event, i.e. the highest intensity and the longest duration of the event. 
Exception: if an adverse event with onset before the first administration of the IMP (i.e. a pre-
treatment adverse event) changes in intensity after the administration of the IMP, this must be 
recorded as two separate events. The initial adverse event should be recorded with outcome “not yet 
recovered” and the date and time of outcome is when the intensity changed. The second adverse 
event should be recorded with date and time of onset when the intensity changed.
Pre-existing conditions not related to the patient’s current clinical setting of vasopressor-dependent 
septic shock are not adverse events, but become adverse events if worsening occurs after 
administration of the IMP during the trial. Pre-existing clinically significant conditions diagnosed 
or observed as a result of the screening procedures must be recorded as medical history.
Note the following: A procedure is not an adverse event; the reason for conducting the procedure is. 
However, a procedure may be captured along with the reason for conducting the procedure if the 
investigator finds it adds value to emphasise the procedure. Hospitalisation is not an adverse event; 
the reason for hospitalisation is. Death is not an adverse event, but the cause of death is (an 
exception is sudden death of unknown cause, which is an adverse event).
Overdoses and medication errors with or without clinical consequences are recorded as adverse 
events. The medication error must be specified. Any clinical consequence must be reported as 
“xxxx due to overdose/medication error”. In the absence of a clinical consequence this must 
specified e.g. “overdose with no clinical consequence”.


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Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the adverse 
event is an abnormal clinically significant laboratory test or outcome of an examination, the onset 
date is the date the sample was taken or the examination was performed. For pre-existing clinically 
significant conditions (diagnosed or observed as a result of the screening procedures) becoming 
worse after administration of the IMP, the date of onset is the date the worsening began. Time is to 
be recorded if relevant for the adverse event.
Intensity
The intensity of an adverse event must be classified using the following 3-point scale:

Mild:
Awareness of signs or symptoms, but no disruption of usual activity.

Moderate:
Event sufficient to affect usual activity (disturbing).

Severe:
Inability to work or perform usual activities (unacceptable).
Causal Relationship to IMP
The possibility of whether the IMP caused the adverse event must be classified as one of the 
following:
Reasonable possibility 
There is evidence or argument to suggest a causal relationship between the IMP and the 
adverse event. The adverse event may occur as part of the pharmacological action of the 
IMP or may be unpredictable in its occurrence. Examples: 

Adverse events that are uncommon but are known to be strongly associated with 
exposure of the IMP.

Adverse events that are not commonly associated with exposure of the IMP, but the 
event occurs in association with other factors strongly suggesting causation, such as 
a strong temporal association or the event recurs on rechallenge.
No reasonable possibility
There is no reasonable evidence or argument to suggest a causal relationship between the 
IMP and the adverse event. Examples:

Known consequences of the underlying disease or condition under investigation.

Adverse events common in the trial population, which are also anticipated to occur 
with some frequency during the course of the trial, regardless of exposure of the 
IMP.
Action Taken to IMP
The action taken to the IMP in response to an adverse event must be classified as one of the 
following:

No change (medication schedule maintained or no action taken).


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
Discontinued (medication schedule modified through permanent termination of prescribed 
regimen of medication).

Paused (medication schedule was modified by temporarily terminating a prescribed regimen 
of medication).
Other Action Taken
Adverse events requiring therapy must be treated with recognised standards of medical care to 
protect the health and well-being of the patient. Appropriate resuscitation equipment and medicines 
must be available to ensure the best possible treatment of an emergency situation.
If medication is administered to treat the adverse event, relevant medication will be entered in the 
medication forms and the serious adverse event form provided in each patient’s eCRF.
Date and Time of Outcome
The date and time (if applicable) the patient recovered or died.
Outcome
The outcome of an adverse event must be classified as one of the following:

Recovering (the event is improving).

Recovered (the event has improved i.e. fully recovered or the condition has returned to the 
level observed at initiation of trial treatment).

Recovered with sequelae (patient recuperated but retained pathological conditions resulting 
from the prior disease or injury e.g. resulted in persistent or significant disability /
incapacity).

Not recovered (the event has not improved).

Fatal (termination of life as result of an adverse event).
8.3
Adverse Events of Special Interest
Some event types are considered especially important to record during this trial as they are 
considered a crucial part of both septic shock and the safety profile of the IMP. Event types that 
should always be reported as adverse events are:

Episodes of atrial fibrillation and other cardiac arrhythmias that require treatment 
intervention, specifying the type of arrhythmia, treatment and/or intervention, severity and 
outcome.

Stroke and other cerebrovascular events.

Ischaemic events (myocardial ischaemia, peripheral ischaemia or mesenteric ischaemia).
8.4
Pregnancy
Known pregnancy is an exclusion criteria and women of child bearing potential will be tested for 
pregnancy and excluded if pregnant.


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8.5
Serious Adverse Events
8.5.1
Serious Adverse Event Definition
An event is defined as being a
serious adverse event if it:
Guidance:
Results in death
Any event resulting in a fatal outcome must be fully documented and reported, 
including deaths occurring within four weeks after the treatment ends and 
irrespective of the causal relationship to the IMP. The death of a patient 
enrolled in a trial is per se not an event, but an outcome (except in case of 
sudden death from unknown cause).
Is life-threatening
The term life-threatening refers to an adverse event in which the patient was at 
immediate risk of death at the time of the event. It does not refer to an event, 
which may have caused death if it were more severe.
Requires in-patient hospitalisation or 
prolongation of existing 
hospitalisation
The term hospitalisation means that the patient was admitted to hospital or that 
existing hospitalisation was extended as a result of an event. Hospitalisation 
describes a period of at least 24 hours. Over-night stay for observation, stay at 
emergency room or treatment on an out-patient basis do not constitute a 
hospitalisation. However, medical judgement must always be exercised and 
when in doubt the case should be considered serious (i.e. if case fulfils the 
criterion for a medically important event). Hospitalisations for administrative 
or social purposes do not constitute a serious adverse event. Hospital 
admissions and/or surgical operations planned before trial inclusion are not 
considered adverse events, if the illness or disease existed before the patient 
was enrolled in the trial, provided that the condition did not deteriorate during 
the trial.
Results in persistent or significant 
disability/incapacity
Disability/incapacity means a substantial disruption of a person’s ability to 
conduct normal life functions. In doubt, the decision should be left to medical 
judgement by the investigator.
Is a congenital anomaly/birth defect
Congenital anomaly/birth defect observed in any offspring of the patient 
conceived during treatment with the IMP.
Is an important medical event
Important medical events are events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the patient 
or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of important medical events include adverse 
events that suggest a significant hazard, contraindication or precaution, 
occurrence of malignancy or development of drug dependency or drug abuse. 
Medical and scientific judgement should be exercised in deciding whether 
events qualify as medically important.
Important medical events include any suspected transmission of an infectious 
agent via a medicinal product. Any organism virus or infectious particle (e.g. 
prion protein transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a patient exposed to a 
medicinal product.


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8.5.2
Collection, Recording and Reporting of Serious Adverse Events
Serious Adverse Event Reporting by the Investigator
All serious adverse events must be reported immediately to Global Pharmacovigilance at Ferring 
as soon as it becomes known to the investigator and not later than within 24 hours of their 
knowledge of the occurrence of a serious adverse event.
The investigator is responsible for submitting the completed serious adverse event report form with 
the fullest possible details within 3 calendar days of his/her knowledge of the serious adverse 
event.
The serious adverse event report form is included in the eCRF system, and must be completed and 
submitted according to the instructions provided. In case the eCRF cannot be accessed and hence 
the serious adverse event report form cannot be filled in within the eCRF system, a paper serious 
adverse event report form should be used and sent to Global Pharmacovigilance at Ferring using the 
contact details below.
Global Pharmacovigilance, Ferring Pharmaceuticals A/S
E-mail: 
Fax: 
Completion of the demographics, adverse events, medical history, and concomitant medication are 
mandatory for initial reports and for follow-up reports if any relevant changes have been made 
since the initial report. Data entries must have been made in the eCRF for Ferring Global 
Pharmacovigilance to access the information.
Additional information relevant to the serious adverse event such as hospital records, results from 
investigations, e.g. laboratory parameters (that are not already uploaded in the eCRF), invasive 
procedures, scans and x-rays, and autopsy results can be faxed or scanned and e-mailed to Ferring 
Global Pharmacovigilance using the contact details in the section above. In any case this 
information must be supplied by the investigator upon request from Ferring. On any copies 
provided, details such as patient’s name, address, and hospital identification number should be 
concealed and instead patient number should be provided.
The investigator will supply Ferring and the IEC/IRB with any additional requested information 
such as results of post-mortem examinations and hospital records.


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Expedited Reporting by Ferring
Ferring will report all adverse events that are serious, unexpected and with a reasonable possible 
causality to the IMP as judged by either the investigator or Ferring to the relevant parties within 
the stipulated timelines.
Taking into consideration the patient population, fatal outcome of certain events occurring in the 
trial will be considered expected; a mortality rate of 20-25% has been assumed. Consequently the 
fatal outcome is not considered to be a reportable event, whereas the investigator must still report 
the events to Ferring as outlined above. If the cause of death is one of the below MedDRA terms or 
those medically judged to be similar, the event will not qualify for expedited reporting: 
Circulatory collapse, distributive shock, endotoxic shock, septic shock, shock, toxic shock
syndrome, acute respiratory failure, cerebral hypoperfusion, hypoperfusion, multi-organ failure.
The expectedness is assessed by Ferring according to the investigator’s brochure for selepressin. 
Serious adverse events will be considered reportable regardless of whether or not the IMP was used 
in accordance with the provisions in the protocol and investigator’s brochure.
8.6
Follow-up of Adverse Events and Serious Adverse Events 
8.6.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each adverse event until it is resolved or until 
the medical condition of the patient is stable.
After the patient’s last visit, the investigator must follow-up on any adverse event that occurred 
during the trial and are classified as serious or considered to have a reasonable possible causality to 
the IMP with the outcome ‘not recovered’ until it is resolved or until the medical condition of the 
patient is stable. All such relevant follow-up information must be reported to Ferring. If the event is 
a chronic condition, the investigator and Ferring may agree that further follow-up is not required.
8.6.2
Collection of Serious Adverse Events with Onset after End of Trial
If an investigator becomes aware of a serious adverse event after the end of the trial, and he/she 
assesses the serious adverse event to have a reasonable possible causality to the IMP, the case will 
have to be reported to Ferring, regardless how long after the end of the trial this takes place.


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9
STATISTICAL METHODS
The Global Biometrics department at Ferring will be responsible for the final statistical analyses. 
External statistical consultancies will be responsible for all interim analyses during the trial. All 
analyses will be detailed in a separate statistical analysis plan.
The Health Economics & Outcome Research department at Ferring will evaluate the cost-
effectiveness of selepressin utilising relevant data recorded in this trial. Details of these analyses 
will be described in a separate health economic analytical plan. 
The department of Experimental Medicine at Ferring will perform an analysis of pharmacokinetic 
parameters in a subset of patients. Details of this analysis will be described in a separate
pharmacokinetic analysis plan.
9.1
Determination of Sample Size
At least 1800 evaluable patients combined for Part 1 and Part 2 are needed for the final analysis.
The overall power of obtaining statistical significance based on combined evidence from Part 1 and 
Part 2 is 91% in situations where all four arms have a true underlying 1.5% lower mortality rate and 
a 1.5-day higher expected number of P&VFDs for survivors (corresponding to an overall treatment 
effect of 1.5 P&VFDs) as compared to placebo. If the effect sizes are 2% on mortality and 2 days 
for P&VFDs in survivors for all four arms (corresponding to an overall treatment effect of 
2 P&VFDs) then the overall power is 98%. In this latter case the probability of engaging into Part 2 
is ~99%. The four arms are described in Table 1.
9.2
Patient Disposition
A summary table will present, for each part of the trial and overall, the number of patients in the 
population sets: ‘Screened’, ‘Intention to treat’, Full analysis set’, ‘Per protocol’, ‘Safety’, 
‘Completed trial’, ‘Withdrawals’, and ’IMP discontinuations’ with a breakdown of 
reasons/categories for and trial withdrawals and IMP discontinuations. 
The patient disposition table will be broken down by each of the stratification variables [the need 
for mechanical ventilation (Yes/No), norepinephrine/noradrenaline requirement at baseline (< or 
≥30 µg/min) and plasma/serum creatinine (< or ≥150 µmol/L)] and broken down chronologically 
displaying number of patients ‘completed’ and ‘withdrawn from trial’ at Day 30, Day 90, and 
Day 180.
The number of patients screened but not randomised/allocated to treatment will be presented with 
the reason(s) for screen failure in a data listing. 
All major protocol deviations (including misrandomisation), based on the full analysis set (FAS), 
will be summarised for each part of the trial. 
Furthermore, 1-Kaplan Meier (KM) plots, based on the intention-to-treat (ITT), will be presented 
for the time to trial withdrawals/IMP discontinuations (whichever comes first) differentiated by 


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reason for trial withdrawal/IMP discontinuation using cumulative incidence functions. Dropout 
rates between treatment groups will be evaluated by the log-rank test.
9.3
Protocol Deviations
Protocol deviations will be classified as ‘minor’ or ‘major’ by the Ferring clinical trial team on the 
basis of a blinded review of data before declaration of clean file and lock of database. 
Major protocol deviations, such as significant non-compliance or other serious unforeseen 
violations deemed to invalidate the data and affect the conclusions of the trial, will lead to 
exclusion of data from the per protocol (PP) analysis set, while data will not be excluded because of 
minor protocol deviations. All major protocol deviations will be detailed and documented in the 
clean file document prior to database release. All protocol deviations (minor and major) will be 
listed in patient data listings.
9.4
Analysis Sets
9.4.1
Intention-to-Treat Analysis Dataset
The ITT analysis set comprises all randomised (as planned) patients.
9.4.2
Full Analysis Set
The FAS comprises data from all randomised (as planned) and dosed patients.
9.4.3
Per Protocol Dataset
Patients in the FAS will be excluded from the PP analysis set if they meet any major protocol 
deviations as defined in the statistical analysis plan. Data will be used up to the point of protocol 
deviation.
9.4.4
Safety Dataset
The safety analysis set comprises all treated patients and is analysed according to the actual 
treatment received.
9.5
Trial Population
9.5.1
Demographics and other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics (including vital signs) will 
be presented for the FAS population by treatment arm and total. 
Categorical data will be summarised using numbers and percentages. The percentages are based on 
the total number of patients with a corresponding assessment. Continuous data will be presented, 
for example, using the number of patients, mean and standard deviation, median, interquartile 
range, minimum and maximum. All baseline characteristics will be listed.


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9.5.2
Medical History and Prior/Concomitant Medication
Medical history will be summarised by treatment arm and total and presented in patient data 
listings.
Prior and concomitant medication will be summarised by treatment arm and total and presented in 
patient data listings. 
9.6
Endpoint Assessments
9.6.1
General Considerations
All statistical tests will be performed using a two-sided test at a 5% significance level. 
If the trial is stopped prematurely due to e.g. futility, the data will be analysed as planned in 
accordance with the statistical analysis plan.
The efficacy endpoints will be analysed for the FAS and the PP analysis set, with the FAS being 
considered as primary and the PP analyses as supportive. 
Categorical data will be summarised using counts and percentages, while continuous data will be 
presented using the number of patients, mean, standard deviation, median, interquartile range,
minimum and maximum.
All assessments will be listed in patient data listings.
9.6.2
Primary Endpoint
The primary endpoint of this trial is “vasopressor and mechanical ventilator-free days (P&VFDs) 
up to Day 30.”
This composite endpoint is defined as the number of days (reported to one decimal place (0.0 to 
30.0)) from start of treatment with the investigational medicinal product (IMP) [selepressin or 
placebo] to 30.0 days thereafter during which the patient is: 1) alive; 2) free of treatment with 
intravenous vasopressors; and 3) free of any invasive mechanical ventilation (see definition below).  
Patient Death
By definition, any patient that dies within this 30-day period will be assigned zero P&VFDs, even if 
there is a period during which the patient is alive and free of both vasopressor treatment and 
mechanical ventilation.
Definition of “Free of Vasopressors”
Free of vasopressors means less than 60 minutes during any contiguous 24-hour period (regardless 
of calendar day). If a patient requires periods of vasopressors longer than 60 minutes in total during 
any 24-hour period, the intervening intervals during which they are free of vasopressors will not be 
included in the period free of vasopressors in the determination of the number of P&VFDs. Thus, 


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the period free of vasopressors begins at the end of the last use of vasopressors that was either: 1) 
longer than 60 minutes in duration; or 2) part of greater than 60 minutes of use within a contiguous 
24-hour period.
Norepinephrine/noradrenaline, phenylephrine, dopamine, epinephrine/adrenaline, vasopressin, 
terlipressin, and IMP (i.e. selepressin and placebo) all constitute a vasopressor for the purpose of 
the primary analysis.
Vasopressor use due to anaesthesia or procedure-induced hypotension during and up to three hours 
after a surgery or procedure (including bedside) is exempt from this rule (i.e. such use of 
vasopressors would not affect the calculation of P&VFDs).
Definition of “Free of Mechanical Ventilation”
Mechanical ventilation is defined as use of endotracheal or tracheostomy tube assisted ventilation 
(>5 cm H2O continuous positive airway pressure and >5 cm H2O of pressure support from the 
ventilator in tracheostomy patients). End of mechanical ventilation is defined as: 1) extubation of 
intubated patients or 2) ≤5 cm H2O continuous positive airway pressure and ≤5 cm H2O of pressure 
support from the ventilator in tracheostomy patients. If non-invasive ventilation by mask or bag 
(>5 cm H2O of pressure support) is deployed to avoid (re)intubation, it also counts as mechanical 
ventilation. However, all other uses of non-invasive ventilation such as chronic night-time use of 
positive airway pressure for COPD or sleep apnea does not count as mechanical ventilation 
(regardless of pressure). Free of mechanical ventilation means less than 60 minutes during any 
contiguous 24-hour period (regardless of calendar day). If a patient requires mechanical ventilation 
for periods longer than 60 minutes in total during any 24-hour 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 the number of P&VFDs. Thus, the period free of 
mechanical ventilation begins at the end of the last use of mechanical ventilation that was either: 
1) longer than 60 minutes in duration; or 2) part of greater than 60 minutes of use within a 
contiguous 24-hour period.
The use of mechanical ventilation associated with anaesthesia or procedural sedation during and up 
to three hours after a surgery or procedure (including bedside) is exempt from this rule (i.e. such 
use of mechanical ventilation would not affect the calculation of P&VFDs).
It is important to note that the determination of freedom from vasopressors and freedom from 
mechanical ventilation are made separately; in other words, periods of vasopressor use and 
mechanical ventilation are not combined when determining whether 60 minutes of use has occurred 
within a 24-hour period.
Missing data during the time of hospitalisation will be imputed using a worst case approach taking 
into account previous and subsequent starting and stopping times of vasopressor administration and 
mechanical ventilation. If only the stop date but not time is given, the imputed time will be
midnight of that date, unless a subsequent starting time was recorded prior to midnight in which 


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case the imputed time would be the start time of the subsequent record. If neither stop date nor time 
is given, the imputed stop time will be the start date and time of the subsequent recording. 
Likewise, missing start dates and times would be imputed as worst case scenarios, i.e. is the patient 
found to be on mechanical ventilation with a date but no time for intubation, the imputed start time 
would be recorded as 00:01 of that day or the stop date of a preceding recording on that same date, 
whichever occurs last. If both start date and time is missing, the imputed start time would be the 
date and time of the preceding stop time recorded. In case of data being completely missing from a 
certain time point and onwards, the “last status carried forward” imputation will be applied. If a 
patient was last seen on either ventilator or vasopressors, it is assumed that the patient remained so, 
and is imputed to a value of 0 (zero) P&VFDs. If the patient was last seen off ventilator and 
vasopressors, it is also assumed that the patient remained so in the remaining 30-day period. If the 
patient was last seen (alive) on e.g. day 10 and at that point had been off both ventilator and 
vasopressors for three days, a value of 23 P&VFDs is imputed.
The primary endpoint, P&VFDs, will be analysed using a van Elteren test, stratified by need for 
ventilation (Yes/No), time from onset of shock (onset of any vasopressor) to start of IMP treatment 
(< or ≥6 hours), and norepinephrine/noradrenaline requirement at baseline (< or ≥30 µg/min). 
The primary analysis will compare all patients on all selepressin arms from both parts of the trial 
(pooled together and treated as a single arm) to all patients on the placebo arm from both parts of 
the trial. The primary analysis will be a test of superiority using a two-sided 5% significance level 
test. This test, within the trial, controls the type 1 error at a two-sided 5% level. Further details are 
provided in the statistical analysis plan.
Treatment effects will be estimated assuming a negative binomial distribution (to allow for possible 
overdispersion in a Poisson distribution) for the quantity (30 minus P&VFDs) for survivors, and a 
binomial distribution to model the probability of surviving. Both models adjusted for need for 
ventilation (Yes/No), time from onset of shock to start of IMP treatment (< or ≥6 hours), and 
norepinephrine/noradrenaline requirement at baseline (< or ≥30 µg/min). Further details are 
provided in the statistical analysis plan.
Furthermore, P&VFDs will be tabulated by treatment arm (including pooled active treatment arms), 
and presented graphically by histograms and cumulative distributions functions. 
The success (statistical/clinical significance) of the trial will be based upon the comparison of the 
analysis above (all patients on all selepressin dosing regimens from both parts of the trial [pooled 
together and treated as a single arm] compared to all patients on the placebo arm from both parts of 
the trial).


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9.6.2.1
Sensitivity Analyses of the Primary Endpoint
As the adaptations of the trial provide a conservative estimate of the p-value, sensitivity p-values 
will be provided using post-simulation bootstrap calculations. 
In order to check for consistency, the primary endpoint treatment differences will, as a minimum,
be estimated and presented by forest plots for the following subgroups:

Region

Age

Gender

Race/ethnicity
Furthermore, the primary endpoint will be stratified by severity of the patients, with risk of dying as 
indicator of severity (see Figure 3). Mortality (the risk of dying) will be analysed by a logistic 
regression model, with relevant baseline characteristics as covariates (e.g. the individual SOFA 
scores and age). The model used to generate the predicted risk (for all patients) will be based on 
patients in the placebo arm only, as the risk of dying should reflect the severity in the absence of 
selepressin. Stratified by the risk of dying (intervals of 20% if suitable, based on the mortality rates 
in the covariate categories in the model), the treatment effect of the primary endpoint will be 
presented graphically, in order to visually inspect whether the average treatment effect is distributed 
evenly across the severity of patients.
Figure 3
Risk-based Heterogeneity of the Treatment Effect on P&VFDs over the Risk of 
Dying (an example)


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The impact and robustness of the imputation of missing data will be checked by analysing data in 
the following ways

excluding all patients with missing/imputed data

imputing the 30-day P&VFD status for patients lost to follow up or otherwise withdrawn 
from trial using the observed ratio of P&VFDs at time of lost to follow up or time of 
withdrawal, to the same proportion for a 30-day status
For this analysis the 30-day P&VFD status for patients lost to follow up or otherwise withdrawn 
from trial will be imputed so that the 30-day ratio of P&VFDs is equal to the ratio of P&VFDs at 
time of lost to follow up or time of withdrawal. E.g. a patient being lost to follow up at Day 15 with 
4 P&VFDs (a ratio of 4/15 P&VFDs per days observed) will be imputed to 8 P&VFDs at Day 30 
(equivalent ratio 8/30 = 4/15). Patients having zero P&VFDs at time of lost to follow up will be 
imputed to a value of zero P&VFDs. 

tipping point analysis
The tipping point analysis will compare all possible combinations of ‘best case’ and ‘worst case’ 
scenarios between placebo and selepressin for patients lost to follow up or otherwise withdrawn 
from trial. Best case being an imputation assuming the remaining days off ventilator and 
vasopressors, and worst case being an imputation of zero P&VFDs. NP and NS will be the number 
of patients in the placebo and selepressin arms with missing data. The tipping point analysis will 
compare all combinations (from 0 to NP) of X patients on placebo imputed best case and NP – X 
imputed worst case, to Y patients on selepressin imputed best case and NS – Y imputed worst case. 
In other words, all NP +1 times NS +1 combinations will be analysed for the primary endpoint. 
Since the ‘best case’ is not the same for all patients (depending on when they were last seen off 
both ventilator and vasopressors), there are multiple outcomes within each combination. For each 
combination, the average p-value of the multiple outcomes will be plotted in the tipping point 
analysis. 
Below is an example of a tipping point analysis of 25 placebo versus 40 selepressin patients with 
imputed values. The x- and y-axis displays the number of patients with the ‘best case’ imputed. In 
the example in Figure 4, the red area displays the non-significant p-values, indicating that one 
would have to impute almost all placebo patients to a ‘best case’ and almost all selepressin to a 
‘worst case’ in order to get non-significant p-values, and hence ‘proving’ the robustness of the 
imputation method.


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Figure 4
Tipping Point Analysis of P&VFDs (an example)
Also, to make sure that the use of vasopressor in each group is not simply being replaced by an 
increased use of inotropic agents, there will be a sensitivity analysis of the primary endpoint in 
which the use of inotropic agents will count as vasopressor use.
9.6.2.2
Additional Analyses 
The primary analysis will be repeated for:

The selected dose only, i.e. comparing all patients on the selected dose (from Part 1) from 
both parts of the trial (pooled), to all patients on the placebo arm from both parts of the trial.

Data from Part 2 only, i.e. comparing the selected dose to placebo on data from Part 2 only.
9.6.3
Secondary Endpoints
For the purpose of a possible label inclusion, the Hochberg procedure for adjustment on 
multiplicity will be implemented to selected key secondary endpoints. Only if the primary efficacy 
analysis leads to a statistically significant result at the (one-sided) 2.5% level, then the Hochberg 
procedure, which is described below, is applied to the selected key secondary analyses. If the 
primary efficacy analysis does not result in statistical significance at the (one-sided) 2.5% level, 
then statistical significance (for the purpose of a possible label inclusion only) will not be declared 
for any of the key secondary analyses, regardless of their p-values.


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The selected key secondary endpoints aimed at further demonstrating treatment effect are:

All-cause mortality (defined as the fraction of patients that have died, regardless of cause) at
Day 90

RRT-free days up to Day 30 (excluding patients on RRT for chronic renal failure at time of 
randomisation)

ICU-free days up to Day 30 
In this application of the Hochberg procedure there are three hypothesis tests of superiority for each 
of the selected secondary endpoints. The target alpha level is (one-sided) 2.5%. The Hochberg 
procedure is as follows:

Order the p-values from the smallest to the largest value, p(1) < p(2) < p(3), with 
corresponding null hypothesis H(1), H(2), and H(3).

Start with the highest p-value. If p(3) < 2.5% (one-sided), then stop and declare all 
three comparisons significant at the 2.5% (one-sided) level (i.e. reject H(1), H(2), and H(3)). 
Otherwise, accept H(3) for the endpoint related to p(3), and go to p(2) the second highest p-
value.

If p(2) < 2.5/2 = 1.25% (one-sided), then stop and declare significance for H(1) and H(2). 
Otherwise, accept H(2), for the endpoint related to p(2), and go to p(1) the lowest p-value.

If p(1) < 2.5/3 = 0.833% (one-sided), then stop and declare significance for H(1). Otherwise, 
accept H(1), for the endpoint related to p(1).
Regardless of the statistical significance declared according to the Hochberg procedure, all analyses 
will be included and presented in the statistical report.
As for the primary analysis, the primary comparison (which determines the success, i.e. statistical 
and clinical significance) for the secondary efficacy endpoints is between all patients on all 
selepressin arms from both parts of the trial (pooled together and treated as a single arm) and all 
patients on the placebo arm from both parts of the trial. 
As an additional analysis, all secondary efficacy analyses will, as for the primary, be repeated for:

The selected dose only, i.e. comparing all patients on the selected dose (from Part 1) from 
both parts of the trial (pooled), to all patients on the placebo arm from both parts of the trial. 

Data from Part 2 only, i.e. comparing the selected dose to placebo on data from Part 2 only.
All free-days endpoints will be reported to one decimal place.
The following secondary endpoints will be defined and analysed in a similar manner as the primary 
endpoint:

Vasopressor-free Days up to Day 30

Mechanical ventilator-free Days up to Day 30


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
RRT-free Days up to Day 30 (excluding patients on RRT for chronic renal failure at time 
of randomisation)

ICU-free Days up to Day 30
Incidence of RRT up to Day 30 (excluding patients on RRT for chronic renal failure at time of 
randomisation) is defined as any form of renal replacement therapy defined as continuous renal 
replacement therapy, intermittent haemodialysis, or peritoneal dialysis. In order to ensure that any 
reduction in incidence of RRT is not caused by an increase in mortality, all patients dying within 
the 30-day period will be counted as on RRT. For patients withdrawn prior to Day 30, incidence of 
RRT will be based on the data available up until the time of withdrawal.
Incidence of RRT will be analysed by a logistic regression model with time from onset of shock to 
start of treatment, baseline creatinine and norepinephrine/noradrenaline requirement at baseline
(µg/kg/min), as covariates, and treatment, and need for ventilation as factors. The 95% confidence 
interval for the difference in proportions between treatment groups will be constructed using the 
delta method. Patients already on RRT at time of inclusion will be excluded from the analysis of 
incidence of RRT.
Non-inferiority will be claimed if the upper limit of the two-sided 95% CI of the adjusted difference 
in proportions is less than 20% of the estimated incidence of RRT in the placebo group. Superiority 
can be claimed if the upper limit is less than 0.
I.e., let 
 and  
 be the estimated incidences of RRT in the combined selepressin groups and the 
placebo group respectively. Non-inferiority will then be claimed if

 −
 + 1.96 ∗(
 −
) < 0.2 ∗

and superiority will be claimed if

 −
 + 1.96 ∗(
 −
) < 0
Furthermore, incidence of RRT will be tabulated by treatment arm (including pooled active 
treatment arms).
A subgroup analysis will be performed on patients without acute RRT at baseline.
Duration of septic shock up to Day 30. Shock is defined as the cumulative periods (>1 hour) from 
start of IMP until Day 30, on IMP or vasopressors. Vasopressor use due to anaesthesia / procedure-
induced hypotension during - and up to three hours after - surgery / procedure (including bedside) is 
exempt from this rule. For patients withdrawn (in the survivors analysis) or dying (in the non-
survivors analysis) while still in septic shock, the duration will be based on the data available up 
until the time of withdrawal or death. 


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Duration of septic shock will be analysed separately for survivors, non-survivors (within the first 
30 days) and overall, comparing treatment arms by an analysis of covariance (ANCOVA) model 
with time from onset of shock to start of treatment and norepinephrine/noradrenaline requirement at 
baseline (µg/kg/min) as covariates, and treatment and need for ventilation (Yes/No) as factors. The 
estimated treatment difference (to placebo) with a 95% confidence interval will be presented.  
Some patients will get out of shock prior to Day 30 (and stay alive until Day 30), some will get out 
of shock and die later on (prior to Day 30), others will die while still in shock (prior to Day 30), and 
the remaining few will not get out of shock prior to Day 30. This means that if mortality rates vary 
between treatment arms, the results of the analysis for the overall population will be influenced by 
the skewed mortality rates. Hence, for the overall population, the distribution of duration of shock 
(time to out of shock), will be presented graphically as competing risks between ‘time to out of 
shock’ and ‘dying while in shock’. Further, a KM (sub)-graph on ‘time to death’ will be presented 
for those getting out of shock (for which some will die later on, prior to Day 30). This is done in 
order to elucidate any skewness in mortality rates, influencing the results of the analysis. The 
duration of septic shock will also be tabulated by treatment arm (including pooled active treatment 
arms). 
The following secondary endpoints will be defined and analysed in a similar manner as for duration 
of septic shock:

Duration of mechanical ventilation up to Day 30

Duration of RRT up to Day 90 (excluding patients on RRT for chronic renal failure at 
time of randomisation)

ICU length of stay up to Day 30
Daily overall (modified) and individual organ scores of the SOFA will be compared between 
treatment arms up until Day 7 using a repeated measures ANCOVA model with baseline SOFA 
score as covariate, treatment, time and treatment by time interaction as factors, and patient as the 
experimental unit. The estimated treatment difference (to placebo) with a 95% confidence interval 
will be presented. 
Last observation carried forward (LOCF) will be used for missing SOFA scores on Days 2-7. No 
LOCF for Day 1 (as previous value is baseline). Patients dying will be imputed with a worst 
possible outcome, i.e. a value of 4 for each individual SOFA score.
Daily overall (modified) and individual SOFA scores will be tabulated by treatment arm (including 
pooled active treatment arms).
Incidence of new organ dysfunction and new organ failure. New organ failure is defined as an 
increase (i.e. worsening) in any of the individual SOFA scores from (0, 1, 2) at baseline to (3, 4) 
post baseline up until the end of the period (Days 7 or 30) (if the SOFA scores goes from [0, 1, 2] to 
[3, 4] and back to [0, 1, 2] again within the period, that will still count as a new organ failure). If a 


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patient dies within the period, he/she is considered to fail on all organs, and the number of new 
organ failures will be all organs except those already failed at baseline. Patients discontinued within 
the period will be evaluated based on the data available at time of discontinuation.
Incidence of new organ dysfunction is defined as an increase ≥1 from baseline to post baseline up 
until the end of the period (e.g. going from 1 to 2) in any of the individual SOFA scores. Patients 
with an individual SOFA score of 4 at baseline can per default not have a new organ dysfunction. If 
a patient dies within the period, he/she is considered to have dysfunction on all organs, and the 
number of new organ dysfunctions will be all organs except those already having a score of 4 at 
baseline. Patients withdrawn within the period will be evaluated based on the data available at time 
of withdrawal.
Incidence of at least one new organ failure will be analysed for any new organ failure (across all 
organ systems) and by individual organ systems, and compared between treatment arms using a 
logistic regression model with age, modified SOFA score, and norepinephrine/noradrenaline 
requirement at baseline (µg/kg/min) as covariates and gender and treatment arm as factors, 
presenting odds ratios with 95% confidence intervals.
Incidence of at least one new organ dysfunction will be analysed for any new organ dysfunction 
(across all organ systems) and by individual organ systems, and will be analysed as above for new 
organ failures.
The number of new organ dysfunctions and new organ failures will be compared between treatment 
arms using a negative binominal model with age, modified SOFA score, and norepinephrine/
noradrenaline requirement at baseline (µg/kg/min) as covariates, and gender and treatment as 
factors. The estimated treatment difference (to placebo) with a 95% confidence interval will be 
presented. The 95% confidence interval for the difference in proportions between treatment groups 
will be constructed using the delta method.
Incidence of any new organ dysfunction and any new organ failure and the number of new organ 
dysfunctions and new organ failures will be tabulated by treatment arm (including pooled active 
treatment arms).
All-cause mortality is defined as the fraction of patients that have died, regardless of cause, by the 
end of Day 30, Day 90, and Day 180 and will be analysed and compared between treatment arms 
using a logistic regression model with the individual SOFA scores and age as covariates and 
treatment arm as factor. The 95% confidence interval for the difference in proportions between 
treatment groups will be constructed using the delta method as for incidence of RRT. There will be 
no imputations for mortality.
Non-inferiority will be claimed if the upper limit of the two-sided 95% CI of the adjusted difference 
in proportions is less than 30% of the estimated incidence of mortality in the placebo group. 
Superiority can be claimed if the upper limit is less than 0.


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Assuming an observed 30-day mortality rate of 20-25% in the placebo group, a non-inferiority limit 
of 30% corresponds to a maximum observed mortality rate of 2-3% in the combined selepressin 
groups in order for selepressin to be non-inferior to placebo.
Furthermore, mortality will be tabulated by treatment arm (including pooled active treatment arms), 
and the time to death presented graphically by a Kaplan-Meier plot.
EQ-5D-5L will be analysed by the index value, the overall quality-adjusted life years (QALY) at 
Day 30 and 180, and the VAS score. The QALY scores will NOT be adjusted to e.g. a half yearly 
time scale at Day 180. As the QALY is not defined for patients with all remaining values missing, 
and hence also not defined for those who die, the analyses will automatically only be analysed for 
those surviving up until Day 30 and Day 180, respectively.
For patients with missing baseline index value, the QALY score will also be set to missing. For 
robustness, a sensitivity analyses will be performed, imputing the missing baseline scores with the 
overall mean of the baseline health index. Baseline is the timing prior to acute admission.
The QALY at Day 30 and Day 180 will be compared between treatment arms using an ANCOVA 
model with baseline health index as covariate, and treatment as factor. Estimated treatment 
differences (to placebo) along with a 95% confidence interval will be presented.
The index value and VAS scores will be analysed separately for survivors and non-survivors at 
Day 180 (since all non-survivors will have non-random missing values, and hence would artificially 
inflate the mean estimates if survivors and non-survivors were analysed together) and will be 
compared between treatment arms using a repeated measures ANCOVA model with baseline health 
index/VAS score as covariate, treatment, time and treatment by time interaction as factors, and 
subject as the experimental unit. Estimated treatment differences (to placebo) along with a 95% 
confidence interval will be presented for Day 30, Day 60, Day 90, and Day 180. There will be no 
imputations for missing values.
The QALY, index value, and VAS scores will be tabulated by treatment arm (including pooled 
active treatment arms), and the index value and VAS scores will be presented graphically.
Daily and cumulative fluid balance (for 7 days or until ICU discharge). Fluid overload is defined 
as fluid balance as a percentage of baseline weight (e.g. if a patient weighs 90 kg at baseline and 
has a fluid balance of 9 litres, fluid overload is then 100% * 9 litres / 90 kg = 10%.
Fluid balance and cumulative fluid balance will be presented both unadjusted and adjusted for 
weight.
Daily and cumulative fluid balance as well as daily and cumulative fluid overload will all be 
compared between treatment arms using a repeated measures ANCOVA model with baseline 
(baseline fluid balance or baseline fluid overload) as covariate, treatment, time and treatment by 


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time interaction as factors, and patient as the experimental unit. Estimated treatment differences (to 
placebo) along with a 95% confidence interval will be presented. 
The absolute values and change from baseline will be tabulated by treatment arm (including pooled 
active treatment arms), and presented graphically. 
All analyses will be presented for ‘all patients’ and for ‘patients in ICU throughout Day 0-7’.
Daily and cumulative Urine Output (for 7 days or until ICU discharge) will be analysed as for 
fluid balance. 
9.6.4
Other Efficacy Endpoints
Other assessments include:

Hospital-free Days up to Day 90
Will be defined and analysed in a similar manner as for the primary endpoint.

Hospital length of stay up to Day 90
Will be defined and analysed in a similar manner as for duration of septic shock.

Norepinephrine/noradrenaline and other vasopressor doses
The dose of norepinephrine/noradrenaline administered (adjusted for baseline weight) will be 
compared between treatment arms using a repeated measures ANCOVA model with baseline dose 
of norepinephrine/noradrenaline as covariate, treatment, time and treatment by time interaction as 
factors, and patient as the experimental unit. Estimated treatment differences (to placebo) along 
with a 95% confidence interval will be presented. If a patient has missing values and the patient is 
still in the trial (not dead or withdrawn) it will be assumed that the specific vasopressor was not 
given and a value of zero will be imputed, unless there is an interval in the timing log covering the 
exact time point (8 AM and 8 PM is the assumed time point for missing morning and evening 
collection time points). In that case LOCF will be used, but only within the time interval.
The mean dose administered will be tabulated by treatment arm (including pooled active treatment 
arms), and presented graphically.
The same analysis (adjusted for baseline dose of norepinephrine/noradrenaline) will be performed 
for the following endpoints:
-
Catecholamines (defined as the sum of doses of norepinephrine/noradrenaline, 
epinephrine/adrenaline, dopamine, and phenylephrine)
-
Catecholamines excluding norepinephrine/noradrenaline
-
Vasopressin


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For the sum of catecholamine doses we define 100 μg dopamine, 1 μg epinephrine, and 2.2 μg 
phenylephrine all equivalent to 1 μg norepinephrine.
Also, the number of patients receiving terlipressin will be summarised.

Patient residence at Day 30, Day 60, Day 90, and Day 180 

MAP

Arterial blood gases and acid/base status (PaO2, PaCO2, SaO2, pH, bicarbonate, base excess) 
and lactate levels 

ScvO2

PaO2/FiO2 (in a subset of patients)

EVLW and PPI (in a subset of patients)

Cardiac output (in a subset of patients)

Cytokines, angiopoietin-1 and -2 levels (in a subset of patients)
These assessments will be presented by descriptive statistics, i.e. the number of patients with data, 
mean (standard deviation), median, interquartile range, minimum, and maximum values, will be 
presented for observed values and change from baseline at each time-point. Baseline value will be 
the value obtained at the last assessment prior to the infusion start of the IMP.

Creatinine clearance
Creatinine clearance will be analysed as for fluid balance with baseline creatinine clearance as a 
covariate, treatment, time and treatment by time interaction as factors, and patient as the 
experimental unit.
9.7
Extent of Exposure and Treatment Compliance
The total amount (adjusted by weight [µg/kg]) of selepressin administered and the number of 
(decimal) days treated with selepressin will be summarised by (active) treatment arm and total 
(active treatment arms).
Furthermore, the mean cumulative amount administered and the mean infusion rate will be 
tabulated by treatment arm and presented graphically (also by treatment arm and total).
9.8
Safety
9.8.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set. All safety summaries will be 
tabulated by treatment arm (including pooled active treatment arms).
9.8.2
Adverse Events
Adverse events will be classified according to the medical dictionary for regulatory activities 
(MedDRA). The MedDRA version will be documented. 


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A pre-treatment adverse event is any adverse event occurring after informed consent and before 
administration of the IMP.
A treatment-emergent adverse event is any adverse event occurring after the administration of the 
IMP and within the time of residual drug effect (i.e. 12 hours), or a pre-treatment adverse event or 
pre-existing medical condition that worsens in intensity after start of IMP and within the time of 
residual drug effect. The time of residual drug effect is the estimated time after the end of the 
administration of the IMP, where the effect of the product is still considered to be present based on 
pharmacokinetic, pharmacodynamic, or other substance characteristics. A generally accepted time 
for residual drug effect is 5 half-lives. The terminal half-life of selepressin is expected to be not 
more than 1.8 hours, and hence, a treatment-emergent adverse event is defined as any adverse event 
occurring after the start of IMP infusion and within 12 hours after the IMP infusion is stopped. 
A post-treatment adverse event is any adverse event occurring after the residual drug effect period.
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of adverse events. A “worst case” approach will be used: if causality is missing, the adverse event 
will be regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse 
event will be regarded as severe; if seriousness is missing the adverse event will be regarded as 
serious; if start date is missing or incomplete, worst case will be assumed and the adverse event will 
be regarded as treatment-emergent (only if the incomplete start date is not compromised). If start 
date is completely missing, start date will be set as same day as start of treatment. If start date is 
incomplete, the date closest to start of treatment will be assumed, without compromising the 
incomplete data available on the start date; if outcome is missing and no date of outcome is present 
the outcome is regarded as ‘not recovered’.
Adverse event overview summary tables will be prepared for treatment-emergent AEs and all AEs 
(treatment-emergent and non treatment-emergent) including the number of patients reporting an
adverse event, the percentage of patients with an adverse event, and the number of events reported, 
for the following categories: 

Adverse events

Deaths 

Serious adverse events 

Adverse events leading to discontinuation of IMP

Severe and life-threatening adverse events 

Adverse drug reactions
Adverse events will be summarised in a table by SOC (sorted alphabetically) and PT (sorted in 
decreasing frequency of occurrence) using MedDRA. The table will display the total number of 
patients reporting an adverse event, the percentage of patients with an adverse event, and the 
number of events reported. 


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For both treatment-emergent AEs and all AEs (treatment-emergent and non treatment-emergent) 
during the treatment period, summary tables will be prepared for:

All adverse events

Adverse events with an incidence ≥5% of patients in any treatment arm

Non-serious adverse events with an incidence ≥5% of patients in any treatment arm

Critical adverse events, details are provided in the statistical analysis plan

Adverse events by causality (related/unrelated)

Adverse events leading to death

Adverse events by intensity 

Serious adverse events 

Adverse events leading to discontinuation of IMP (related/unrelated)
Supporting data listings will be provided for:

All adverse events sorted by trial site and patient number

All adverse events sorted by MedDRA PT

Serious adverse events 

Adverse events leading to death

Adverse events leading to discontinuation of IMP (related/unrelated)

Post-treatment adverse events
9.8.3
Safety Laboratory Variables
Safety laboratory variables will be grouped under ‘Clinical Chemistry’, ‘Haematology’, and 
‘Coagulation’.
Baseline for all safety laboratory variables will be the values obtained at the last assessment prior to 
the infusion start of the IMP. End of treatment period will include the last post-baseline observation 
during the trial up until Day 30. 
Mean change and mean percentage change from baseline at end of treatment period will be 
presented for each laboratory variable. In addition, descriptive statistics, i.e. the number of patients 
with data, mean (standard deviation), median, interquartile range, minimum, and maximum values, 
will be presented for observed values and change from baseline at each time-point for each 
laboratory variable. 
Also, summary tables will be presented, displaying by time and laboratory parameter, the number 
of patients with a clinically significant result which is unanticipated in the setting of septic shock.
Furthermore, a summary table will be prepared for selected laboratory variables that display the 
number and percentage of patients in each treatment arm with X% increments (increase or 


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decrease) from baseline at each time-point. The selected laboratory variables and categories are 
detailed in the statistical analysis plan. 
9.8.4
Vital Signs and Central Venous Pressure
Baseline for all vital signs variables and CVP will be the values obtained at the last assessment 
prior to the IMP infusion start. End of treatment period will include the last post-baseline 
observation during the trial up until Day 30.
Mean change and mean percentage change from baseline at end of treatment period will be 
presented for each variable. In addition, descriptive statistics, i.e. the number of patients with data, 
mean (standard deviation), median, interquartile range, minimum, and maximum values, will be 
presented for observed values and change from baseline at each time-point for each variable. 
Also, summary tables will be presented, displaying by time and vital signs parameter, the number 
of patients with a clinically significant result which is unanticipated in the setting of septic shock.
Furthermore, a summary table will be prepared for each variable that display the number and 
percentage of patients in each treatment arm with X% increments (increase or decrease) from 
baseline at each time-point and end of treatment period. The variables and categories are detailed in 
the statistical analysis plan.
9.8.5
Episodes of Hypotension
Descriptive statistics of number of patients with episodes of hypotension and the total length of 
periods with hypotension will be summarised by treatment arm.
The total length of periods with hypotension will be summarised for both all patients, and patients 
having one or more episodes of hypotension.
9.9
Interim Analyses
There will be no interim analyses with the potential to stop the trial early for treatment efficacy. 
However, once the “burn-in” period in Part 1 is completed (first 200 treated patients), interim 
analyses will be conducted regularly to improve the efficiency of dose selection and to allow early 
termination of the part or the trial for futility or for successful dose selection. The following steps 
will be considered at each interim analysis:

When 200 patients are treated, the allocation probabilities for the active treatment arms are 
changed using response-adaptive randomisation (with placebo still 1/3). For the two-thirds 
of patients assigned to the active arms, the probability that a given active arm is assigned to 
a patient is proportional to the probability that that arm is the arm with the largest expected 
number of P&VFD.

Potentially stopping the trial for futility during Part 1. This occurs if no active arm has better 
than a 5% predictive probability of a significant result in Part 2 if it were to start 


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immediately. This decision can occur at any interim during Part 1 after 200 evaluable 
patients.

Potentially ending Part 1 and selecting an active treatment arm to continue to Part 2. This 
decision can occur at any interim analysis between 300 evaluable and 800 treated patients, 
and it occurs if some arm has a predictive probability of a successful trial of at least 90% 
before 800 treated patients, and the threshold drops to 25% for the final Part 1 interim 
analysis at 800 treated patients. The selected arm is the arm with the largest posterior 
predictive probability of trial success. This will generally be the best-performing active arm, 
but if multiple arms are performing equally well, it will be the arm with the lowest dosing 
level. If Part 1 ends after N patients, then Part 2 will consist of up to 1800 - N evaluable 
patients.

If the trial is not stopped for futility or proceeding to Part 2 and active treatment Arm 4 has 
not yet been approved for assignment of patients, the decision can be made to open up 
Arm 4. Arm 4 is only opened between 200 evaluable and 600 treated patients and if there is 
at least a 50% probability that Arm 3 has a higher expected P&VFD than Arm 2 and if data 
from the lower dosing levels do not suggest any significant safety signals.

If Part 1 reaches its maximum of 800 treated patients and no arm has a predictive 
probability of Part 2 success of more than 25%, the trial stops with an inconclusive result 
and will be interpreted as a standalone Phase 2b trial.
During Part 2, interim analyses will be conducted regularly (until 1600 patients have been treated) 
to allow early termination of the trial for futility. This occurs if the predictive probability of an 
overall significant result is less than 5%. In addition, if the predictive probability of observing a 
more than 2% higher mortality in the active arms compared to placebo is greater than 90% then the 
trial will stop for futility.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data – ICH Definition
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).
Source Documents - ICH Definition
Source documents are defined as original documents, data, and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial).
Trial-specific Source Data Requirements – Ferring
The investigators must maintain patient records. For each randomised patient, the investigators will 
indicate in the hospital/medical source records that the patient participates in this trial and the date 
of obtaining the informed consent. The records will include data on the condition of the patient at 
the time the patient is enrolled in the trial in order to document (and enable verification of) 
eligibility. Signed and dated informed consent forms will be stored and archived in accordance with 
local requirements. 
The following information, as a minimum, has to be recorded in the hospital/medical source records 
for each patient:

Documentation of informed consent obtained

Trial identification

Screening/patient (randomisation) number

Patient’s name

Demographic data including date of birth, race, and ethnic origin

Diagnosis, septic shock characteristics

Relevant medical history 

Relevant concomitant medications/procedures

Body weight and height

Eligibility for participation in the trial (documenting all inclusion/exclusion/eligibility
criteria)


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
Details of the administration of IMP

Details of the administration of norepinephrine/noradrenaline and other vasopressors

Details of the MAP during the IMP infusion

Details of mechanical ventilation (including spontaneous breathing trials) and RRT

Functional/survival status of the patient throughout the trial

ED/ICU/hospital admission and discharge dates and times 

Details and results of all other examinations and tests performed

Date of each visit/contact

Details of adverse events

Reason for discontinuation/withdrawal, if applicable
Information included in the patient’s hospital records may be subject to local regulations. If there is 
a discrepancy between local requirements and the trial protocol, local regulations should be 
followed. The identification of source data for each variable may then be described in a separate 
document.
Documents collected during the trial (e.g. health-related quality of life questionnaires, laboratory 
reports, print-outs of MAP and ECG) should be stored and archived together with the patient’s
hospital/medical records or in the investigator file as agreed upon prior to the trial start at each trial 
site.
No specific protocol data can be recorded directly in the eCRF without prior written or electronic 
record.
10.2
Electronic Case Report Form (eCRF)
An eCRF system provided by an independent third-party contract research organisation will be 
used for data capture. Contact details of the contract research organisation are provided in a trial-
specific contact list. The system is validated and access at all levels to the system is 
granted/revoked following Ferring and vendor procedures, in accordance with regulatory and 
system requirements.
Data should be entered into the system within a reasonable time after source data is collected.
The investigator will approve/authorise the eCRF entries for each patient with an electronic 
signature which is equivalent to a handwritten signature. 
The eCRF system and the database will be hosted at and administered by the independent third 
party contract research organisation. After the trial database is declared clean and released to the 
statistician, a final copy of the database will be stored at Ferring. The investigator will also receive 
a copy of the trial site’s final and locked data (including audit trail, electronic signature and queries) 
as write-protected PDF-files produced and distributed by the independent third party contract 


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research organisation. The PDF-files will be stored on a CD and will be provided to the investigator 
before read access to the eCRF is revoked.
Modification of data entered into the eCRF will be captured in an electronic audit trail detailing the 
date and time of the correction and the user name of the person making the correction. Only site 
coordinator and investigator have privileges to modify data.
10.3
Data Management 
A data management plan will be created under the responsibility of the Global Biometrics 
department at Ferring. The data management plan will be issued before data collection begins and 
will describe all functions, processes, and specifications for data collection, cleaning, and 
validation.
The data management plan will describe capture methods, who is authorised to enter the data, 
decisions about ownership of data, source data storage, which data will be transferred (including
timing of transfers), the origin and destination of the data, and who will have access to the data at 
all times.
10.4
Provision of Additional Information
On request, the investigators will provide Ferring with additional data relating to the trial, duly 
anonymised and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitors will contact and visit the investigators periodically to ensure adherence to the 
protocol, International Conference of Harmonisation-Good Clinical Practice (ICH-GCP), standard 
operating procedures and applicable regulatory requirements, maintenance of trial-related source 
records, completeness, accuracy and verifiability of eCRF entries compared to source data, 
verification of drug accountability, and compliance to safety reporting instructions. The 
investigators will permit the monitors direct access to all source data, including electronic medical 
records, and/or documents in order to facilitate data verification. The investigators will co-operate 
with the monitors to ensure that any discrepancies that may be identified are resolved. The 
investigators are expected to be able to meet the monitors during these visits. The first on-site 
monitoring visit will take place shortly after randomisation of the first patient. The frequency of the 
on-site monitoring visits is dependent on the number of enrolled patients at the trial site. 
The source data verification process and definition of key variables to be monitored will be 
described in the trial-specific monitoring plan.
11.2
Audit and Inspection
The investigators will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspector(s) or 
representative(s) from IECs/IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki and all other relevant regulations.
The patients must be informed by the investigators and in the informed consent documents that 
authorised Ferring representatives and representatives from regulatory authorities and IECs/IRBs 
may wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the screening/ 
randomisation number will appear on these copies.
The investigators should notify Ferring without any delay of any inspection by a regulatory 
authority or IEC/IRB.
11.3
Confidentiality of Patient Data
The investigators will ensure that the confidentiality of the patients’ data will be preserved. In the 
eCRF or any other documents submitted to Ferring, the patients will not be identified by their 
names, but by an identification system, which consists of an assigned number in the trial. 
Documents that are not for submission to Ferring, e.g. the confidential patient identification code 
and the signed informed consent documents, will be maintained by the investigators in strict 
confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the TSC, investigators, and Ferring prior to its implementation. Amendments may 
be submitted for consideration to the approving IECs/IRBs and regulatory authorities, in 
accordance with local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial 
patients may be implemented prior to IECs/IRBs approval/favourable opinion.
12.2
Deviations from the Protocol
The investigators must inform the monitor if deviations from the protocol occur and the 
implications of the deviation must be reviewed and discussed. Any deviation must be documented, 
either as an answer to a query in the eCRF, in a protocol deviation report, or a combination of both. 
A log of protocol deviation reports will be maintained by Ferring. Protocol deviation reports and 
supporting documentation must be kept in the investigator’s file and the trial master file.
12.3
Premature Trial Termination
Both the investigators (with regard to his/her participation) and Ferring reserve the right to 
terminate the trial at any time. Should this become necessary, the procedures will be agreed upon 
after consultation between the two parties. In terminating the trial, Ferring and the investigators will 
ensure that adequate consideration is given to the protection of the best interests of the patients. 
Regulatory authorities and IECs/IRBs will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial sites. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter patients at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigators. 
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigators and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
Sponsor recognises and accepts that investigators may have a meaningful right to publish research
results of the trial. Investigators must agree that the first publication of trial results is to be a joint 
publication covering all trial sites, and that subsequent publications will reference that primary 
publication. At the end of the trial, one or more manuscripts (including manuscripts, presentation, 
abstracts, posters etc.) for joint publication may be prepared in collaboration between the 
investigators and the TSC and Ferring, and the criteria for such publication shall be coordinated 
through the TSC. As the trial is a multi-centre trial, all publications shall be joint publications 
covering all trial sites unless specific written permission is obtained in advance from the TSC. 
However, if a joint manuscript has not been submitted for publication within 18 months of 
completion or termination of the trial, the investigators shall be free to publish separately. Any 
publication of results must acknowledge all trial sites. 
Under the coordination of the TSC, authorship is granted based on the International Committee of 
Medicinal Journal Editors (ICMJE) criteria (see current official version: http/www.ICMJE.org). 
Any external contract research organisation or laboratory involved in the conduct of this trial has no 
publication rights regarding this trial.
Any publication, whether joint or independent, on the results of the trial must be submitted in 
writing to the TSC and Ferring for comment prior to submission at least 60 days in advance of the 
submission of such proposed publication to the applicable journal or other forum in which the 
publication or presentation may be published or presented. At Ferring’s request, the respective 
institution and/or investigator shall arrange for an additional delay in publication or presentation, 
not to exceed an additional 60 days, to enable Ferring to request deletion of Ferring Confidential 
Information and to arrange for filing of patent applications or other intellectual property protection. 
This statement does not give Ferring editorial rights over the content of a publication, other than to 
restrict the disclosure of Ferring’s intellectual property. If the matter considered for publication is 
deemed patentable by Ferring, scientific publication will not be allowed until after a filed patent 


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application is published. Under such conditions the publication will be modified or delayed to allow 
sufficient time for Ferring to seek patent protection of the invention.
13.3.2
Public Disclosure Policy 
ICMJE member journals have adopted a trials-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate public registry, i.e.
www.ClinicalTrials.gov which is a website maintained by the National Library of Medicine at the 
U.S. National Institutes of Health. The trial will also be made publicly available at the EU Clinical 
Trials Register at www.clinicaltrialsregister.eu. Trial registration may occur in other registries in 
accordance with local regulatory requirements. A summary of the trial results is made publicly 
available in accordance with applicable regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Independent Ethics Committees or Institutional Review Boards
Independent ethics committees/institutional review boards will review the protocol and any 
amendments. The IECs/IRBs will review the patient information sheet and the informed consent 
form, their updates (if any), and any written materials given to the patients. A list of all IECs/IRBs 
to which the protocol has been submitted will be included in the clinical trial report.
14.2
Regulatory Authorities Authorisation / Approval / Notification
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a patient is 
exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
End of-trial is defined as the date of the last trial-related contact with the last patient ongoing in the 
trial. At the end-of-trial, Ferring shall notify the regulatory authorities and the IECs/IRBs in the 
participating countries about the completion of the clinical trial in accordance with national/local 
regulations.
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (World Medical Association, 2013), in compliance with the approved 
protocol, ICH-GCP, and applicable regulatory requirements.
14.5
Patient Information and Consent
Critically ill patients receiving care in the EDs/ICUs represent a highly vulnerable population with 
regard to informed consent as these patients are often not capable of participating in the consent 
process. Because of this, proxies are often required to provide consent and other health decisions
for impaired patients. 
The informed consent process in this trial will be obtained in accordance with national/local 
regulations. 
The investigator (or the person delegated by the investigator) will obtain a freely given written 
consent in accordance with national/local regulations from each patient or his/her legally acceptable 
representative after an appropriate explanation of the aims, methods, anticipated benefits, potential 
hazards, and any other aspects of the trial which are relevant to the patient’s decision to participate. 
The patient or the legal representative should be given ample time to consider participation in the 
trial, before the consent is obtained. The patient (and the legal representative, if applicable) will 
receive a copy of the patient information and the signed informed consent form.


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The investigator (or the person delegated by the investigator) will explain that it is completely free 
to refuse to enter the trial or to withdraw from trial at any time, without any consequences for the 
patient’s further care and without the need to justify the decision.
The investigator (or the person delegated by the investigator) will inform that the monitor(s) and 
quality assurance auditor(s) mandated by Ferring, IRB/IEC representatives, or regulatory authority 
inspector(s), in accordance with applicable regulatory requirements, may review the patient’s 
source records and data. Data protection will be handled in compliance with the national/local 
regulations.
If new information becomes available that may be relevant to the willingness to continue 
participation in the trial, a new patient information and informed consent form will be forwarded to 
the IECs/IRBs and the regulatory authorities, if required. The trial patients (and the legal 
representatives, if applicable) will be informed about this new information and re-consent will be 
obtained.
14.6
Patient Information Card
If required by local regulations, the patient will be provided with a patient information card bearing 
required trial-related information.
Each patient’s primary care physician will be notified of their participation in the trial by the 
investigator, if the patient agrees.
14.7
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, the European Union Clinical Trials 
Directive, 21 CFR Part 312, and other national laws in the countries where the trial takes place shall 
constitute the main reference guidelines for ethical and regulatory conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitors, and the investigators are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The investigators are responsible for adhering to the ICH-GCP responsibilities of 
investigators, for dispensing the IMP in accordance with the approved protocol or an approved 
amendment, and for its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
In case of any damage or injury occurring to a patient in association with the IMP or the 
participation in the trial, Ferring has contracted an insurance which covers the liability of Ferring, 
the investigators, and other persons involved in the trial in compliance with the laws in the 
countries involved.


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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the site to be fully understood, in compliance with ICH-GCP. The trial documentation including 
all the relevant correspondence should be kept by the investigator for at least 15 years (or longer if 
so required by local law) after the completion or discontinuation of the trial, if no further 
instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential patient 
identification code which provides the sole link between named patient source records and 
anonymous eCRF data for Ferring. The investigator must arrange for the retention of this patient 
identification log and signed informed consent documents for at least 15 years (or longer if so 
required by local law) after the completion or discontinuation of the trial.
No trial site document may be destroyed without prior written agreement between the investigator 
and Ferring. Should the investigator elect to assign the trial documents to another party, or move 
them to another location, Ferring must be notified. If the investigator retires and the documents can 
no longer be archived by the site, Ferring can arrange having the investigator file archived at an 
external archive.
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
REFERENCES
Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. 
Blood 2003;101:3765–3777.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for 
Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med. 2013;41:580-637.
The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208.
The EuroQol Group http://www.euroqol.org.
Ferring Pharmaceuticals. A randomized, double-blind, placebo-controlled, infusion proof-of-
concept trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
ascending doses of FE 202158 in patients with vasodilatory hypotension in early septic shock. 
FE 202158 CS02 Clinical Trial Report. 25 Aug 2013.
Ferring Pharmaceuticals. First time administration of FE 202158 in man: Safety, tolerability, 
pharmacokinetics, and pharmacodynamics after intravenous infusion of single ascending doses of 
the V1a receptor agonist FE 202158. A double-blind, placebo-controlled, within group randomized 
study in healthy subjects. FE 202158 CS01 Clinical Trial Report. 17 Aug 2009.
Fjell CD, Thair S, Hsu JL, Walley KR, Russell JA, Boyd J. Cytokines and signaling molecules 
predict clinical outcomes in sepsis. PLOS ONE 8(11): e79207, 2013.
Jozwiak et al. Extravascular lung water is an independent prognostic factor in patients with acute 
respiratory distress syndrome Crit Care Med. 2013;41:472-80.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med 1985;13:818-29.
Laporte R, Kohan A, Heitzmann J et al. Pharmacological characterization of FE 202158, a novel, 
potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment 
of vasodilatory hypotension. JPET 337:786-796, 2011.
Maybauer DM, Enkhbaatar P, Laporte R, Wiśniewska H, Traber LD, Lin C, Fan J, Hawkins HK, 
Cox RA, Wiśniewski K, Schteingart CD, Landry DW, MD, Rivière P, Traber DL. The Selective 
Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Block Vascular Leak in Ovine 
Severe Sepsis. Crit Care Med. 2014;42:e525–e533.
Monnet et al Assessing pulmonary permeability by transpulmonary thermodilution allows 
differentiation of hydrostatic pulmonary edema from ALI/ARDS Int Crit Care Med. 2007;33:448-
453.
Rehberg S, Enkhbaatar P, Rehberg J, et al. Unlike arginine vasopressin, the selective V1a receptor 
agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor. Crit 
Care Med. 2012;40(6):1957-1960. (b)
Rehberg S, Yamamoto Y, Sousse L, et al. Selective V1a agonism attenuates vascular dysfunction 


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and fluid accumulation in ovine severe sepsis. Am J Physiol Heart Circ Physiol. 
2012;303(10):H1245-1254. (a)
Rehberg S, Ertmer C, Vincent JL, Morelli A, Schneider M, Lange M, Van Aken H, Traber D, 
Westphal M. Role of selective V1a receptor agonism in ovine septic shock. Crit Care Med. 
2011;39:119-125.
Russell JA, Walley KR. Vasopressin and its immune effects in septic shock. J Innate Immun. 
2010;2(5):446-460.
Russell JA, Fjell CD, Hsu JL, Lee T, Boyd J, Thair S, Singer J, Patterson AJ, Walley KR. 
Vasopressin compared to norepinephrine augments the decline of plasma cytokine levels in septic 
shock. Am J Resp Crit Care Med. 2013;188(3):356-364.
Su F, He X, Taccone FS, Xie K, Mouhamed M, Kjolbye AL, Laporte R, Reinheimer T, Vincent 
JL. 123: Early administration of the selective V1a receptor agonist selepressin is superior to 
arginine vasopressin or norepinephrine in a sheep model of septic shock. [Abstract] Crit Care Med. 
Dec 2012;40(12) (Supplement 1):1-328.
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score 
to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems 
of the European Society of Intensive Care Medicine. Intensive Care Med. 1996; 22:707-710.
World Medical Association. Declaration of Helsinki – Ethical Principles for Medical Research 
Involving Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, October 2013.

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Date: 20 Nov 2017
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Statistical Analysis Plan
Ferring Pharmaceuticals
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
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
SEPSIS-ACT
Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial
000133
Investigational Product:
Selepressin; concentrate for solution for infusion
                                                             Placebo; sterile 0.9% sodium chloride solution
Indication:
Vasopressor-dependent Septic Shock
Phase:
2b/3
Author:
Date of issue:
November 20th - 2017
Version:
Final - Ver. 9.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Ferring Pharmaceuticals
CONFIDENTIAL
Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1
2
3
4
5
Dec 17-2014
Dec 19-2014
Dec 19-2014
Mar 24-2015
May 27-2015
Original SAP
Format change only. No content was changed
Format change only. No content was changed
Added endpoint: Episodes of hypotension
Modified endpoint: Norepinephrine/ 
noradrenaline and other vasopressor doses
Updated section on definition of P&VFDs 
and imputations for P&VFDs
Various minor elaborations of endpoint 
definitions and minor changes to analyses
Added sensitivity analysis for primary 
endpoint.
Appendix 4 notation updated and estimate for 
number of new organ dysfunctions and 
failures included
Appendix 5 updated to reflect tenths of days.
Appendix 6 updated to make proof more 
readable.
Various editorial clarifications
Not applicable
Version 1
Version 2
Version 3
Version 4


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6
July 8 - 2016
Expanded definition of onset of shock to 
include ANY vasopressors
Replaced two AE tables regarding adverse 
events based on changes in vital 
signs/laboratory values assessed as 
unanticipated in the setting of septic shock, as 
we do not collect sufficient data to produce 
these tables. Modified tables presented.
The analysis of other vasopressors has been 
split into several components.
Sensitivity analyses added to ICU-free days 
and ICU length of stay.
Fluid balance/Urinary output analyses 
updated
Terlipressin added to list of vasopressors for 
derivation of primary endpoint etc.
Definition of primary endpoint imputation for 
patients lost to follow-up is extended to 
include any type of withdrawal before Day 
30.
List of critical adverse events updated (same 
as before, just re-grouped).
No AE tables on AEs leading to withdrawal, 
as it is not an option to withdraw patient from 
trial due to AE.
Added alternative analysis to “duration of” 
endpoints, in case normality cannot be 
assumed for the whole of the data.
Small edit in formula in Appendix 5.
Continuous version of baseline 
norepinephrine version is adjusted for weight 
(categorical version from strata is unadjusted)
Added imputation rules for NE and other 
vasopressors (section 9.4.5) and IMP 
(section 8.1.1)
Appendix 2 slightly updated with corrections.
List of protocol deviations modified 
(section 5)
Version 5


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7
Nov 9 - 2017
Additional analyses to MAP analyses.
Analysis for duration of septic shock changed 
from ANCOVA to negative binomial (as 
blinded data suggests a better fit) with 
permutation test as backup in case model 
assumptions do not hold.
Analyses for duration of ventilation and 
duration of RRT changed from ANCOVA to 
zero inflated negative binomial (as blinded 
data suggests a better fit) also with 
permutation test as backup in case model 
assumptions do not hold.
Analysis for ICU length of stay and hospital 
length of stay changed from ANCOVA to 
permutation test (as blinded data suggested a 
non-parametric model). Covariates were 
dichotomized accordingly.
Appendix 4 removed as no longer needed.
Appendix 3 updated with variance correction 
for difference in PVFDs
Analyses in 9.4.8, 9.4.9, and 9.4.10 will not 
be repeated for the selected arm only and data 
from part 2 only, as they are measured on a 
subset of patients, probably only in part 1.
A “time” by “baseline value” interaction term 
has been added to the repeated ANCOVA 
analyses in 9.3.1.5, 9.3.3.1, 9.3.4.1, 9.3.4.2, 
and 9.4.5 as it is likely that the trajectory over 
time for each patient will depend on the 
baseline value. 
The supportive competing risk and Kaplan-
Meier graphs for duration of RRT has been 
taken out as it makes no sense since RRT 
durations are short and repetitive. It is more 
meaningful to just look at 90 day mortality. 
For the remaining ‘duration’ endpoints 
withdrawal rates has been added to the 
competing risk and Kaplan-Meier graphs.
As this is a superiority trial, the PP analysis 
will only be performed for the primary 
endpoint, and hence not performed for 
secondary as previously stated.
Version 6


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8
9
Nov 9 - 2017
Nov 20 - 2017
Only major protocol deviations will be listed.
Adverse events graphs added to output.
Fluid balance analyses updated.
Analyses for norepinephrine/noradrenaline 
and other vasopressor doses updated.
Forest plots added for incidence of RRT 
(section 9.3.1.8) and mortality 
(section 9.3.2.3).
Format change only. No content was changed
Format change only. No content was changed
Version 7
Version 8


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Ferring Pharmaceuticals
CONFIDENTIAL
Signed agreement on Statistical Analysis Plan
The original analysis plan was reviewed by,
!
 Global Biometrics, Ferring 
Pharmaceuticals A/S
!
 Clinical R&D, Selepressin, Ferring Pharmaceuticals 
A/S
!
 Global Pharmacovigilance, Ferring 
Pharmaceuticals A/S
!
 Clinical 
R&D, Selepressin, Ferring Pharmaceuticals A/S
!
 Health Economics & Outcomes Research, Clinical and 
Non-Clinical Development, Ferring Pharmaceuticals A/S
And reviewed and approved (signed electronically) by,
!
 Biometrics, Ferring Pharmaceuticals A/S
Subsequent editions reviewed and approved (signed electronically) by,
!
 Biometrics, Ferring Pharmaceuticals A/S


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TABLE OF CONTENTS
1
Introduction........................................................................................................................................ 10
1.1
Definitions/ Abbreviations...................................................................................................... 10
1.1.1
Definition of Terms.................................................................................................... 10
1.1.2
Abbreviations............................................................................................................. 10
2
Trial Objectives and Endpoints........................................................................................................ 12
2.1
Objectives ............................................................................................................................... 12
2.2
Endpoints ................................................................................................................................ 12
2.2.1
Primary Endpoint....................................................................................................... 12
2.2.2
Key Secondary Endpoints.......................................................................................... 12
2.2.3
Secondary Endpoints ................................................................................................. 12
2.2.4
Safety Endpoints........................................................................................................ 13
2.2.5
Additional Endpoints ................................................................................................. 13
2.2.6
Other Assessments..................................................................................................... 14
3
Trial design......................................................................................................................................... 15
3.1
General Design Considerations............................................................................................... 15
3.2
Determination of Sample Size ................................................................................................ 17
4
Patient Disposition............................................................................................................................. 18
5
Protocol Deviations............................................................................................................................ 19
6
Analysis sets........................................................................................................................................ 20
6.1
Intention-To-Treat Analysis Set.............................................................................................. 20
6.2
Full-Analysis Set..................................................................................................................... 20
6.3
Per Protocol Analysis Set........................................................................................................ 20
6.4
Safety Analysis Set ................................................................................................................. 20
7
Trial population ................................................................................................................................. 21
7.1
Demographics and Other Baseline Characteristics................................................................. 21
7.1.1
Demographics ............................................................................................................ 21
7.1.2
Vital Signs at Baseline............................................................................................... 21
7.1.3
SOFA Score, APACHE II Score and Septic Shock Characteristics .......................... 21
7.2
Medical History....................................................................................................................... 21
7.3
Prior and Concomitant Medication......................................................................................... 21
8
Exposure and Treatment Compliance ............................................................................................. 22
8.1.1
Extent of Exposure..................................................................................................... 22
9
Efficacy ............................................................................................................................................... 23
9.1
General Considerations........................................................................................................... 23
9.2
Primary Endpoint.................................................................................................................... 23
9.2.1
Primary Variable Analysis......................................................................................... 25
9.2.2
Sensitivity Analyses................................................................................................... 26
9.2.3
Additional Analyses................................................................................................... 28
9.3
Secondary Endpoints............................................................................................................... 29
9.3.1
Organ Dysfunction..................................................................................................... 30
9.3.1.1
Vasopressor-free Days up to Day 30............................................................30
9.3.1.2
Mechanical Ventilator-free Days up to Day 30............................................30
9.3.1.3
Duration of Septic Shock up to Day 30........................................................30


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9.3.1.4
Duration of Mechanical Ventilation up to Day 30.......................................31
9.3.1.5
Daily Overall and Individual Organ (Cardiovascular, Respiratory, 
Renal, Hepatic, Coagulation) Scores using the Modified Sequential 
Organ Failure Assessment (SOFA) Scores Until ICU Discharge................32
9.3.1.6
Incidence of New Organ Dysfunctions and New Organ Failures (Based 
on the SOFA score) up to Days 7 and 30.....................................................32
9.3.1.7
Renal Replacement Therapy (RRT)-free Days up to Day 30 (excluding 
patients on RRT for chronic renal failure at time of randomisation) ...........33
9.3.1.8
Incidence of RRT up to Day 30 (counting patients who die as on RRT 
and excluding patients on RRT for chronic renal failure at time of 
randomisation)..............................................................................................33
9.3.1.9
Duration of RRT up to Day 90 (excluding patients on RRT for chronic 
renal failure at time of randomisation).........................................................34
9.3.2
Morbidity/Mortality................................................................................................... 35
9.3.2.1
Intensive Care Unit (ICU)-free Days up to Day 30......................................35
9.3.2.2
ICU Length of Stay up to Day 30 ................................................................35
9.3.2.3
All-cause Mortality (Defined as the Fraction of Patients That Have 
Died, Regardless of Cause, by the end of Day 30, Day 90, and Day 
180) 35
9.3.3
Health-Related Quality of Life .................................................................................. 36
9.3.3.1
Change in utility, based on EQ-5D-5L, up to Day 180................................36
9.3.4
Fluid Balance ............................................................................................................. 37
9.3.4.1
Daily and Cumulative Fluid Balance Until ICU Discharge (for a 
Maximum of 7 Days) ...................................................................................37
9.3.4.2
Daily and Cumulative Urinary Output Until ICU Discharge (for a 
Maximum of 7 Days) ...................................................................................38
9.4
Other Endpoints/Assessments................................................................................................. 38
9.4.1
Hospital-free Days up to Day 90................................................................................ 38
9.4.2
Hospital Length of Stay up to Day 90........................................................................ 38
9.4.3
Patient Residence at Day 30, Day 60, Day 90, and Day 180..................................... 39
9.4.4
Mean Arterial Pressure, Until ICU Discharge (for a Maximum of 7 Days).............. 39
9.4.5
Norepinephrine/Noradrenaline and Other Vasopressor Doses .................................. 39
9.4.6
Pulmonary Function (PaO2/FiO2) (in a subset of patients)....................................... 40
9.4.7
Arterial Blood Gases and Acid/Base Status (PaO2, PaCO2, pH, SaO2, 
Bicarbonate, Base Excess), Lactate and Oxygen Saturation in Vena Cava 
Superior (ScvO2) ....................................................................................................... 40
9.4.8
Cytokines, ANG-1 and ANG-2 (in a Subset of 100-350 Patients) ............................ 41
9.4.9
EVLW and PPI (in a Subset of 100-350 Patients)..................................................... 41
9.4.10 Cardiac Output (in a Subset of 100-350 Patients)...................................................... 41
9.4.11 Creatinine Clearance.................................................................................................. 41
10
Safety................................................................................................................................................... 42
10.1
General Considerations........................................................................................................... 42
10.2
Adverse Events ....................................................................................................................... 42
10.2.1 Overview of Adverse Events ..................................................................................... 42
10.2.2 Incidence of Adverse Events...................................................................................... 43
10.3
Safety Laboratory Variables ................................................................................................... 44
10.3.1 Summary Statistics..................................................................................................... 44
10.3.2 Data Listings.............................................................................................................. 45


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10.4
Vital Signs (including CVP) ................................................................................................... 45
10.4.1 Summary Statistics..................................................................................................... 45
10.4.2 Data Listings.............................................................................................................. 46
10.5
Episodes of Hypotension ........................................................................................................ 46
11
Interim analyses................................................................................................................................. 47
12
Deviations from protocol analysis .................................................................................................... 48
13
References........................................................................................................................................... 49
14
Tables, Listings and Figures ............................................................................................................. 50
Appendix 1
EQ-5D-5L Quality Adjusted Life Year (QALY)................................................................ 51
Appendix 2
Critical Adverse Events and Classification of Adverse Events Based on Changes in 
Safety Laboratory Variables............................................................................................................. 52
Appendix 3
Estimation of Treatment Effects for P&VFDs ................................................................... 53
Appendix 4
Estimation of Treatment Effects for Difference of Proportions in Incidence of RRT, 
and Difference in Number of New Organ Failures and Number of New Organ 
Dysfunctions ....................................................................................................................................... 57
Appendix 6
Formal Proof of Type I Error Control................................................................................ 69
Appendix 7
Randomisation Plan.............................................................................................................. 74
Appendix 8
Bias on Treatment Estimate for P&VFDs .......................................................................... 79


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1
Introduction
This document describes the planned statistical analyses for selepressin (FE202158) 000133, and is 
based on protocol dated July 8th 2016 including amendments 1 and 2.
All analyses in the SAP were planned and pre-specified prior to trial termination due to futility.
1.1
Definitions/ Abbreviations
1.1.1
Definition of Terms
Terms
Definitions
Evaluable patient
Randomised
Patient who has been treated with IMP and 30 days  have passed 
since initiation of IMP infusion
Patient randomised to trial treatment
Screened
Patient who enters the screening phase
Selepressin
Treated patient
1-KM curve
FE 202158
Randomised and dosed
1 minus Kaplan Meier curve
1.1.2
Abbreviations
Abbreviations
Meaning of abbreviations in document
AE
ANCOVA
AUC
CVP
EVLW
EQ-5D-5L
Adverse Event
Analysis of covariance
Area Under the Curve
Central venous pressure
Extra-vascular lung water
EuroQol – 5 Dimensions – 5 Levels
FAS
ICU
Full-Analysis Set
Intensive care unit
IMP
Investigational Medicinal Product
ITT
LOCF
Intention-to-treat
Last observation carried forward
MAP
Mean Arterial Pressure
MedDRA
Medical Dictionary for Regulatory Activities
NE
Norepinephrine
PK
Pharmacokinetic
PP
PPI
PT
P&VFD
QALY
RAR
RRT
ScvO2
Per-Protocol
Pulmonary permeability index 
Preferred term
Vasopressor and mechanical ventilator free days
Quality adjusted life years
Response adaptive randomisation
Renal replacement therapy
Oxygen Saturation in Vena Cava Superior 
SOFA
Sequential Organ Failure Assessment score


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Abbreviations
Meaning of abbreviations in document
SOC
WBC
System Organ Class
White blood cells


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2
Trial Objectives and Endpoints
2.1
Objectives
Primary Objective
!
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 patients with vasopressor-dependent septic shock
Secondary Objectives
!
To determine the efficacy of selepressin on: 
o
Organ dysfunction
o
Morbidity and mortality
o
Fluid balance
o
Health-related quality of life 
!
To determine the safety profile of selepressin
!
To determine the pharmacokinetics of selepressin
!
To determine the health economics of selepressin
!
To further evaluate a range of biomarkers in relation to the mode of action of 
selepressin
2.2
Endpoints
2.2.1
Primary Endpoint
!
Vasopressor- and mechanical ventilator-free days (P&VFDs) up to day 30
2.2.2
Key Secondary Endpoints
!
All-cause mortality (defined as the fraction of patients that have died, regardless of 
cause, by the end of Day 90)
!
Renal replacement therapy (RRT)-free days up to Day 30 (excluding patients on RRT 
for chronic renal failure at time of randomisation)
!
Intensive care unit (ICU)-free days up to Day 30 
2.2.3
Secondary Endpoints
Organ dysfunction
!
Vasopressor-free days up to Day 30 
!
Mechanical ventilator-free days up to Day 30
!
Duration of septic shock up to Day 30


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!
Duration of mechanical ventilation up to Day 30 
!
Incidence of RRT up to Day 30 (counting patients who die as on RRT and excluding 
patients on RRT for chronic renal failure at time of randomisation)
!
Duration of RRT up to Day 90 (excluding patients on RRT for chronic renal failure at 
time of randomisation)
!
Daily overall and individual organ (cardiovascular, respiratory, renal, hepatic, 
coagulation) scores using the modified Sequential Organ Failure Assessment (SOFA) 
scores until ICU discharge 
!
Incidence of new organ dysfunctions and new organ failures (based on the SOFA 
score) up to Days 7 and 30
Morbidity/mortality
!
ICU length of stay up to Day 30 
!
All-cause mortality (defined as the fraction of patients that have died, regardless of cause, 
by the end of Days 30 and 180)
Fluid balance 
!
Daily and cumulative fluid balance until ICU discharge (for a maximum of 7 days)
!
Daily and cumulative urinary output until ICU discharge (for a maximum of 7 days)
Health-related quality of life
!
Change in utility, based on EQ-5D-5L, up to Day 180
2.2.4
Safety Endpoints
!
Incidence of adverse events (type, frequency, and intensity) with specific emphasis on:
o
Ischaemic events (e.g. myocardial, skin, cerebral, mesenteric, and limb ischaemia)
!
Changes in vital signs and safety laboratory variables, including:
o
Number of clinically significant results assessed as unanticipated in the setting of 
septic shock
!
Episodes of hypotension
2.2.5
Additional Endpoints
!
Hospital-free days up to Day 90
!
Hospital length of stay up to Day 90
!
Patient residence at Day 30, Day 60, Day 90, and Day 180
!
Mean arterial pressure (MAP), until ICU discharge (for a maximum of 7 days)


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!
Norepinephrine/noradrenaline and other vasopressor doses
!
Pharmacokinetic response (in a subset of approximately 200 patients) - to be reported 
separately according to a pre-specified pharmacokinetic analysis plan 
!
Health economic evaluation – to be reported separately according to a pre-specified 
health economic analytical plan 
!
Creatinine Clearance
!
PaO2/FiO2 ratio (in a subset of 100-350 patients)
!
Extravascular Lung Water and Pulmonary Permeability Index (in a subset of 100-350 
patients)
!
Cardiac output (in a subset of 100-350 patients)
!
Cytokines (in a subset of 100-350 patients)
!
Angiopoietin 1 and 2 levels (in a subset of 100-350 patients)
2.2.6
Other Assessments
!
Central Venous Pressure 
!
Central Venous Oxygen Saturation 
!
Arterial Blood Gases (PaO2, PaCO2, SaO2, pH, HCO3, base excess) and Lactate 


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3
Trial design
3.1
General Design Considerations
The overall adaptive design is a Phase 2b/3 trial, in which dose-ranging with response-adaptive 
randomization (RAR) (see Appendix 5 for details) is utilized in a first part (the Phase 2b part – Part 
1), followed by a traditional 1:1 randomised comparison of selepressin to placebo in the second part 
(the Phase 3 part – Part 2). The final analysis uses patients from both parts of the trial. The entire 
trial, combining both parts, represents an adequate and well-controlled comparison of selepressin 
and placebo. 
In Part 1 of the trial, up to four dosing regimens will be investigated.
Arm 1: Starting dose at 1.7 ng/kg/min, and a max. dose of 2.5 ng/kg/min
Arm 2: Starting dose at 2.5 ng/kg/min, and a max. dose of 3.75 ng/kg/min
Arm 3: Starting dose at 3.5 ng/kg/min, and a max. dose of 5.25 ng/kg/min
Arm 4: Starting dose at 5 ng/kg/min, and a max. dose of 7.5 ng/kg/min
Part 1 comprises a minimum of 300 evaluable patients and a maximum of 800 treated patients. 
During Part 1, patients will be randomised to placebo or selepressin (Arms 1 to 3). Arm 4 will only 
be opened between 200 evaluable- 600 treated patients and if there is at least a 50% probability that 
Arm 3 has a higher expected P&VFD than Arm 2 and if data from the lower dosing levels do not 
suggest any significant safety signals. To minimize the risk of imbalance between treatment arms, 
randomisation will be stratified based on trial site, the need for mechanical ventilation (Yes/No),
norepinephrine/noradrenaline requirement at baseline (< or ≥30 μg/min) and creatinine (< or ≥150 
μmol/L) (See Appendix 7 for details).
Part 1 will begin with a 200-patients treated “burn-in” period during which fixed randomisation
across the treatment arms will be used (one-third of the patients randomised to placebo and two-
ninths of the patients to each of the selepressin arms [Arms 1 to 3]). The factors described above 
will be used to stratify the randomisation.
After completion of the burn-in period, Part 1 will utilize response-adaptive randomisation to 
preferentially place patients into the arms that appear to have the maximum benefit with respect to 
the primary endpoint. A fixed fraction (one third) of patients will be randomised to placebo 
throughout Part 1 to ensure contemporaneous control patients are enrolled throughout the trial.
If Part 1 culminates in the decision to run Part 2, Part 2 will be a 1:1 comparison of placebo to the 
best-performing active treatment arm. The best-performing active treatment arm will be identified 
at the end of Part 1. Part 2 will utilize a fixed 1:1 randomisation proportion, with stratified 
randomisation as described for Part 1. Part 2 can begin after any interim analysis after 300
evaluable -800 treated patients in Part 1 and the size of Part 2 will include enough patients to bring 
the total number of evaluable patients in Part 1 and Part 2 up to 1800, ensuring a minimum sample 
size of Part 2 of 1000 evaluable patients.


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Figure 1:
Design Flow Chart


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3.2
Determination of Sample Size
At least 1800 evaluable patients combined for Part 1 and Part 2 are needed for the final analysis. 
The overall power of obtaining statistical significance based on combined evidence from Part 1 and 
Part 2 is 91% in situations where all 4 arms have a true underlying 1.5% lower mortality rate and a 
1.5-day higher expected  number of P&VFDs for survivors as compared to placebo (corresponding 
to an overall treatment effect of 1.5 P&VFDs). If the effect sizes are 2% on mortality and 2 days for 
P&VFDs in survivors for all 4 arms (corresponding to an overall treatment effect of 2 P&VFDs), 
then the overall power is 98%. In this latter case the probability of engaging into Part 2 is ~99%.


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4
Patient Disposition
A summary table will present, for each part of the trial and overall, the number of patients in the 
population sets: ‘Screened’, ‘Intention to treat’, Full analysis set’, ‘Per protocol’, ‘Safety’, 
‘Completed trial’, ‘Withdrawals’, and ‘IMP discontinuations’ with a breakdown of 
reasons/categories for trial withdrawals and IMP discontinuations.
The patient disposition table will be broken down by each of the stratification variables [the need 
for mechanical ventilation (Yes/No), norepinephrine/noradrenaline requirement at baseline (< or 
≥30 μg/min) and creatinine (< or ≥150 μmol/L)] and broken down chronologically displaying 
number of patients ‘completed’ and ‘withdrawn from trial’ at Day 30, Day 90 and Day 180.
The number of patients screened but not randomised/allocated to treatment will be presented with 
the reason(s) for screen failure in a data listing. 
All major protocol violations (including misrandomisations), based on the Full analysis set, will be 
summarised for each part of the trial.
Furthermore 1-KM plots, based on the ITT, will be presented for the time to trial withdrawals/IMP 
discontinuations (whichever comes first) differentiated by reason of trial withdrawal/IMP 
discontinuation using cumulative incidence functions. Dropout rates between treatment groups will 
be evaluated by the log-rank test.


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5
Protocol Deviations
Patient data in the full analysis set (FAS) will be excluded from the per-protocol (PP) analysis set if 
they meet any of the following criteria:
!
Dosing errors expected to significantly impact efficacy
!
More than 16 hours from onset of vasopressor treatment to start of IMP
!
Failed to receive a continuous infusion of norepinephrine/noradrenaline base greater than 
4.5 ug/min for at least one hour or received less than 4.5 ug/min of 
norepinephrine/noradrenaline base at start of IMP infusion
!
Violation of exclusion criteria 2: Primary cause of hypotension not due to sepsis (e.g., major 
trauma including traumatic brain injury, hemorrhage, burns, or congestive heart 
failure/cardiogenic shock)
!
Violation of exclusion criteria 6: Chronic mechanical ventilation for any reason OR severe 
chronic obstructive pulmonary disease (COPD) requiring either continuous daily oxygen 
use during the preceding 30 days or mechanical ventilation (for acute exacerbation of 
COPD) during the preceding 30 days
!
Violation of exclusion criteria 9: Decision to limit full care taken before obtaining informed 
consent
!
Violation of exclusion criteria 10: Use of vasopressin in the past 12 hours prior to start of 
IMP infusion or use of terlipressin within 7 days prior to start of IMP infusion
!
Violation of exclusion criteria 12: Prior use of an investigational medicinal product within 
the last month OR planned or concurrent participation in a clinical trial for any 
investigational drug or investigational device
Furthermore, any other major protocol violations, such as serious unforeseen violations deemed to 
invalidate the data and affect the conclusions of the study will lead to exclusion of data from the PP 
analysis set.
Major protocol deviations will lead to exclusion of data from the PP analysis, while data will not be 
excluded because of minor protocol deviations. The list of major protocol deviations will be 
detailed and documented in the clean file document prior to database release.
All major protocol deviations will be listed in patient data listings.


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6
Analysis sets
6.1
Intention-To-Treat Analysis Set
The intention-to-treat (ITT) analysis set comprises of all randomised (as planned) patients.   
6.2
Full-Analysis Set
The FAS comprises data from all randomised (as planned) and dosed patients.
6.3
Per Protocol Analysis Set
Patients in the FAS will be excluded from the PP analysis set if they meet any major protocol 
violations defined in (Section 5). Data will be used up to the point of protocol violation.
6.4
Safety Analysis Set 
The safety analysis set comprises all treated patients and are analysed according to the actual 
treatment received.


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7
Trial population
7.1
Demographics and Other Baseline Characteristics
Categorical data will be summarised using numbers and percentages. The percentages are based on 
the total number of patients with a corresponding assessment. Continuous data will be presented, 
for example, using the number of patients (N), mean and standard deviation, median, interquartile 
range, minimum and maximum. All baseline characteristics will be listed.
Demographics and baseline characteristics of the study population will be summarised for the FAS.
7.1.1
Demographics
Descriptive statistics of baseline demographics variables will be summarized by treatment arm and 
total.
7.1.2
Vital Signs at Baseline
Baseline vital signs will be summarised by treatment arm and total.
7.1.3
SOFA Score, APACHE II Score and Septic Shock Characteristics
Baseline SOFA score (modified), APACHE II score and information on septic shock (infection 
proven/suspected, primary infection type and location will be summarised by treatment arm and 
total.
7.2
Medical History
Medical history recorded at screening visit will be summarised by treatment arm and total.
Furthermore, medical history will be presented in patient data listings.
7.3
Prior and Concomitant Medication
Prior and concomitant medication will be summarised by treatment arm and total. 
Furthermore, concomitant medication will be presented in patient data listings.


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8
Exposure and Treatment Compliance
8.1.1
Extent of Exposure 
The total amount (adjusted by weight (μg/kg)) of selepressin administered and the number of days 
(reported to one decimal place) treated with selepressin will be summarised by (active) treatment 
arm and total (active treatment arms).
Furthermore, the mean cumulative amount administered and the mean infusion rate will be 
tabulated by treatment arm and presented graphically (also by treatment arm and total).
If a patient has missing infusion rate and the patient is still in the trial (not dead or withdrawn) it 
will be assumed that selepressin was not administered and a value of zero will be imputed, unless 
there is an interval in the timing log covering the exact time point (8 AM and 8 PM is the assumed 
time point for missing morning and evening collection time points). In that case LOCF will be used, 
but only within the time interval.
If a patients has missing cumulative selepressin volume and the patient is still in the trial (not dead 
or withdrawn), LOCF will be used assuming that selepressin was not administered and hence 
keeping the cumulative volume constant.


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9
Efficacy
9.1
General Considerations
All statistical tests will be performed using a two-sided test at a 5% significance level. 
If the trial is stopped prematurely due to e.g. futility, the data will be analysed as planned in this 
statistical analysis plan.
All efficacy endpoints will be analysed for the FAS analysis set, and as a sensitivity the analyses for 
the primary endpoint will be repeated for the PP population. 
Categorical data will be summarised using counts and percentages, while continuous data will be 
presented using the number of patients (N), mean, standard deviation, median, interquartile range, 
minimum and maximum. All efficacy endpoints will be listed in patient data listings.
9.2
Primary Endpoint
!
Vasopressor- and mechanical ventilator-free days (P&VFDs) up to day 30
This composite endpoint is defined as the number of days  (reported to one decimal place (0.0 to 
30.0) ) from start of treatment with the investigational medicinal product (IMP) [selepressin or 
placebo] to 30.0 days thereafter during which the patient is: 1) alive; 2) free of treatment with 
intravenous vasopressors; and 3) free of any invasive mechanical ventilation (see definition below).  
Patient Death
By definition, any patient that dies within this 30-day period will be assigned zero P&VFDs, even if 
there is a period during which the patient is alive and free of both vasopressor treatment and 
mechanical ventilation.
Definition of “Free of Vasopressors”
Free of vasopressors means less than 60 minutes during any contiguous 24-hour period (regardless 
of calendar day). If a patient requires periods of vasopressors longer than 60 minutes in total during 
any 24-hour period, the intervening intervals during which they are free of vasopressors will not be 
included in the period free of vasopressors in the determination of the number of P&VFDs.  Thus, 
the period free of vasopressors begins at the end of the last use of vasopressors that was either: 1) 
longer than 60 minutes in duration; or 2) part of greater than 60 minutes of use within a contiguous 
24-hour period.
Norepinephrine/noradrenaline, phenylephrine, dopamine, epinephrine/adrenaline, vasopressin, 
terlipressin, and IMP (i.e. selepressin and placebo) all constitute a vasopressor for the purpose of 
the primary analysis.
Vasopressor use due to anaesthesia or procedure-induced hypotension during and up to three hours 
after a surgery or procedure (including bedside) is exempt from this rule (i.e. such use of 
vasopressors would not affect the calculation of P&VFDs).


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Definition of “Free of Mechanical Ventilation”
Mechanical ventilation is defined as use of endotracheal or tracheostomy tube assisted ventilation 
(>5 cm H2O continuous positive airway pressure and >5 cm H2O of pressure support from the 
ventilator in tracheostomy patients). End of mechanical ventilation is defined as: 1) extubation of 
intubated patients or 2) ≤5 cm H2O continuous positive airway pressure and ≤5 cm H2O of pressure 
support from the ventilator in tracheostomy patients. If non-invasive ventilation by mask or bag (>5 
cm H2O of pressure support) is deployed to avoid (re)intubation, it also counts as mechanical 
ventilation. However, all other uses of non-invasive ventilation such as chronic night-time use of 
positive airway pressure for chronic obstructive pulmonary disease (COPD) or sleep apnea does not 
count as mechanical ventilation (regardless of pressure). Free of mechanical ventilation means less 
than 60 minutes during any contiguous 24-hour period (regardless of calendar day). If a patient 
requires mechanical ventilation for periods longer than 60 minutes in total during any 24-hour 
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 the number of 
P&VFDs.  Thus, the period free of mechanical ventilation begins at the end of the last use of 
mechanical ventilation that was either: 1) longer than 60 minutes in duration; or 2) part of greater 
than 60 minutes of use within a contiguous 24-hour period.
The use of mechanical ventilation associated with anaesthesia or procedural sedation during and up 
to three hours after a surgery or procedure (including bedside) is exempt from this rule (i.e. such 
use of mechanical ventilation would not affect the calculation of P&VFDs).
It is important to note that the determination of freedom from vasopressors and freedom from 
mechanical ventilation are made separately; in other words, periods of vasopressor use and 
mechanical ventilation are not combined when determining whether 60 minutes of use has occurred 
within a 24-hour period.
Missing data during the time of hospitalization will be imputed using a worst case approach taking 
into account previous and subsequent starting and stopping times of vasopressor administration and 
mechanical ventilation (see Figure 2). If only the stop date but not time is given, the imputed time 
will be midnight of that date (example A), unless a subsequent starting time was recorded prior to 
midnight in which case the imputed time would be the start time of the subsequent record (example
B). If neither stop date nor time is given, the imputed stop time will be the start date and time of the 
subsequent recording. Likewise, missing start dates and times would be imputed as worst case 
scenarios, i.e. is the patient found to be on mechanical ventilation with a date but no time for 
intubation, the imputed start time would be recorded as 00:01 of that day or the stop date of a 
preceding recording on that same date, whichever occurs last. If both start date and time is missing, 
the imputed start time would be the date and time of the preceding stop time recorded. In case of 
data being completely missing from a certain time point and onwards, the “last status carried 
forward” imputation (example C) will be applied. If a patient was last seen on either ventilator or 
vasopressors, it is assumed that the patient remained so, and is imputed to a value of 0 (zero) 
P&VFDs. If the patient was last seen off ventilator and vasopressors, it is also assumed that the 
patient remained so in the remaining 30-day period. If the patient was last seen (alive) on e.g. day 


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10 and at that point had been off both ventilator and vasopressors for three days, a value of 23 
P&VFDs is imputed.
Figure 2:
Missing Data Imputation of P&VFDs (Examples)
9.2.1
Primary Variable Analysis
The primary endpoint, P&VFDs, will be analyzed using a van Elteren test, stratified by need for 
ventilation (Yes/No), time from onset of shock (onset of any vasopressor) to start of treatment (< or 
≥6 hours), and norepinephrine/noradrenaline requirement at baseline (< or ≥30 μg/min).
The primary analysis will compare all patients on all selepressin arms from both parts of the trial 
(pooled together and treated as a single arm) to all patients on the placebo arm from both parts of 
the trial (see Appendix 7 for a discussion on treatment estimate bias).
The primary analysis will be a test of superiority using a two-sided 5% significance level test.
Treatment effects will be estimated assuming a negative binomial distribution (to allow for possible 
overdispersion in a Poisson distribution) for the quantity (30 minus P&VFDs) for survivors, and a 
binomial distribution to model the probability of surviving. Both models adjusted for need for 
ventilation (Yes/No), time from onset of shock to start of treatment (< or ≥6 hours), and 
norepinephrine/noradrenaline requirement at baseline (< or ≥30 μg/min) (see Appendix 3 for 
details). For completeness, the proportion of patients dying, and the P&VFDs for survivors will 
also be presented.


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Furthermore, P&VFDs will be tabulated by treatment arm (including pooled active treatment arms), 
and presented graphically by histograms and cumulative distributions functions.
The success (statistical/clinical significance) of the trial will be based upon the comparison of the 
analysis above (all patients on all selepressin arms from both parts of the trial (pooled together and 
treated as a single arm) compared to all patients on the placebo arm from both parts of the trial). 
9.2.2
Sensitivity Analyses 
The primary analysis will be repeated for the PP analysis set.
As the adaptations of the trial provide a conservative estimate of the p-value, sensitivity p-values 
will be provided using post-simulation bootstrap calculations (see Appendix 6 for details).
In order to check for consistency the primary endpoint treatment differences will, as a minimum, be 
estimated and presented by forest plots for the following subgroups
!
region (US/Canada vs. Europe)
!
age (<65, 65-74, 75-84, ≥85)
!
gender
!
race/ethnicity
Furthermore, the primary endpoint will be stratified by severity of the patients, with risk of dying as 
indicator of severity (Figure 3). Mortality (the risk of dying) will be predicted by a logistic 
regression model, with relevant baseline characteristics as covariates (e.g. the individual SOFA 
scores and age). The model used to generate the predicted risk (for all patients) will be based on 
patients in the placebo arm only, as the risk of dying should reflect the severity in the absence of 
selepressin. Stratified by the risk of dying (intervals of 20% if suitable, based on the mortality rates 
in the covariate categories in the model), the treatment effect of the primary endpoint will be 
presented graphically, in order to visually inspect whether the average treatment effect is distributed 
evenly across the severity of patients.


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Figure 3:
Risk Based Heterogeneity of the Treatment Effect on P&VFDs over the Risk of 
Dying (an Example)
The impact and robustness of the imputation of missing data will be checked by analysing data in 
the following ways
!
excluding all patients with missing/imputed data
!
imputing the 30-day P&VFD status for patients lost to follow up (or otherwise withdrawn 
from trial) using the observed ratio of P&VFDs at time of lost to follow up (or time of 
withdrawal), to the same proportion for a 30-day status
For this analysis the 30-day P&VFD status for patients lost to follow up (or otherwise withdrawn 
from trial) will be imputed so that the 30-day ratio of P&VFDs is equal to the ratio of P&VFDs at 
time of lost to follow up (or time of withdrawal). E.g. a patient being lost to follow up at Day 15 
with 4 P&VFDs (a ratio of 4/15 P&VFDs per days observed) will be imputed to 8 P&VFDs at Day 
30 (equivalent ratio 8/30 = 4/15). Patients having zero P&VFDs at time of lost to follow up will be 
imputed to a value of zero P&VFDs.
!
tipping point analysis
The tipping point analysis will compare all possible combinations of ‘best case’ and ‘worst case’ 
scenarios between placebo and selepressin (Figure 4) for patients lost to follow up (or otherwise 
withdrawn from trial). Best case being an imputation assuming the remaining days off ventilator 
and vasopressors, and worst case being an imputation of 0 P&VFDs. Let Np and Ns be the number 
of patients in the placebo and selepressin arms with missing data. The tipping point analysis will 
compare all combinations (from 0 to Np) of X patients on placebo imputed best case and Np – X 


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imputed worst case, to Y patients on selepressin imputed best case and Ns – Y imputed worst case. 
I.e all Np +1 times Ns +1 combinations will be analysed for the primary endpoint. Since the ‘best 
case’ is not the same for all patients (depending on when they were last seen off both ventilator and 
vasopressors) there are multiple outcomes within each combination. For each combination, the 
average P-value of the multiple outcomes will be plotted in the tipping point analysis. Below is an 
example of a tipping point analysis of 25 placebo patients vs. 40 selepressin patients with imputed 
values. The x- and y-axis displays the number of patients with the ‘best case’ imputed. In the 
example below the red area displays the non-significant p-values, indicating that one would have to 
impute almost all placebo patients to a ‘best case’ and almost all selepressin to a ‘worst case’ in 
order to get non-significant p-values, and hence ‘proving’ the robustness of the imputation method.
Figure 4:
Tipping Point Analysis of P&VFDs (an Example)
Also, to make sure that the use of vasopressor in each group is not simply being replaced by an 
increased use of inotropic agents (e.g. dobutamine, milrinone, levosimendan, and amrinone), there 
will be a sensitivity analysis of the primary endpoint in which the use of inotropic agents will count 
as vasopressor use.
9.2.3
Additional Analyses 
The primary analysis will be repeated for:
!
the selected arm only, i.e. comparing all patients on the selected arm (from part 1) from both 
parts of the trial (pooled), to all patients on the placebo arm from both parts of the trial.


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!
data from part 2 only, i.e. comparing the selected arm to placebo on data from part 2 only
9.3
Secondary Endpoints
For the purpose of a possible label inclusion, the Hochberg procedure (4) for adjustment on 
multiplicity will be implemented to selected key secondary endpoints. Only if the primary efficacy 
analysis leads to a statistically significant result at the (one-sided) 2.5% level, then the Hochberg 
procedure which is described below is applied to selected key secondary analyses. If the primary 
efficacy analysis does not result in statistical significance at the (one-sided) 2.5% level, then 
statistical significance (for the purpose of a possible label inclusion only) will not be declared for 
any of the key secondary analyses, regardless of their p-values.
The selected key secondary endpoints aimed at further demonstrating treatment effect are:
!
All-cause mortality (defined as the fraction of patients that have died, regardless of cause, 
by the end of Day 90) 
!
Renal replacement therapy-free days up to Day 30 (excluding patients on RRT for chronic 
renal failure at time of randomisation)
!
ICU-free days up to Day 30
In this application of the Hochberg procedure there are three hypothesis tests of superiority for each 
of the selected secondary endpoints. The target alpha level is (one-sided) 2.5%. The Hochberg 
procedure is as follows:
!
Order the p-values from the smallest to the largest value, p(1) < p(2) < p(3), with 
corresponding null hypothesis H(1), H(2), and H(3).
!
Start with the highest p-value. If p(3) < 2.5% (one-sided), then stop and declare all three 
comparisons significant at the 2.5% (one-sided) level (i.e. reject H(1), H(2), and H(3)). 
Otherwise, accept H(3) for the endpoint related to p(3), and go to p(2) the second highest p-
value.
!
If p(2) < 2.5/2 = 1.25% (one-sided), then stop and declare significance for H(1) and H(2). 
Otherwise, accept H(2), for the endpoint related to p(2), and go to p(1) the lowest p-value.
!
If p(1) < 2.5/3 = 0.833% (one-sided), then stop and declare significance for H(1). Otherwise, 
accept H(1), for the endpoint related to p(1).
Regardless of the statistical significance declared according to the Hochberg procedure, all analysis 
will be included and presented in the statistical report.
As for the primary analysis, the primary comparison (which determines the success, i.e. statistical 
and clinical significance) for the secondary efficacy endpoints is between all patients on all 
selepressin arms from both parts of the trial (pooled together and treated as a single arm) and all 
patients on the placebo arm from both parts of the trial. 


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As an additional analysis, all secondary efficacy analyses will, as for the primary, be repeated for:
!
the selected arm only, i.e. comparing all patients on the selected arm (from part 1) from 
both parts of the trial (pooled), to all patients on the placebo arm from both parts of the 
trial.
!
data from part 2 only, i.e. comparing the selected arm to placebo on data from part 2 
only
All free-days endpoints will be reported to one decimal place.
9.3.1
Organ Dysfunction
9.3.1.1
Vasopressor-free Days up to Day 30
Vasopressor-free Days up to Day 30 will be defined and analyzed in a similar manner as the 
primary endpoint, with the van Elteren test stratified by need for ventilation (Yes/No), time from 
onset of shock to start of treatment (< or ≥6 hours), and norepinephrine/noradrenaline requirement 
at baseline (< or ≥30 μg/min).
9.3.1.2
Mechanical Ventilator-free Days up to Day 30
Ventilator -free Days up to Day 30 will be defined and analyzed in a similar manner as the primary 
endpoint, with the van Elteren test stratified by need for ventilation (Yes/No), time from onset of 
shock to start of treatment (< or ≥6 hours), and norepinephrine/noradrenaline requirement at 
baseline (< or ≥30 μg/min).
9.3.1.3
Duration of Septic Shock up to Day 30 
Duration of septic shock is defined as the cumulative periods (>1 hour) from start of IMP until Day 
30, on IMP or vasopressors. Vasopressor use due to anaesthesia / procedure-induced hypotension 
during - and up to three hours after - surgery / procedure (including bedside) is exempt from this 
rule
For patients withdrawn (in the survivors analysis) or dying (in the non-survivors analysis) while 
still in septic shock, the duration will be based on the data available up until the time of withdrawal 
or death.
Duration of septic shock will be analyzed separately for survivors, non-survivors (within the first 
30 days) and overall, comparing treatment arms by a negative binomial model with time from onset 
of shock to start of treatment and norepinephrine/noradrenaline requirement at baseline (μg/kg/min) 
as covariates, and treatment and need for ventilation (Yes/No) as factors. The estimated treatment 
difference (to placebo) with a 95% confidence interval will be presented. As duration of septic 
shock is derived with two decimal points (with values in the range of 0.00, 0.01, ..., 30.00), duration 
of septic shock MAY be transformed (for model stability) to integer values (with values in the 
range of 0, 1, ..., 3000) by multiplying with 100. Treatment estimates will be back transformed


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Some patients will get out of shock prior to Day 30 (and stay alive until Day 30), some will get out 
of shock and die later on (prior to Day 30), others will die or be withdrawn while still in shock 
(prior to Day 30), and the remaining few will not get out of shock prior to Day 30. This means that 
if mortality and withdrawal rates vary between treatment arms, the results of the analysis for the 
overall population will be influenced by the skewed mortality and withdrawal rates. Hence, for the 
overall population, the distribution of duration of shock (time to out of shock), will be presented 
graphically as competing risks between ‘time to out of shock’, ‘withdrawn while in shock’ and 
‘dying while in shock’. Further, Kaplan-Meier (sub)-graphs on ‘time to death’ and ‘time to 
withdrawal’ will be presented for those getting out of shock (for which some will die or be 
withdrawn later on, prior to Day 30). This is done in order to elucidate any skewness in mortality 
and withdrawal rates, influencing the results of the analysis.
Furthermore, duration of septic shock will be tabulated by treatment arm (including pooled active 
treatment arms).
In case the model assumptions does not hold, covariates will be dichotomised (in same manner as 
they have been dichotomised for other endpoint analyses) and duration of septic shock will be 
analysed using a stratified permutation test (Monte Carlo estimate of p-value). Treatment effects
(and treatment difference) will be the raw (unadjusted/non-stratified) means. The confidence 
intervals for the individual treatment arms will be derived by bootstrapping 5000 samples (within 
treatment group) with same number of observations (within treatment group), and taking the 2.5 
and 97.5% percentiles from the distribution of the 5000 means from the bootstrapped samples. The 
confidence interval for the treatment difference will be derived via significance testing (based on 
the stratified permutation test), i.e. the confidence interval will be constructed by including the 95% 
confidence region for all those values for which the significance test of the hypothesis that the true 
value is the given value is not rejected at a 5% significance level (e.g. if we test is treatment 
difference=1 and p-value >0.05 then we include 1 in the confidence interval, and so on). The seed 
for both the Monte Carlo derived p-value and the bootstrapped confidence intervals will 
(appropriately) be seed=133.
9.3.1.4
Duration of Mechanical Ventilation up to Day 30
Duration of mechanical ventilation is defined as the cumulative periods (>1 hour) from start of IMP 
until Day 30, on mechanical ventilation. Mechanical ventilation during - and up to three hours after 
- surgery / procedure is exempt from this rule.
For patients withdrawn or dying while still on mechanical ventilation, the duration will be based on 
the data available up until the time of withdrawal or death.
Duration of mechanical ventilation will be analyzed separately for survivors, non-survivors (within 
the first 30 days) and overall using a zero inflated negative binomial model with time from onset of 
shock to start of treatment, and norepinephrine/noradrenaline requirement at baseline (μg/kg/min)
as covariates, and treatment and need for ventilation as factors. As duration of ventilation is derived 
with two decimal points (with values in the range of 0.00, 0.01, ..., 90.00), duration of ventilation 


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will be transformed (for model stability) to integer values (with values in the range of 0, 1, ..., 9000)
by multiplying with 100. Treatment estimates will be back transformed.
In case the model assumptions for duration of ventilation does not hold, the permutation test 
specified in Section 9.3.1.3 will be used including an analysis of the expected proportion of patients 
with 0 duration, and estimates of the duration for those with a positive duration.
9.3.1.5
Daily Overall and Individual Organ (Cardiovascular, Respiratory, Renal, Hepatic, 
Coagulation) Scores using the Modified Sequential Organ Failure Assessment 
(SOFA) Scores Until ICU Discharge 
Last observation carried forward (LOCF) will be used for missing SOFA scores on Days 2-7. No 
LOCF for Day 1 (as previous value is baseline). Patients dying will be imputed with a worst 
possible outcome, i.e. a value of 4 for each individual SOFA score.
Daily overall (modified) and individual SOFA scores will be compared between treatment arms up 
until Day 7 using a repeated measures ANCOVA model with baseline SOFA score as covariate, 
treatment, time and treatment by time interaction as factors, baseline SOFA score by time 
interaction, and patient as the experimental unit. The estimated treatment difference (to placebo) 
with a 95% confidence interval will be presented. 
Furthermore, daily overall and individual SOFA scores will be tabulated by treatment arm 
(including pooled active treatment arms).
9.3.1.6
Incidence of New Organ Dysfunctions and New Organ Failures (Based on the 
SOFA score) up to Days 7 and 30
Incidence of new organ failures is defined as a change in any of the individual SOFA scores from 
(0,1,2) at baseline to (3,4) post baseline up until the end of the period (Day 7 or 30) (if the SOFA 
scores goes from (0,1,2) to (3,4) and back to (0,1,2) again within the period, that will still count as a 
new organ failure). If a patient dies within the period, he is considered to fail on all organs, and the 
number of new organ failures will be all organs except those already failed at baseline. Patients 
withdrawn within the period will be evaluated based on the data available at time of withdrawal.
Incidence of new organ dysfunction is defined as an increase ≥ 1 from baseline to post baseline up 
until the end of the period (e.g. going from 1 to 2) in any of the individual SOFA scores. Patients 
with an individual SOFA score of 4 at baseline can per default not have a new organ dysfunction. If 
a patient dies within the period, he is considered to have dysfunction on all organs, and the number 
of new organ dysfunctions will be all organs except those already having a score of 4 at baseline. 
Patients withdrawn within the period will be evaluated based on the data available at time of 
withdrawal.
As the SOFA score is only collected for patients still in the ICU, it is assumed that as soon as the 
patient leaves the ICU, the patient will not experience any new organ dysfunctions or organ 
failures. Unless of course the patient dies.


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Incidence of at least one new organ failure will be analyzed for any new organ failure (across all 
organ systems) and by individual organ systems, and compared between treatment arms using a 
logistic regression model with age, modified SOFA score and norepinephrine/noradrenaline 
requirement at baseline (μg/kg/min) as covariates and gender and treatment arm as factors, 
presenting odds ratios with 95% confidence intervals.
Incidence of at least one new organ dysfunction will be analyzed for any new organ dysfunction 
(across all organ systems) and by individual organ systems, and will be analyzed as above for new 
organ failures.
The number of new organ failures and the number of new organ dysfunctions will be compared 
between treatment arms using a negative binomial model with age, modified SOFA score and 
norepinephrine/noradrenaline requirement at baseline (μg/kg/min) as covariates, and gender and 
treatment as factors. The estimated treatment difference (to placebo) with a 95% confidence 
interval will be presented. The 95% confidence interval for the difference in proportions between 
treatment groups will be constructed using the delta method (see Appendix 4 for details).
Furthermore, incidence of any new organ failure and any new organ dysfunction, and the number of 
new organ failures and new organ dysfunctions will be tabulated by treatment arm (including 
pooled active treatment arms).
9.3.1.7
Renal Replacement Therapy (RRT)-free Days up to Day 30 (excluding patients on 
RRT for chronic renal failure at time of randomisation)
RRT-free Days is defined as for the primary endpoint with free of treatment with any form of renal 
replacement therapy defined as continuous renal replacement therapy, intermittent hemodialysis or 
peritoneal dialysis.
RRT-free Days will be analyzed excluding patients on RRT for chronic renal failure at time of 
randomisation.
RRT-free Days up to Day 30 will be analyzed in a similar manner as the primary endpoint, with the 
van Elteren test stratified by need for ventilation (Yes/No), time from onset of shock to start of 
treatment (< or ≥6 hours), norepinephrine/noradrenaline requirement at baseline (< or ≥30 μg/min)
and baseline creatinine (< or ≥150 μmol/L).
9.3.1.8
Incidence of RRT up to Day 30 (counting patients who die as on RRT and 
excluding patients on RRT for chronic renal failure at time of randomisation)
RRT is defined as any form of renal replacement therapy defined as continuous renal replacement 
therapy, intermittent hemodialysis or peritoneal dialysis. In order to ensure that any reduction in 
incidence of RRT is not caused by an increase in mortality, all patients dying within the 30-day 
period will be counted as on RRT. For patients withdrawn prior to Day 30, incidence of RRT will 
be based on the data available up until the time of withdrawal.


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Incidence of RRT will be analysed by a logistic regression model with time from onset of shock to 
start of treatment, baseline creatinine and norepinephrine/noradrenaline requirement at baseline
(μg/kg/min) as covariates, and treatment and need for ventilation as factors. The 95% confidence 
interval for the difference in proportions between treatment groups will be constructed using the 
delta method (see Appendix 4 for details). Patients already on RRT for chronic renal failure at time 
of inclusion will be excluded from the analysis of incidence of RRT. 
Non-inferiority will be claimed if the upper limit of the two-sided 95% CI of the adjusted difference 
in proportions is less than 20% of the estimated incidence of RRT in the placebo group. Superiority 
can be claimed (5) if the upper limit is less than 0.
I.e., let 
 and 
 be the estimated incidences of RRT in the combined selepressin groups and the 
placebo group respectively. Non-inferiority will then be claimed if

 −
 + 1.96 ∗(
 −
) < 0.2 ∗

and superiority will be claimed if

 −
 + 1.96 ∗(
 −
) < 0
A forest plot including the non-inferiority tests for all analyses will be presented.
Furthermore, incidence of RRT will be tabulated by treatment arm (including pooled active 
treatment arms).
A subgroup analysis will be performed on patients without acute RRT at baseline.
9.3.1.9
Duration of RRT up to Day 90 (excluding patients on RRT for chronic renal failure
at time of randomisation)
Duration of RRT is defined as the cumulative periods with RRT (continuous renal replacement 
therapy, intermittent hemodialysis or peritoneal dialysis) and will be analyzed excluding patients on 
RRT for chronic renal failure at time of randomisation.
For patients withdrawn or dying while still on RRT, the duration will be based on the data available 
up until the time of withdrawal or death.
Duration of RRT will be analyzed as for duration of ventilation (also by transforming to integers) 
in Section 9.3.1.4 with time from onset of shock to start of treatment, baseline creatinine and 
norepinephrine/noradrenaline requirement at baseline (μg/kg/min) as covariates, and treatment and 
need for ventilation as factors. The supportive competing risk and Kaplan-Meier graphs described 
in Section 9.3.1.4 will not be performed as it makes no sense since RRT durations are short and 
repetitive. It is more meaningful to just look at 90 day mortality and withdrawal rates to take 
eventual skewed mortality and withdrawal rates into account. 


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9.3.2
Morbidity/Mortality
9.3.2.1
Intensive Care Unit (ICU)-free Days up to Day 30
ICU -free Days up to Day 30 will be defined and analyzed in a similar manner as the primary 
endpoint, with the van Elteren test stratified by need for ventilation (Yes/No), time from onset of 
shock to start of treatment (< or ≥6 hours), and norepinephrine/noradrenaline requirement at 
baseline (< or ≥30 μg/min) and baseline creatinine (< or ≥150 μmol/L).
A sensitivity analysis will be performed where the definition of time spent in the ICU will include 
first admission to emergency department, as some patients will be enrolled and have first IMP 
treatment in the emergency department.
9.3.2.2
ICU Length of Stay up to Day 30 
ICU length of stay is defined as the cumulative periods spent in ICU from start of IMP to 30 days 
after.
For patients withdrawn or dying while still in ICU up to Day 30, the duration will be based on the 
data available up until the time of withdrawal or death.
ICU length of stay will be analyzed between treatment groups using the permutation test specified 
in Section 9.3.1.3 stratified by the combination of time from onset of shock to start of treatment (< 
or ≥6 hours), baseline creatinine (< or ≥150 μmol/L), norepinephrine/noradrenaline requirement at 
baseline (< or ≥30 μg/min) and need for ventilation (Yes/No).
A sensitivity analysis will be performed where the definition of time spent in the ICU will include 
first admission to emergency department, as some patients will be enrolled and have first IMP 
treatment in the emergency department.
9.3.2.3
All-cause Mortality (Defined as the Fraction of Patients That Have Died, 
Regardless of Cause, by the end of Day 30, Day 90, and Day 180)
Mortality will be analysed by a logistic regression model with the individual SOFA scores and age
as covariates and treatment arm as factor. The 95% confidence interval for the difference in
proportions between treatment groups will be constructed using the delta method as for incidence of 
RRT (section 9.3.1.8). There will be no imputations for mortality.
Non-inferiority will be claimed if the upper limit of the two-sided 95% CI of the adjusted difference 
in proportions is less than 30% of the estimated incidence of mortality in the placebo group. 
Superiority can be claimed (5) if the upper limit is less than 0.
I.e., let 
 and 
 be the estimated incidences of mortality in the combined selepressin groups and 
the placebo group respectively. Non-inferiority will then be claimed if


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
 −
 + 1.96 ∗(
 −
) < 0.3 ∗

and superiority will be claimed if

 −
 + 1.96 ∗(
 −
) < 0
Assuming observed mortality rates of 20-25% in the placebo group, a non-inferiority limit of 30% 
corresponds to a maximum observed mortality rate of 2-3% in the combined selepressin groups in 
order for selepressin to be non-inferior to placebo. A forest plot including the non-inferiority tests 
for all analyses will be presented.
Furthermore, mortality will be tabulated by treatment arm (including pooled active treatment arms), 
and the time to death presented graphically by a Kaplan-Meier plot.
9.3.3
Health-Related Quality of Life
9.3.3.1
Change in utility, based on EQ-5D-5L, up to Day 180
EQ-5D-5L will be analyzed by the index value, the overall QALY (Quality-Adjusted Life Years) at 
Day 30 and 180 (see Appendix 1 for details), and the VAS score.
The QALY scores will NOT be adjusted to e.g. a half yearly time scale at Day 180.
As the QALY is not defined for patients with all remaining values missing, and hence also not 
defined for those dead, the analyses will automatically only be analyzed for those surviving up until 
Day 30 and 180 respectively.
For patients with missing baseline index value, the QALY score will also be set to missing. For 
robustness, a sensitivity analyses will be performed, imputing the missing baseline scores with the 
overall mean of the baseline health index. Baseline is the timing prior to acute admission.
The QALY at Day 30 and 180 will be compared between treatment arms using an ANCOVA model
with baseline health index as covariate, and treatment as factor. Estimated treatment differences (to 
placebo) along with a 95% confidence interval will be presented.
The index value and VAS scores will be analysed separately for survivors and non-survivors at Day 
180 (since all non-survivors will have non-random missing values, and hence would artificially 
inflate the mean estimates if survivors and non-survivors were analysed together) and will be 
compared between treatment arms using a repeated measures ANCOVA model with baseline health 
index/VAS score as covariate, treatment, time and treatment by time interaction as factors, baseline 
index/VAS score by time interaction, and patient as the experimental unit. Estimated treatment 
differences (to placebo) along with a 95% confidence interval will be presented for Day 30, 60, 90 
and 180. There will be no imputations for missing values.


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Furthermore, the QALY, index value and VAS scores will be tabulated treatment arm (including 
pooled active treatment arms), and the index value and VAS scores will be presented graphically.
9.3.4
Fluid Balance
9.3.4.1
Daily and Cumulative Fluid Balance Until ICU Discharge (for a Maximum of 7 
Days)
Fluid overload is defined as fluid balance volume (L) as a percentage of baseline weight. E.g. if a 
patient weighs 90 kg at baseline and has a fluid balance of 9 liters, fluid overload is then 100% * 9L 
/ 90kg = 10%.
Fluid balance (as a rate of time) and cumulative fluid balance (total volume) will be presented both 
unadjusted and adjusted for weight.
Baseline fluid balance (as a rate of time) and baseline fluid balance volume (mL) will be based on 
the time from onset of sepsis induced hypotension to start of IMP.
All analyses will be presented for ‘all patients’ and for ‘patients in ICU throughout Day 0-7’.
Fluid balance, cumulative fluid balance, fluid overload and cumulative fluid overload will all be 
compared between treatment arms using a repeated measures ANCOVA model with baseline 
(baseline fluid balance volume (mL) or baseline fluid overload) as covariate, treatment, time and 
treatment by time interaction as factors, baseline score by time interaction, and patient as the 
experimental unit. Estimated treatment differences (to placebo) along with a 95% confidence 
interval will be presented. 
Fluid overload and balance will be based on a sectioning  of the intervals between the actual 
sampling time points on baseline, Day 1, 2, etc., in order to be able to make 24 hour intervals from 
start of IMP.. For Days 1, 2, etc. sampling time points will be every 24 hours from start of IMP.
Patients withdrawn or dead will be set to missing.
Endpoints (absolute values and change from baseline) will be tabulated by treatment arm (including 
pooled active treatment arms), and presented graphically.
Furthermore, in order to assess all patients at Day 3 and 7 (regardless of mortality), the composite 
endpoint ‘critical edema-free survival’ will be derived at both Day 3 and 7. 
A patient will be categorised as being critically edema-free and alive at Day 3 (or 7 respectively) if:
!
fluid overload < 10% at Day 3, or
!
patient is discharged from ICU and emergency department prior to Day 3 with a fluid 
overload < 10% at day of discharge (or previous day if discharged before fluid balance 
measurement), and patient is alive at Day 3.
The patient will be categorised as not being critically edema free or dead if:
!
fluid overload ≥ 10% at Day 3, or


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!
patient is discharged from ICU and emergency department prior to Day 3 with a fluid 
overload ≥ 10% at day of discharge (or previous day if discharged before fluid balance 
measurement), or
!
patient is dead on Day 3 (prior to fluid balance measurement)
Patients withdrawn at the given time point will be set to missing (less than 20 patients total in the 
trial are expected to be withdrawn prior to Day 7). The endpoints will be analysed using a logistic 
regression model with baseline fluid overload as a covariate and treatment arm as a factor, 
presenting odds ratios with 95% confidence intervals. 
9.3.4.2
Daily and Cumulative Urinary Output Until ICU Discharge (for a Maximum of 7 
Days) 
Urinary output and cumulative urinary output (absolute values) will all be will be compared 
between treatment arms using a repeated measures ANCOVA model with baseline urinary output 
volume (mL) as covariate, treatment, time and treatment by time interaction as factors, baseline 
score by time interaction, and patient as the experimental unit. Estimated treatment differences (to 
placebo) along with a 95% confidence interval will be presented. 
Urinary output and cumulative urinary output will be presented both unadjusted and adjusted for 
weight.
All analyses will be presented for ‘all patients’ and for ‘patients in ICU throughout Day 0-7’.
Urinary output will be derived in the same manner as fluid balance.
Endpoints (absolute values and change from baseline) will be tabulated by treatment arm (including 
pooled active treatment arms), and presented graphically.
9.4
Other Endpoints/Assessments
9.4.1
Hospital-free Days up to Day 90
Hospital stay is defined (from the eCRF) as “Other acute care hospital” or “Still in trial hospital”
Hospital-free Days up to Day 90 will be defined and analyzed in a similar manner as the primary 
endpoint, with the van Elteren test stratified by need for ventilation (Yes/No), time from onset of 
shock to start of treatment (< or ≥6 hours), and norepinephrine/noradrenaline requirement at 
baseline (< or ≥30 μg/min) and baseline creatinine (< or ≥150 μmol/L).
9.4.2
Hospital Length of Stay up to Day 90 
Hospital length of stay is defined as the cumulative periods spent in hospital (“Other acute care 
hospital” or “Still in trial hospital”) from start of IMP to 90 days after.
For patients withdrawn or dying while still in hospital up to Day 90, the duration will be based on 
the data available up until the time of withdrawal or death.


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Hospital length of stay will be analyzed between treatment groups using the permutation test 
specified in Section 9.3.1.3 stratified by the combination of time from onset of shock to start of 
treatment (< or ≥6 hours), baseline creatinine (< or ≥150 μmol/L), norepinephrine/noradrenaline
requirement at baseline (< or ≥30 μg/min) and need for ventilation (Yes/No).
9.4.3
Patient Residence at Day 30, Day 60, Day 90, and Day 180
Patient location at Day 30, 60, 90 and 180 will be summarized by treatment arm (including pooled 
active treatment arms). Baseline is the timing prior to acute admission.
Shift tables will be presented at each time point to assess whether patients have returned to their 
location at enrollment. There will be no imputations of missing values.
9.4.4
Mean Arterial Pressure, Until ICU Discharge (for a Maximum of 7 Days)
Mean arterial pressure will be tabulated by treatment arm (including pooled active treatment arms)
and presented graphically (at pre-specified time points, i.e. not when NE/NA infusion changes, and 
only until ICU discharge/day 7) for both MAP alone, and the difference from MAP to target MAP 
(which is 65, unless the investigator judges it to be otherwise). There will be no imputations of 
missing values.
MAP will be displayed both for MAP measurements taken while patients are in and out of septic 
shock, i.e. while patients are on and off IMP/vasopressors (as defined for the primary endpoint).
Difference to target MAP will only be displayed for MAP measurements taken while patients are in 
septic shock.
9.4.5
Norepinephrine/Noradrenaline and Other Vasopressor Doses
The cumulative dose of norepinephrine/noradrenaline administered (adjusted for baseline weight) 
will be derived as an area under the curve (AUC) of the actual norepinephrine doses and actual time 
points (although analysed at planned time points). Linear interpolation will be used to derive the
AUC (taking into account that only patients enrolled before noon will have a measurement at 36 
hours after IMP start). Patients dead or withdrawn will be set to missing. The cumulative doses 
(μg/kg) will be compared between treatment arms using a repeated measures ANCOVA model with 
baseline dose of norepinephrine/noradrenaline (μg/kg/min) as covariate, treatment, time and 
treatment by time interaction as factors, baseline dose by time interaction, and patient as the 
experimental unit. Estimated treatment differences (to placebo) along with a 95% confidence 
interval will be presented. 
If a patient has missing values and the patient is still in the trial (not dead or withdrawn) it will be 
assumed that the specific vasopressor was not given and a value of zero will be imputed, unless 
there is an interval in the timing log covering the exact time point (8 AM and 8 PM is the assumed 
time point for missing morning and evening collection time points). In that case LOCF will be used, 
but only within the time interval.


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The mean dose and cumulative dose administered will be tabulated by treatment arm (including 
pooled active treatment arms), and presented graphically.
To assess the time needed to wean the patients off norepinephrine, the percentage change from 
baseline in norepinephrine dose (μg/kg/min) will be compared between treatment arms using a 
repeated measures ANCOVA model with baseline dose of norepinephrine/noradrenaline
(μg/kg/min) as covariate, treatment, time and treatment by time interaction as factors, baseline dose 
by time interaction, and patient as the experimental unit. Estimated treatment differences (to 
placebo) along with a 95% confidence interval will be presented at 1, 3, 6, 12 and 24 hours after 
start of IMP treatment.
The same analyses (adjusted for baseline dose of norepinephrine/noradrenaline (μg/kg/min)) will be 
performed for the following endpoints:
-
Catecholamines (defined as the sum of doses of norepinephrine/noradrenaline, 
epinephrine/adrenaline, dopamine, and phenylephrine) (ug/kg)
-
Catecholamines excluding norepinephrine/noradrenaline (ug/kg)
-
Vasopressin (U/kg)
For the sum of catecholamine doses we define 100 μg dopamine, 1 μg epinephrine, and 2.2 μg 
phenylephrine all equivalent to 1 μg norepinephrine.
Also, the number of patients receiving terlipressin will be summarised.
9.4.6
Pulmonary Function (PaO2/FiO2) (in a subset of patients)
Baseline for PaO2/FiO2 will be the values obtained at the last assessment prior to the first dose of 
IMP. There will be no imputations of missing values.
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
interquartile range, minimum, and maximum values, will be presented for observed values and 
change from baseline at each time-point by treatment arm (including pooled active treatment arms). 
9.4.7
Arterial Blood Gases and Acid/Base Status (PaO2, PaCO2, pH, SaO2, Bicarbonate, 
Base Excess), Lactate and Oxygen Saturation in Vena Cava Superior (ScvO2)
Baseline for arterial blood gases, lactate and ScvO2 will be the values obtained at the last 
assessment prior to the first dose of IMP. There will be no imputations of missing values.
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
interquartile range, minimum, and maximum values, will be presented for observed values and 
change from baseline at each time-point by treatment arm (including pooled active treatment arms).


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9.4.8
Cytokines, ANG-1 and ANG-2 (in a Subset of 100-350 Patients)
Baseline values will be the values obtained at the last assessment prior to the first dose of IMP.
There will be no imputations of missing values.
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
minimum, and maximum values, will be presented for observed values and change from baseline at 
each time-point by treatment arm (including pooled active treatment arms).
These analyses will not be repeated for the selected arm only and data from part 2 only.
9.4.9
EVLW and PPI (in a Subset of 100-350 Patients)
Baseline for EVLW and PPI will be the values obtained at the last assessment prior to the first dose 
of IMP. There will be no imputations of missing values.
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
interquartile range, minimum, and maximum values, will be presented for observed values and 
change from baseline at each time-point by treatment arm (including pooled active treatment arms).
These analyses will not be repeated for the selected arm only and data from part 2 only.
9.4.10
Cardiac Output (in a Subset of 100-350 Patients)
Baseline for cardiac output values will be the values obtained at the last assessment prior to the first 
dose of IMP. There will be no imputations of missing values.
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
interquartile range, minimum, and maximum values, will be presented for observed values and 
change from baseline at each time-point by treatment arm (including pooled active treatment arms).
These analyses will not be repeated for the selected arm only and data from part 2 only.
9.4.11
Creatinine Clearance
Creatinine clearance is determined by estimated glomular filtration rate (using creatinine, age, and 
gender as per Cockcroft-Gault).
Cockcroft-Gault equation: creatinine clearance (mL/min) = ((140 - age in years) x weight (kg)) / 
creatinine (μmol/L) for women. For men, multiply result by 1.2.
Creatinine clearance will be analyzed up until day 3 as for fluid balance in Section 9.3.4.1, with 
baseline creatinine clearance as a covariate, treatment, time and treatment by time interaction as 
factors, and patient as the experimental unit.


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10
Safety
10.1
General Considerations
Safety parameters will be evaluated for the safety analysis data set.
All safety summaries will be tabulated by treatment arm (including pooled active treatment arms).
10.2
Adverse Events
Adverse events (AEs) are classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The version of MedDRA will be documented in the clinical report.
Written narratives will be issued for all serious AEs (including deaths) and AEs leading to 
withdrawal.
A pre-treatment adverse event is any untoward medical occurrence arising or observed between 
informed consent and administration of the IMP.
A treatment emergent adverse event is any adverse event occurring after the administration of the 
IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after start of IMP and within the time of residual drug 
effect. 
The time of residual drug effect is the estimated period of time after the end of the administration of 
the IMP, where the effect of the product is still considered to be present based on pharmacokinetic, 
pharmacodynamic or other substance characteristics. A generally accepted time for residual drug 
effect is 5 half-lives. The terminal half-life of the IMP is expected to be not more than 1.8 hours, 
and treatment-emergent AEs are defined as AEs occurring after the start of study drug infusion to 
within 12 hours after study drug infusion is stopped.
A post-treatment adverse event is any adverse event occurring after the residual drug effect period.
Missing values will be treated as missing, except for causality, intensity, seriousness, and outcome 
of adverse events. A “worst case” approach will be used: if causality is missing, the adverse event 
will be regarded as related to the IMP; if the intensity of an adverse event is missing, the adverse 
event will be regarded as severe; if seriousness is missing the adverse event will be regarded as 
serious; if start date is missing or incomplete, worst case will be assumed and the AE will be 
regarded as treatment emergent (only if the incomplete start date is not compromised). If start date 
is completely missing, start date will be set as same day as start of treatment. If start date is 
incomplete, the date closest to start of treatment will be assumed, without compromising the 
incomplete data available on the start date; if outcome is missing and no date of outcome is present 
the outcome is regarded as ‘not recovered’.
10.2.1
Overview of Adverse Events
AE overview summary tables will be prepared for treatment-emergent AEs and all AEs (treatment-
emergent and non treatment-emergent) during the treatment period, including the number of 


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patients reporting an AE, the percentage of patients (%) with an AE, and the number of events (E) 
reported, for the following categories: 
!
Adverse events
!
Deaths 
!
Serious adverse events 
!
Adverse events leading to discontinuation of IMP
!
Severe and life threatening adverse events 
!
Adverse drug reactions
10.2.2
Incidence of Adverse Events
Adverse events will be summarised in a Table by SOC and PT for MedDRA. The Table will 
display the total number of patients reporting an AE, the percentage of patients (%) with an AE, 
and the number of events (E) reported. AEs will be presented by system organ class (SOC) sorted 
alphabetically and preferred term (PT) sorted in decreasing frequency of occurrence.
For both treatment-emergent AEs and all AEs (treatment-emergent and non treatment-emergent) 
during the treatment period, summary tables will be prepared for:
!
All adverse events
!
Adverse events with an incidence ≥ 5% of patients in any treatment arm
!
Non-serious adverse events with an incidence ≥ 5% of patients in any treatment arm
!
Critical adverse events (see Appendix 2 for details)
!
Adverse events by causality (related/unrelated)
!
Adverse events leading to death
!
Adverse events by intensity 
!
Serious adverse events 
!
Adverse events leading to discontinuation of IMP (related/unrelated)
Supporting data listings will be provided for:
!
All adverse events sorted by centre and patient no.
!
All adverse events sorted by MedDRA Preferred Term
!
Serious adverse events 
!
Adverse events leading to death
!
Adverse events leading to discontinuation of IMP (related/unrelated)
!
Post treatment-emergent adverse events. 


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Furthermore, for both treatment-emergent AEs and all AEs (treatment-emergent and non treatment-
emergent) during the treatment period, graphs showing the most frequent adverse events and the 
difference and 95% confidence interval between placebo and selepressin pooled will be presented 
for:
!
All adverse events
!
Adverse events with an incidence ≥ 5% of patients in any treatment arm
!
Critical adverse events (see Appendix 2 for details)
!
Adverse events leading to death
!
Serious adverse events 
10.3 Safety Laboratory Variables
Baseline for all laboratory analyses will be the values obtained at the last assessment prior to (or at)
the first dose of the investigational medicinal product (IMP). End of treatment period will include 
the last post-baseline observation during the trial up until Day 30. 
Laboratory variables will be grouped under “Haematology”, “Clinical Chemistry” or 
“Coagulation”.
10.3.1
Summary Statistics
Mean change and mean percentage (%) change from baseline at end of treatment period will be 
presented for each laboratory variable. In addition, descriptive statistics, i.e., the number of patients 
with data, mean (standard deviation), median, interquartile range, minimum, and maximum values, 
will be presented for observed values and change from baseline at each time-point for each 
laboratory variable.
Furthermore, summary tables will be presented, displaying by time and laboratory parameter, the 
number of patients with a clinically significant result assessed as unanticipated.
Also, a summary table will be prepared for selected laboratory variables that display the number 
and percentage of patients in each treatment arm with X% increments (increase or decrease) from 
baseline at pre-specified timepoints and end of treatment period. The following categories for 
summary tables are defined:
!
≤ -3*X%:
Values with more than 3*X% decrease from baseline
!
> -3*X% - -2*X%:
Values with 2-3*X% decrease from baseline
!
> -2*X% - -1*X%: 
Values with 1-2*X% decrease from baseline
!
> -1*X% - 0*X%: 
Values with 0-1*X% decrease from baseline
!
< 0*X%- < 1*X%: 
Values with 0-1*X% increase from baseline


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!
1*X%- < 2*X%: 
Values with 1-2*X% increase from baseline
!
2*X%- < 3*X%: 
Values with 2-3*X% increase from baseline
!
≥ 3*X%: 
Values with more than 3*X% increase from baseline
The following key laboratory variables will be summarised:
!
Hemoglobin: 20% change
!
WBC: 50% change
!
Platelets: 50% change
!
Creatinine: 20% change
!
Sodium: 5% change 
!
Lactate: 50% change
10.3.2
Data Listings
Data listings will be prepared by centre, treatment arm, patient and time-point (including baseline)
displaying all laboratory values for all patients. 
10.4 Vital Signs (including CVP)
Baseline for all vital signs analyses will be the values obtained at the last assessment prior to the 
first dose of IMP. 
10.4.1
Summary Statistics
Descriptive statistics, i.e., the number of patients with data, mean (standard deviation), median, 
interquartile range, minimum, and maximum values, will be presented for observed values and 
change from baseline at each time-point for each vital signs variable. 
Furthermore, summary tables will be presented, displaying by time and vital signs parameter, the 
number of patients with a clinically significant result assessed as unanticipated.
Also, a summary table will be prepared for each vital signs variable that display the number and 
percentage of patients in each treatment arm with X% increments (increase or decrease) from 
baseline. The following categories for summary tables are defined:
!
≤ -3*X%:
Values with more than 3*X% decrease from baseline
!
> -3*X% - -2*X%:
Values with 2-3*X% decrease from baseline
!
> -2*X% - -1*X%: 
Values with 1-2*X% decrease from baseline
!
> -1*X% - 0*X%: 
Values with 0-1*X% decrease from baseline
!
< 0*X%- < 1*X%: 
Values with 0-1*X% increase from baseline


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!
1*X%- < 2*X%: 
Values with 1-2*X% increase from baseline
!
2*X%- < 3*X%: 
Values with 2-3*X% increase from baseline
!
≥ 3*X%: 
Values with more than 3*X% increase from baseline
The following % changes will be summarised:
!
Heart rate: 50% change
!
Blood pressure: 25% change
10.4.2
Data Listings
Data listings will be prepared by centre, treatment arm, patients and time-point (including baseline)
displaying all vital signs values for all patients with an indication of abnormal values.
10.5 Episodes of Hypotension
Descriptive statistics of number of patients with episodes of hypotension and the total length of 
periods with hypotension will be summarized by treatment arm.
The total length of periods with hypotension will be summarized for both all patients, and patients 
having one or more episodes of hypotension.


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11
Interim analyses
There will be no interim analyses with the potential to stop the trial early for treatment efficacy. 
However, once the “burn-in” period in Part 1 (first 200 treated patients) is completed, regular
interim analyses will be conducted to improve the efficiency of dose selection and to allow early 
termination of the part or the trial for futility or for successful dose selection. The following steps 
will be considered at each interim analysis:
!
When 200 patients are treated, the allocation probabilities for the active treatment arms are 
changed using response-adaptive randomisation (with placebo still 1/3). For the two-thirds 
of patients assigned to the active arms, the probability that a given active arm is assigned 
to a patient is proportional to the probability that that arm is the arm with the largest 
expected number of P&VFD
!
Potentially stopping the trial for futility during Part 1. This occurs if no active arm has 
better than a 5% predictive probability of a significant result in Part 2 if it were to start 
immediately. This decision can occur at any interim during Part 1 after 200 evaluable 
patients.
!
Potentially ending Part 1 and selecting an active treatment arm to continue to Part 2. This 
decision can occur at any interim analysis between 300 evaluable and 800 treated patients, 
and it occurs if some arm has a predictive probability of a successful trial of at least 90% 
before 800 treated patients, and the threshold drops to 25% for the final Part 1 interim 
analysis at 800 treated patients. The selected arm is the arm with the largest posterior 
predictive probability of trial success. This will generally be the best-performing active 
arm, but if multiple arms are performing equally well, it will be the arm with the lowest 
dosing level. If Part 1 ends after N patients, then Part 2 will consist of up to 1800 - N
evaluable patients.
!
If the trial is not stopped for futility or proceeding to Part 2 and active treatment Arm 4 has 
not yet been approved for assignment of patients, the decision can be made to open up 
Arm 4. Arm 4 is only opened between 200 evaluable and 600 treated patients and if there 
is at least a 50% probability that Arm 3 has a higher expected P&VFD than Arm 2 and if 
data from the lower dosing levels do not suggest any significant safety signals.
!
If Part 1 reaches its maximum of 800 treated patients and no arm has a predictive 
probability of Part 2 success of more than 25%, the trial stops with an inconclusive result 
and will be interpreted as a standalone Phase 2b trial.
During Part 2, interim analyses will be conducted regularly (until 1600 patients have been treated)
to allow early termination of the trial for futility. This occurs if the predictive probability of an 
overall significant result is less than 5%. In addition, if the predictive probability of observing a 
more than 2% higher mortality in the active arms compared to placebo is greater than 90% then the 
trial will stop for futility.


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12
Deviations from protocol analysis
See change log.


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13
References
1
The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy 16(3): 199-208
2
EuroQoL Home page: http://www.euroqol.org/home.html
3
Mehta, C.R. and Pocock, S.J. (2011) Adaptive increase in sample size when interim results 
are promising: A practical guide with examples.  Statistics in Medicine, 30, 3267-3284.
4
Hochberg (1988). A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 75(4):800-802
5
EMEA. (2000). Points to consider on switching between superiority and non-inferiority. 
CPMP/EWP/482/99.


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14
Tables, Listings and Figures
The document with tables, figures and listings (TLF) shells will be presented in a separate 
document.


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Appendix 1
EQ-5D-5L Quality Adjusted Life Year (QALY)
We calculate Quality Adjusted Life Year (QALY) (1), (2) at Day 30 and 180 in three steps:
(1) A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions 
of EQ-5D-5L. Each health state is referred to in terms of a 5 digit code. For example, state 12345 
indicates no problems with mobility, slight problems with washing or dressing, moderate problems 
with doing usual activities, severe pain or discomfort and extreme anxiety or depression.
(2) Convert each EQ-5D-5L health state into a single EQ-5D-5L index value. The index values are 
country specific and we will use the value sets for US and apply these values to all patients in this 
trial.
(3) QALY for a patient is then defined to be the area under the curve (AUC) for a Time (with unit 
of Year) versus index values. AUC will be calculated by the linear trapezoidal method. See below 
for a schematic presentation where the y-axis is the index value with y0, y1 and y2, etc. represent the 
index values at baseline, Day 30, 60, 90 and 180. The x-axis is Time (in Years) and the t0 is the 
start of treatment period, i.e. baseline, and t1 and t2 are time of the actual Day 30 and 60, 
respectively, and so on.
If the index value at baseline is missing then we set QALYs at Day 30 and 180 to missing. No 
LOCF imputation will be used. However, linear interpolation will be used between data points with 
missing data in between (e.g. t0 to t2, if t1 is missing). 
      
Figure 5:
EQ-5D-5L QALY Calculation
Index value
time
y0
y1
t1
t2
y2
0
t0


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Appendix 2
Critical Adverse Events and Classification of Adverse Events Based on Changes 
in Safety Laboratory Variables
Table 1:
Critical Adverse Events
Critical adverse event
MedDRA terms or SMQ used for search
Potential hypersensitivity reactions
Anaphylactic reaction (SMQ) (Narrow Scope)
Angioedema (SMQ) (Narrow Scope)
Myocardial infarction / ischemia
Ischaemic heart disease (SMQ) (Broad scope)
Episodes of atrial fibrilation and 
other cardiac arrythmias 
Cardiac Arrhythmias (SMQ) (Broad scope)
Cerebrovascular accident
Haemorrhagic central nervous system vascular conditions (SMQ) (Broad 
Scope)
Ischaemic central nervous system vascular conditions (SMQ) (Broad Scope)
Conditions associated with central nervous system haemorrhages and 
cerebrovascular accidents (SMQ) (Broad scope)
Digital ischemia
Peripheral ischaemia
Pallor
Peripheral coldness
Renal failure
Acute Renal failure (SMQ)
Mesenteric ischemia
Ischaemic colitis (SMQ) (Narrow scope)
Hepato-biliary adverse events
Drug related hepatic disorders - severe events only (SMQ) (Broad Scope)


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Appendix 3
Estimation of Treatment Effects for P&VFDs
Let Y be the number of P&VFDs for both survivors and non-survivors, let p be the probability of 
surviving, and say that for survivors (30-Y) has a negative binomial distribution (with for Y=0 
consuming all values ≥30).
( = ) =
⎩
⎪
⎨
⎪
⎧
(1 −) +  ∗! Γ(#$% + k)
Γ(#$%)'! )
* ∗#
1 + * ∗#+
,
)
1
1 + * ∗#+
-./
,012
 ∗Γ(#$% + 30 −y)
Γ(#$%)(30 −)! )
* ∗#
1 + * ∗#+
(12$4)
)
1
1 + * ∗#+
-./
56  > 0
56  = 0
In the trial it is expected we have a mean of around 5-8 days on vasopressors and mechanical 
ventilation for those surviving.
Therefore, the probability of getting zero P&VFDs for those surviving 
∑
9:-./;<=
9(-./),! >
?∗-
%;?∗-@
,
>
%
%;?∗-@
-./
,012
is negligible (and can be omitted from the model), 
For d=1/16
μ
5
6
7
8
9
10
11
Var =μ+ μ2d
6.56
8.25
10.06
12
14.06
16.25
18.56
P(K≥30)
1.4*10-9
4.2*10-8
6*10-7
5*10-6
2.8*10-5
1.2*10-4
4*10-4
μ
12
13
14
15
Var =μ+ μ2d
21
23.56
26.25
26.09
P(K≥30)
1.1*10-3
2.5*10-3
5.4*10-3
1*10-2
For Y1,...,YN we then get two likelihood functions,
A% = B(1 −)
4CD2
and,
AE = B  ∗Γ(#$% + 30 −y)
Γ(#$%)(30 −)! )
* ∗#
1 + * ∗#+
(12$4)
)
1
1 + * ∗#+
-./
4CF2
Assuming that p is modeled as 
GH/
%;GH/ , and μ as IJK, the two log-likelihoods then become,
                     L% = ∑
ln(
4CD2
%
%;GH/) = ∑
−ln(1 + IJ/)
4CD2


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and,
LE = ! O% −ln(
4CF2
1 + IJ/) + ln:Γ(#$% + 30 −P)= −ln:Γ(#$%)= −ln:(30 −P)!=
+ (30 −P):OE + ln:1 + IJK== −#$% ∗ln:1 + IJK=
Maximizing the full log-likelihood is thus maximizing L% + LE.
And as can be clearly seen, the maximization of L% and LE with regards to O% does not depend on OE
and vice-versa. Hence, O% and OE can be estimated separately from two independent models, i.e. a 
logistic regression for the probability of surviving, and a poisson regression (or negative binomial 
to allow for overdispersion) for the distribution of days on vasopressors and mechanical ventilation 
for those surviving.
In practice, and with the model adjusted for A, B and C, this means that the probability of surviving 
will be estimated from a logistic regression adjusted for A, B and C and treatment group. From 
each treatment group we can do an LSMEANS and get an ‘overall’ O% along with the standard error 
of O%.
For a given treatment group the mean probability of surviving is given as: 
IJ/
1 + IJ/
The distribution of days on vasopressors and mechanical ventilation (30- PVFD’s) for those 
surviving will be estimated from a negative binomial regression (poisson with a potential 
overdispersion), also adjusted for A, B and C and treatment group. From each treatment group we 
can do an LSMEANS and get an ‘overall’ OE along with the standard error of OE.
For a given treatment group the mean PVFD’s for survivors is given as: 
(30 −IJK)
The mean PVFD’s for all subjects (survivors and non-survivors) is then given as:
IJ/
1 + IJ/ ∗(30 −IJK)
Let 
5(O%, OE ) =
IJ/
1 + IJ/ ∗(30 −IJK)
Using the delta method we can calculate the variance of f(O%, OE ):


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5R(O%, OE ) = S:30 −IJK = ∗
IJ/
(1 + IJ/)E ,
IJ/
(1 + IJ/) ∗(−IJK )T
Hence,
[5(O%, OE )] = 5R(O%, OE ) W
XJ/
E
0
0
XJK
E Y 5R(O%, OE )Z
= WXJ/
E ∗:30 −IJK = ∗
IJ/
(1 + IJ/)E
XJK
E ∗
IJ/
(1 + IJ/) ∗(−IJK )Y
⎝
⎜
⎛:30 −IJK = ∗
IJ/
(1 + IJ/)E
IJ/
(1 + IJ/) ∗(−IJK )
⎠
⎟
⎞
= XJ/
E ∗:30 −IJK =
E ∗W
IJ/
(1 + IJ/)EY
E
+ XJK
E ∗W
IJ/
(1 + IJ/)Y
E
∗IEJK
The 95% CI for the mean PVFD’s then become
IJ/
a
1 + IJ/
a ∗:30 −IJK
a= ± 1.96 ∗c[5:O%
a, OE
a=]
Let s indicate selepressin and p indicate placebo, the estimated treatment difference then becomes,
# =
GH/d
e
%;GH/d
e ∗:30 −IJKd
a = −
GH/f
e
%;GH/f
e ∗(30 −IJKf
a )
With 95% CI,
IJ/d
a
1 + IJ/d
a ∗:30 −IJKd
a = −
IJ/f
a
1 + IJ/f
a ∗>30 −IJKf
a @ ± 1.96 ∗[#]
Where [#] is derived again using the delta method as,
g#(O%h, O%i, OEh, OEi)j = #R
⎝
⎜⎜
⎛
XJ/d
E
XJ/dJ/f
E
XJ/dJ/f
E
XJ/f
E
0
0
0
0
0
0
0
0
XJKd
E
XJKdJKf
E
XJKdJKf
E
XJKd
E
⎠
⎟⎟
⎞
#RZ
With,


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#R(O%h, O%i, OEh, OEi)Z =
⎝
⎜
⎜
⎜
⎜
⎜
⎜
⎛
:30 −IJKd= ∗
IJ/d
(1 + IJ/d)E
−:30 −IJKf= ∗
IJ/f
(1 + IJ/f)E
−
IJ/d
(1 + IJ/d) ∗IJKd
IJ/f
:1 + IJ/f= ∗IJKf
⎠
⎟
⎟
⎟
⎟
⎟
⎟
⎞
In the above reasoning, it is assumed that P&VFDs can only take on integer values between 0 and 
30. In practice, P&VFDs will be analysed with one decimal (with values in the range of 0, 0.1, ..., 
29.9, 30.0) and hence the distribution of days on vasopressors and mechanical ventilation for those 
surviving will be estimated from a negative binomial regression model scaled up to 300 
(transforming the P&VFDs from 0.0, 0.1, ..., 29.9, 30.0 to 0, 1, ..., 299, 300), and later scaled back 
to one decimal. 
Let X = 10*Y (scaling Y from 0 to 300) and k% and kE the corresponding estimated parameters 
from the logistic regression and negative binomial regression models based on the modeling of X.
Transforming back to Y, the 95% CI for the mean P&VFDs (E(Y)) then become
Il/
a
1 + Il/
a ∗W30 −IlK
a
10Y ± 1.96 ∗m[5:k%n , kE
a=]
100
Again with s indicating selepressin and p indicating placebo, the estimated treatment difference 
then becomes,
Go/d
a
%;Go/d
a ∗)30 −
GoKd
a
%2 + −
Go/f
e
%;Go/f
e ∗(30 −
GoKf
e
%2 )
With 95% CI,
Il/d
a
1 + Il/d
a ∗W30 −IlKd
a
10 Y −
Il/f
a
1 + Il/f
a ∗S30 −IlKf
a
10 T ± 1.96 ∗mg5:k%h
a , kEh
a , k%i
a , kEi
a =j
100


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Appendix 4
Estimation of Treatment Effects for Difference of Proportions in Incidence of 
RRT, and Difference in Number of New Organ Failures and Number of New 
Organ Dysfunctions
Estimation of Treatment Effects for Difference of Proportions in Incidence of RRT
Let Y be the incidence of RRT (and/or death).
Y can then be modelled using a logistic regression, adjusted for various factors and covariates.
In practice, and with the model adjusted for A, B and C, this means that the probability of RRT 
incidence will be estimated from a logistic regression (PROC GENMOD preferred over PROC 
LOGISTIC as estimates can be subtracted by ODS output) adjusted for A, B and C and treatment 
group. From each treatment group we can do an LSMEANS and get an ‘overall’(adjusted) O along 
with the standard error of O and the covariance between the estimates from each treatment group. 
I.e. we get Oh, Oi, XJd,XJf, and XJdJf
E
.
For a given treatment group the mean probability of RRT incidence is given as: 
IJ
1 + IJ
The difference in proportions of RRT incidence is then given as:
IJd
1 + IJd −
IJf
1 + IJf
Using the delta method we can calculate the variance of f(Oh, Oi ):
5R:Oh, Oi = = S
IJd
(1 + IJd)E , −
IJf
:1 + IJf=
E T
Hence,
[5:Oh, Oi =] = 5R:Oh, Oi = S
XJd
E
XJdJf
E
XJdJf
E
XJf
E
T 5R:Oh, Oi =
Z
= S
XJd
E ∗IJd
(1 + IJd)E −
XJdJf
E
∗IJf
:1 + IJf=
E ,
−XJf
E ∗IJf
:1 + IJf=
E +
XJdJf
E
∗IJd
(1 + IJd)ET
⎝
⎜
⎛
IJd
(1 + IJd)E
−IJf
(1 + IJf)E ⎠
⎟
⎞
= XJd
E ∗W
IJd
(1 + IJd)EY
E
+ XJf
E ∗S
IJf
:1 + IJf=
ET
E
−2 ∗XJdJf
E
∗
IJd
(1 + IJd)E ∗
IJf
:1 + IJf=
E


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The 95% CI for the difference in proportions of RRT incidence then become
IJd
a
1 + IJd
a −
IJf
a
1 + IJf
a ± 1.96 ∗cg5:Ohn , Oi
a =j
Estimation of Treatment Effects for Difference in Number of New Organ Failures and Number 
of New Organ Dysfunctions
Let Y be the number of new organ dysfunctions (or organ failures).
Y can then be modelled using a negative binomial model (poisson model with possible 
overdispersion), adjusted for various factors and covariates.
In practice, and with the model adjusted for A, B and C, this means that the number of new organ 
failures will be estimated from a negative binomial model (PROC GENMOD) adjusted for A, B
and C and treatment group. From each treatment group we can do an LSMEANS and get an 
‘overall’(adjusted) O along with the standard error of O and the covariance between the estimates 
from each treatment group. I.e. we get Oh, Oi, XJd,XJf, and XJdJf
E
.
For a given treatment group the mean number of new organ dysfunctions is given as: 
IJ
The difference in the number of new organ dysfunctions is then given as:
IJd −IJf
Using the delta method we can calculate the variance of f(Oh, Oi ):
5R:Oh, Oi = = :IJd , −IJf =
Hence,
[5:Oh, Oi =] = 5R:Oh, Oi = S
XJd
E
XJdJf
E
XJdJf
E
XJf
E
T 5R:Oh, Oi =
Z
= :XJd
E ∗IJd −XJdJf
E
∗IJf,
XJdJf
E
∗IJd −XJf
E ∗IJf= ) IJd
−IJf +
= XJd
E ∗IEJd + XJf
E ∗IEJf −2 ∗XJdJf
E
∗IJd ∗IJf
The 95% CI for the difference in the number of new organ dysfunctions then become
IJd
a −IJf
a ± 1.96 ∗cg5:Ohn , Oi
a =j
Appendix 5
Statistical Model for Adaptive Design Decisions
An Example Trial


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This section presents the results of an example trial in order to illustrate how the design behaves.  
The selected scenario includes defining the probability distributions that describe how patients 
given placebo behave, and also defining the effects of all four selepressin dosing regimens. In the 
example trial we work with P&VFD data recorded to the nearest day instead of the nearest tenth of 
a day. 
Figure 6 shows the data available at the first interim analysis, and the results of the statistical 
analyses performed using those data that are then used to make decisions. The leftmost of the three 
plots shows the raw data for each of the five arms, with mortality data in the legend and P&VFD 
data for survivors in the barplots. Red represents the placebo arm, and the shades of blue and black 
represent the active arms, with darker colors indicating larger maximum doses. The curves added to 
the plot are naïve density estimates that are not related to the statistical models used in the trial, 
scaled so that they have the same maximum. Active arm 2 has observed the highest mortality rate, 
while active arms 1 and 3 have seen tentative improvements compared to placebo. Active arm 3 has 
had the more surviving patients with small numbers of P&VFDs than the other arms. Active arm 4 
is not yet allowed to accept patients. The middle plot displays estimates of mean P&VFDs (with 
fatalities scored as zero P&VFDs), together with 95% uncertainty intervals. The placebo arm is 
estimated to be the least effective, and uncertainties are smallest for the intermediate doses. The 
rightmost plot displays predictive probabilities and updated allocation probabilities. The circles 
show the allocation probabilities for the next 30 days: the probability for placebo remains at 1/3 for 
the duration of Part 1, and active arm 3 is assigned the lowest probability for any active arm. The 
rightmost plot also features squares showing the predictive probability that this trial would be 
successful if Part 1 were to terminate and Part 2 were to begin with each of the four arms as the 
chosen arm (It is too early to choose an arm: this can only happen when final data have been 
observed for at least 300 patients). If all four active arms had predictive probabilities less than 0.05
the trial would terminate for futility. Also, if the predictive probability were at least 90% that the 
final data set would show an observed increase in mortality of greater than 2%, regardless of which 
of the four active arms were selected, the trial would stop for futility for that reason, but these 
predictive probabilities are not shown in the figures.


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Figure 6:
Data and interim analysis results at time of first interim analysis in an example 
trial
Moving ahead to the second interim analysis shown in Figure 7, when we have observed final data 
for 199 patients. Mortality has remained high for active arm 2. For survivors, the frequency of 
small numbers of P&VFDs is lowest for the placebo arm, but all three active arms have seen more 
patients with very large numbers of P&VFDs than has placebo. According to the rightmost plot, 
predictive probabilities for trial success are around 40% for all active arms. For the next 30 days, 
arm 3 will receive the highest allocation probability among the active arms, and since (not shown) 
the probability is at least 50% that arm 3’s expected P&VFDs is higher than for arm 2, arm 4 
becomes eligible for patient allocation to explore whether the apparent increasing trend in efficacy 
continues. 
Figure 7:
Data and analysis results for second interim analysis in example trial.
We skip ahead to the fourth interim analysis, shown in Figure 8, which is the first interim analysis 
after final data are available for at least 300 patients, so this is the first opportunity to choose a dose 
and move on to Part 2. The first data from arm 4 have come in, and arms 1, 3, and 4 are all 
achieving mortality rates no worse than placebo. The placebo arm continues to have the smallest 
probability of large numbers of P&VFDs among survivors. Since the predictive probability of trial 


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success is largest for arm 3 and its value exceeds 90% (shown by the light green line), the trial 
elects to terminate Part 1 and proceed to Part 2 with arm 3. The allocation probabilities change to 
50% each for placebo and active arm 3. Unless the trial stops earlier for futility, Part 2 will consist 
of 1430 patients since 370 are in the trial currently.  The decision to select arm 3 occurs with only 
11 patients allocated to arm 4, and with arm 4 looking promising thus far, but arm 3 has a high 
enough probability of a successful trial that the trial advances to Part 2. 
Figure 8:
Data and analysis results for fourth interim analysis in example trial
During this interim analysis, Part 1 terminates and the trial proceeds to Part 2 with active arm #3.
The first interim analysis of Part 2 takes place after 63 more patients are allocated to arm 3 or 
placebo. Final data continue to come in for the other active arms as well. Since data are relatively 
favourable for the placebo arm in this month, the predictive probability of a successful trial at 1800 
patients drops to about 0.80, which is much larger than the 5% futility boundary for Part 2 of the 
trial.  
Figure 9:
First interim analysis during Part 2
Interim analyses continue every 30 days (frequency chosen for this example), with the only 
available decision being whether or not to stop for futility. The predictive probability of trial 
success never approaches the 5% value that would trigger a futility stop. The final data at the end of 


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the trial are shown in Figure 9. Observed mortality was 2% lower for active arm 3 than for placebo, 
and the final analysis will be based on a smaller difference than this due to the inclusion of the data 
from other active arms. The simulation assumed true mortalities and expected P&VFD distributions 
for survivors are shown in the middle plot: the doses increase in effectiveness at both preventing 
mortality and increasing P&VFDs for survivors, with arms 3 and 4 each reducing mortality by 
1.5% and increasing expected P&VFDs by 1.5 days for survivors. The rightmost plot shows the 
final p-value for the Wilcoxon test: the p-value for the comparison between patients given placebo 
and patients given any active arm is lower than 0.025, so this is a successful trial.  
Figure 10: Results of final analysis.  The trial is successful, with a p-value of 0.0068.
Statistical Model for Adaptive Design Decisions
A patient’s outcome can be either death or a number of vasopressor and mechanical ventilator-free 
tenths of days between 0 and 300.  Label #P as the dose regimen assigned to patient p, and denote by 
qP the stratum to which the patient belongs (qP ∈{0,1, … ,7}). First, define the distribution of these 
potential outcomes for patients treated with placebo (#P = 0).  If the i’th patient dies, write wP = 1,
otherwise wP = 0.  So,
Pr{wP = 1| #P = 0, qP = 0} = ∆.
Intuitive parameterization of the P&VFD model
To motivate the strategy for modeling the distribution of the number of P&VFD given placebo and 
survival, we first define a version of the model that is more intuitive but less computationally 
convenient and is asymmetric with respect to the strata.  The version actually recommended is 
defined below in the section “Symmetric, computational parameterization of the P&VFD model “.  
The distribution can be modeled nonparametrically:
Pr{P = '|#P = 0, qP = 0, wP = 0} = |,, with ∑
|}
122
}D2
= 1.
Note that patients who die are modelled separately from patients who survive, but nevertheless 
accumulate zero P&VFD, although these patients are handled together in the final analysis. We 
model the treatment effect for a given dose # with two parts: the effect on mortality ~- and the 


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effect on P&VFD given survival, -. The differences between the strata are modeled similarly to 
the effects of the different doses, with a stratum effect on mortality denoted by h and a stratum 
effect on P&VFD given survival denoted by h. By definition 2 = 2 = 0. We model the effect 
on mortality, ~-, on the log-odds scale:
Pr{wP = 1|#P = #, qP = q} =
∆
{∆+ (1 −∆) exp(~- + h)},
where we have defined the effect so that larger values of ~- or h are beneficial (decrease 
mortality). We model the effects of the dose arm and the stratum on the number of P&VFDs for 
survivors using an exponential family whose sufficient statistic is the number of P&VFD:
Pr{P = '|#P = #, qP = q, wP = 0} =
|,I,(;d)
∑
|}I}(;d)
122
}D2
.
In particular, given a dose arm, a sample of P&VFD, and a probability vector |, the maximum 
likelihood estimators of - and h set the expected values of P&VFD equal to their sample means.  
In the final analysis, however, patients who died are treated in the same way as patients who 
survived but who had 0 P&VFD.  
For the simpler statistical model with no consideration of stratum effects, the h and h are 
omitted.
Symmetric, computational parameterization of the P&VFD model
The version of the statistical model we will actually use is as follows. There are still parameters 
|2, … , |122, but they do not correspond directly to any stratum and do not have a clear 
interpretation of their own. Instead of assuming that 2 = 2 = 0, we use another choice of 
identifiability assumptions:  ∑
h = 0

hD%
and ∑
h = 0

hD%
. Now we have 
Pr{P = '|#P = #, qP = q, wP = 0} =
|,I,(;d)
∑
|}I}(;d)
122
}D2
for all # and q, where we have defined the placebo parameter 2 = 0. This parameterization 
facilitates the definition of prior distributions for the h and h, and ensures that the results of the 
analysis do not depend on which stratum is identified with q = 0, etc. We assume hierarchical 
models on the stratum parameters, with h~(0, 
E) and h~(0, 
E ) (conditionally on observing 
the identifiability assumptions), and with ~Uniform(0,1) and ~Uniform(0,1).  


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Inverted-U dose-response models for the dose effects ~ and .
Figure 11: Inverted-U dose-response model
The x-axis represents dose regimen (which is interpreted as maximum dose in the 
selepressin trial), and the y-axis represents the treatment effect.  The model 
parameters , ,   define theoretical special doses (e.g.  is the smallest dose that 
gives maximal effect), while  denotes the maximum achievable treatment effect.
An inverted-U dose-response model is used for the effects on both mortality and P&VFD. This is a 
flexible family that allows for the possibilities that small doses have no effect at all (if those doses 
are smaller than ), and that large doses can start to become less effective than smaller doses (if 
those doses are larger than k). Most importantly for this trial, the model allows all doses to be 
equally effective, since, for a given patient, any assigned maximum dose could be titrated to a 
similar delivered treatment. In the parameterization, shown in Figure 10,  is the smallest dose that 
delivers maximal effect, k is the largest dose that delivers maximal effect,  is the largest dose that 
delivers no effect, O is the rate at which performance degrades beyond dose k, and  is the size of 
the largest effect ( ≤0 is also allowed and there is a prior distribution for  which is symmetric 
about zero. To maintain an inverted U shape, O is constrained to be positive). Care must be taken to 
avoid important identifiability problems: in particular, it is insisted that the interval (, k) contains 
at least one dose for which data can potentially be obtained, otherwise the largest treatment effect is 
not uniquely defined. However,  can be smaller than any active dose, in which case the data 
contain no information about , and k can be larger than any active dose, in which case the data 
contain no information about O, but neither of these nonidentifiabilities are serious problems since 
they do not impact the ability to predict future data.  


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In the case where the candidate doses are 1, 2, 3, and 4, a prior distribution is assumed in which 
k −~Uniform(1,5),
|k~Uniform(0, k −1), and
|~Uniform(0, ).
It is assumed that ~- = (#|%, %, %, k%, O%) and - = (#|E, E, E, kE, OE) for # = 1,2,3,4, 
where the inverted-U function is defined as 
(#|, , , k, O) = {(1 −1 −
(-$) 
(¡$) ];@
;
−O(# −k);}, where ¢; = max(¢, 0).
There is no assumed relationship between the  parameters and the ~ parameters.
For a specific example, suppose % = 0.2, % = 1.5, % = 2.5, and k% = 4 (so that the value of O% is 
irrelevant for doses 1, 2, 3, and 4). Then ~% = 0, ~E = 0.1, ~1 = ~¤ = 0.2.
To complete the specification of the prior distribution, it is assumed that
Δ~¦I§ >
%
1 ,
%
1@, (|2, |%, … , |122)~Dirichlet >
%
12 ,
%
12 , … ,
%
12@,
%~Uniform(−0.35,0.35),
E~Uniform(−0.01334,0.01334),
O%~Uniform(0,10), and
OE~Uniform(0,1).
The limits for the  parameters are selected to be large but not completely absurd; e.g. % = 0.35
corresponds to a 5% benefit to a 20% mortality rate. Given P&VFD data, one can use a variable-at-
a-time Metropolis-Hastings algorithm to sample from the posterior distribution of the unknown 
parameters (Δ, |2, |%, … , |122, %, %, %, k%, O%, E, E, E, kE, OE). These samples can be used to 
estimate the predictive probability of a successful Part 2, the probability that each doses maximizes 
the expected number of P&VFDs, and the probability that dose regimen 3 provides a larger value of 
expected P&VFDs than does dose regimen 2.  
The scale of E depends on how P&VFDs are measured. Here they are recorded as integer numbers 
of tenths.  If integer days are used instead, the prior range should be expanded by a factor of ten.  
The Dirichlet prior exponents we use also depend on how P&VFDs are measured: with integer 
days, we use exponents of 1/3 instead of 1/30.  In either case the prior distribution corresponds to 
approximately ten equivalent observations.


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Response-Adaptive Randomisation Probabilities
Beginning with the first interim analysis, allocation probabilities for the selepressin arms are 
adjusted based on the posterior distribution (the allocation probability for placebo remains fixed at 
1/3 throughout Part 1). The allocation probability for active arm j is proportional to the posterior 
probability that arm j is one of the arms that maximizes the expected number of P&VFD (where the 
mortality probabilities are included in the calculations). Note that the inverted-U models allow for 
multiple arms to have exactly the same expected number of P&VFD. 
Posterior Predictive Probability Calculations
Computations of the predictive probability of a successful Part 2 are critical to the design. These 
computations proceed by drawing samples from the posterior distribution of the unknown 
parameters. We first discuss the predictive probability calculation for the simplified case in which 
there are no strata and the final analysis is a Wilcoxon test; this is the case that applies in the 
operating characteristics simulations presented in this report. For a given posterior sample, we use a 
normal approximation to the predictive distribution of the Wilcoxon statistic that will be obtained 
from the currently available data for placebo and the pooled active arms. The calculation is tedious 
but straightforward, based on writing the Wilcoxon statistic in terms of
!
!
qp¬­:%P −E}=,
®
}D%
¯
PD%
where %%, … , %¯ are the P&VFDs for sample 1 (i.e. the active arm) and E%, … , E® are the 
P&VFDs for sample 2 (i.e. the placebo arm). For a given set of P&VFD probabilities for the two 
arms, one can calculate the expected value and variance of the Wilcoxon statistic, and use this to 
calculate the probability of a significant result (the variance depends on the number of ties, and we 
plug in the expected value of the tie component based on a Poisson approximation). The process is 
then repeated for more posterior samples, and the results are averaged to give the overall estimate 
of the predictive probability of a successful trial. The predictive probability calculation is 
performed for each active arm being the one that proceeds to Part 2. The calculation uses the same 
(pooled) data set for each arm, but each arm has a different posterior distribution of treatment effect 
and hence a different predictive distribution of future data.  
The approximate formula for predictive probability of a successful Wilcoxon test is faster 
computationally than simulating many final data sets and calculating whether each one attains 
success, so it plays a key role in simulating the trial to estimate operating characteristics. When 
time permits, such as when the design is being executed, however, the direct Monte Carlo 
simulation should also be performed.  
The extension to the case in which there are eight strata and in which the final analysis is a van 
Elteren test, is straightforward but adds another layer of complexity. For the purpose of this 
calculation, we introduce a Dirichlet-multinomial model for the stratum probabilities: the eight 
stratum probabilities begin with a Dirichlet prior distribution with parameters equal to 1/3 and then 


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are updated with the stratum counts observed in the trial. This stratum probability model operates 
independently of the remainder of the statistical modeling. Suppose that we are interested in 
calculating the predictive probability of success assuming that half the remaining patients are 
allocated to the placebo and the other half are allocated to active arm 1. For a given posterior 
sample, we draw a sample from the Dirichlet posterior distribution of the stratum, and then draw 
multinomial samples for the stratum counts for the future patients allocated to placebo, and 
separately to the active arm. We then loop over the strata and either 
!
using the posterior sample, simulate numbers of deaths and P&VFDs for survivors for each 
arm and each stratum and then evaluate the Wilcoxon test statistic, its theoretical null 
hypothesis mean, and its theoretical null hypothesis variance (which depends on the 
numbers of ties in the data set), or
!
based on the posterior sample and the current numbers of deaths and P&VFD counts in each 
arm and the current stratum, calculate the predictive mean and variance of the Wilcoxon 
statistic, its theoretical null hypothesis mean, and an approximation to the expected value of 
the theoretical null hypothesis variance.  The current data for all the active arms are 
aggregated together. 
Denoting the Wilcoxon test statistic for the qth stratum by °h, the simulated final number of patients 
in stratum q by h, and the null hypothesis expected value and variance by ±(°h|²2) and 
³(°h|²2) respectively, the van Elteren test statistic is
° =
∑
{°h −±(°h|²2)}/(h + 1)

hD%
{∑
³(°h|²2)/(h + 1)E}

hD%
%/E
For the Monte Carlo estimate of predictive probability, evaluate this statistic for every simulated 
final data set and compute the fraction of final data sets for which this statistic exceeded the 97.5th
Gaussian percentile. To use the approximate formula, denote the predictive mean of °h by 
±(°h|µ, p), the predictive variance by ³(°h|µ, p), and the estimated null hypothesis variance by 
±{³(°h|²2)|µ, p)}; µ denotes the current data and p denotes that we are using the pth posterior 
sample. The approximate predictive probability for posterior sample p is then computed using 
Gaussian tail probabilities based on the expected value and variance of ° given by
±(°|p) =
∑
{±(°h|µ, p) −±(°h|²2)}/(h + 1)

hD%
{∑
±{³(°h|²2)|µ, p)}/(h + 1)E}

hD%
%/E
³(°|p) =
∑
{³(°h|µ, p)}/

hD%
(h + 1)E
∑
±{³(°h|²2)|µ, p)}/(h + 1)E

hD%
Similar but simpler calculations apply for estimating the predictive probability that the final data set 
will have a mortality rate among the patients assigned to an active arm that is at least 2% higher 
than among the placebo patients.  
  


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Control of Type I Error
This design achieves control of Type I error through analytical means. While the trial can stop early 
for futility, a successful trial can only be achieved at a total of 1800 patients. At this time, a single 
test statistic is calculated, and it compares two populations that are defined before the trial begins, 
namely patients allocated to placebo compared to patients that are allocated to any active arm. In 
particular, no patients are excluded from the final analysis for any reason related to their outcomes 
(in contrast, if the final analysis compared placebo to the best performing of the active arms, that 
would inflate Type I error).  
This argument demonstrates that Type I error is controlled even for the modification of the design 
in which early stopping for futility is disabled (See Appendix 6 for a formal proof of Type I error 
control).  The potential for early stopping for futility, including the 25% predictive probability 
requirement at 800 patients, further reduces Type I error probability below the nominal value.  


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Appendix 6
Formal Proof of Type I Error Control
The following assumptions are made in the statistical discussions of type I error.  
1. The primary analysis is based on a Wilcoxon-Mann-Whitney test (Van Elteren’s Test) on 
the P&VFDs. The normal approximation to the sampling distribution of the test statistic is 
assumed for type I error discussions (as it would in a fixed trial).
2. The primary analysis combines all the active arms together for the final analysis. Under the 
null hypothesis, all arms (placebo and active) have the same mean and therefore the active 
arms can be combined in to a single arm.
3. The final analysis is based on 1800 patients.
4. The only “adaptive” aspect of the trial is the time in which randomisation switches from 2:1 
(active to placebo) to (1:1).  
a.
It is assumed that if the randomisation was 2:1 for the entire 1800 patients that type I 
error is controlled.
b. It is assumed that if at a fixed point in time (deterministic) randomisation went from 
2:1 to 1:1 that type I error is controlled.
We demonstrate the control of type I error by first considering a one-sample problem. We use the 
one-sample result to then extend to the two-sample problem. The proof focuses on the notion that 
when the data are positive in the first part of the trial it triggers a shift to a randomisation that 
increases the effective sample size of the trial. As demonstrated in Mehta and Pocock (2011) (3) this 
controls type I error when the data that triggers the shift are appropriately positive.  
The hypothesis test is 
²¶: * = 0
²%: * > 0
Assume iid normally distributed random variables are observed with mean ∀and known variance of 
1. At the interim time point a random variable, based on n0 observations, ¸2 = ­2w¹2 is observed. 
After this time point two different random variables (with entirely different observations, X) could 
be observed: ¸% = ­%w¹% or ¸E = ­Ew¹E.  We use the notation N(∀,#2) for a normal distribution with 
mean ∀and variance #∃2
So, under the null hypotheses, 
¸¶~(0, ­2)
¸%~(0, ­%)
and,
¸E~(0, ­E).


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The adaptive design specifies that if the data are unfavorable we will observe Z1, and if the data are 
favorable we will observe Z2. Therefore, for some value b,
1. If the data are unfavorable (Z0 < b) we observe a second random variable Z1 ~ N(0, n1). The 
trial is declared a success at the end of the second stage if 
Z2 + Z% > a­2 + ­%
where 
a = Φ$%(1 −p).
If b=∞ then it is deterministic (select Z1) and the probability of success is p (the type 1 error of a 
fixed design, under the null).  
2. If the data are favorable (Z0 > b) we observe the random variable Z2 ~ N(0, n2).  We 
assume that the sample size for Z2 is n2 = rn1.  The parameter r is a flexible parameter for 
increase (r>1) or decrease (r<1) in the sample size in the second part of the trial, so r>1 
implies n2 > n1. The trial is declared a success at the end of the second stage if 
Z2 + ZE > a­2 + ­%
The critical value has been set so that if b=–∞ (again deterministic to select Z2) then the probability 
of success is p (type I error under a fixed design).  
The value of b then determines the type I error of the adaptive design. The probability of a type I 
error of the adaptive design, for f the pdf of Z0, is then
∫
5(½)
¾
$¿
À )
Á$ÂÃÄ;Ã/
√Ã/
+ #½ + ∫
5(½)
¿
¾
À )
Á$ÂÃÄ;ÆÃ/
√ÆÃ/
+ #½
(1)
If r=1 there is no change in the trial and the above (1) is equal to p. In this trial r > 1. If the 
expression in (1) is nonincreasing in r then this demonstrates that the type I error is not inflated 
above p in this design. A sufficient condition is if  
Á$ÂÃÄ;ÆÃ/
√ÆÃ/
is decreasing in r. The derivative of 
this is
#
# W
½ −­2 + ­%
√­%
Y = −
­%
2(­%)
1
E
W½ −
­2
­2 + ­%
Y
which is negative in the second integral (z > b) if 
Ç >
ÂÃÄ
ÃÄ;ÆÃ/.                                                                (2)


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Therefore, the type I error of the design is guaranteed if expression (2) holds. It is potentially 
possible to find a smaller b that guarantees a reduction in type I error, but that is not required here 
(see Mehta and Pocock (2011) for further discussion of this reduction). To interpret the constraint 
on b, note that the MLE of ∀based on Z0 is *2
 =
ÈÄ
ÃÄ, and that the MLE of ∀based on Z0 and Z2 is 
*2;E
É =
ÈÄ;ÈK
ÃÄ;ÃK. To elect to observe Z2 we require 
*2
 =
ÈÄ
ÃÄ ≥
¾
ÃÄ >
Â
ÃÄ;ÆÃ/, 
and to show significance at the end of the trial we require 
*2;E
É =
ÈÄ;ÈK
ÃÄ;ÃK >
ÂÃÄ;ÆÃ/
ÃÄ;ÆÃ/
=
Â
ÃÄ;ÆÃ/.
In other words, if we are to elect to observe the larger sample size with Z2 , the observed data at the 
interim must achieve what would need to be observed at the conclusion of the trial in order to be a 
successful trial (meeting the definition of 50% conditional power). This interpretation is convenient 
for discussing the Ferring decision rules.
Two-Sample Extension
The condition above is expressed as a single-sample case. We demonstrate the extension to the two-
dimensional case. In the single-sample case the test-statistic based on unit-variance normal X1, …, 
XM is
∑
wË = Ìw¹Ë
Í
ËD%
,
which has variance M. For the two-sample case (X1, …, XM and Y1, …, YN) the analogous statistic is 
ÍÎ
Í;Î (w¹Í −¹Î), which has variance 
ÍÎ
Í;Î (functions like the sample size). The joint distribution of 
ÍÏÎÏ
ÍÏ;ÎÏ :w¹ÍÏ −¹ÎÏ= for k=1,2,… where the sample sizes Mk and Nk are nondecreasing in k, is the 
distribution of Brownian motion with drift E(X1) –E(Y1) evaluated at the times 
ÍÏÎÏ
ÍÏ;ÎÏ : k=1,2,…, 
which is exactly the same as the one-sample case.
In the Ferring trial since for fixed M+N the effective sample size 
ÍÎ
Í;Î is maximized when M=N, an 
earlier shift to 1:1 randomisation is synonymous with an increase in sample size.  
Decision to “Increase Sample Size”  
In the Ferring trial the decision to shift to 1:1 and thus increase the sample size is not based on a 
conditional power or a point estimate, but rather is based on Bayesian predictive probability. The 
design will shift to 1:1 randomisation early if the predictive probability is greater than 90% 
(typically a 50% predictive probability is consistent with observed data at the interim larger than 
what would need to be seen at the final analysis). This can be demonstrated explicitly in the 


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Gaussian case with prior distribution centered at no treatment effect. For the special case of a flat, 
improper prior and unit variances, we have that the predictive probability of success
Pr Ðw¹ÍÄ;ÍK −¹ÎÄ;ÎK > m
1
Ì2 + ÌE
+
1
2 + E
|w¹ÍÄ, ¹ÎÄÑ
is equal to
À Ò
Ó¹ÔÄ$Õ¹ÖÄ$Âc
/
ÔÄ ÔK;
/
ÖÄ ÖK
c /
ÔK; /
ÖK$
/
ÔÄ ÔK$
/
ÖÄ ÖK
×.
If the predictive probability is greater than 50% then the numerator is positive and the point 
estimate at the interim is larger than what is needed for success at the final analysis. If the prior is 
not improper, but is conjugate normal with mean zero, then the observed effect at the interim must 
be even larger for a 50% predictive probability of success. In the Ferring trial the prior is more 
complicated -- given the joint model over multiple active arms, but each of these arms has prior 
mean the same as the placebo.  
Hence the condition of 90% predictive probability to shift to the 1:1 randomisation provides a 
conservative type I error for the final analysis.
All simulations have reinforced the conservative nature of the final analysis, accounting for the 
Wilcoxon final analysis.
Post-Simulation P-value  
Next to the p-value based on the asymptotic normality of the Van Elteren test, post-simulation 
bootstrap p-values will be provided as sensitivity analyses.  
To this end, the primary outcome for each patient in the trial, regardless of the treatment arm 
(restricted to the evaluable patients) will be placed in a vector and used to simulate complete trials 
and bootstrapped test-statistics. 
The following procedure will be used:
1. The adaptive trial will be simulated exactly as designed in the protocol
2. The following assumptions will be used for the simulated trial:
a.
The day of enrollment during the actual trial, for each patient that was evaluable will 
be noted. These days will be used deterministically for the simulated trials.
b. Additionally the strata in which that actual patient belonged will be recorded and 
used deterministically in the trial. 
3. The randomization rules will follow the adaptive algorithm and design.
4. All, patients, from any arm, will be simulated with replacement from all patients in the 
actual trial with the same stratification membership.
5. The final test-statistic (Van Elteren’s) will be calculated for each simulated trial. 


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6. This process will be repeated 100,000 times. The probability of a test statistic more extreme 
than the observed test-statistic is the empirical estimate of the p-value
A second simulation will run identically, but there will be no futility stopping in the simulated trial.


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Appendix 7
Randomisation Plan
Part 1:  Burn-In:
During burn-in randomisation will be conducted using blocked randomisation. At each site separate 
lists will be conducted for each of the following 8 strata:
Strata
Mechanical 
Ventilation
Creatinine
norepinephrine/ 
noradrenaline
1
Yes
<150 
∀mol/L
<30 ∀g/min
2
Yes
<150 
∀mol/L
≥30 ∀g/min
3
Yes
≥150 
∀mol/L
<30 ∀g/min
4
Yes
≥150 
∀mol/L
≥30 ∀g/min
5
No
<150 
∀mol/L
<30 ∀g/min
6
No
<150 
∀mol/L
≥30 ∀g/min
7
No
≥150 
∀mol/L
<30 ∀g/min
8
No
≥150 
∀mol/L
≥30 ∀g/min
Each blocked list will be generated using random block sizes of 9 and 18 with ratios of 3:2:2:2:0 for 
the placebo and active treatment arms 1, 2, 3, and 4, respectively.
Part 1: Adaptive Randomisation:
After burn-in randomisation will be conducted using a mixture of blocking and response adaptive 
randomisation (RAR) with stratification weighting.
A blocking system will be created for placebo and active arms within each of the 8 strata.  Using 
random block sizes of 3 and 6, lists will be made with ratios of 1:2 for placebo to active.  These 
lists will be created for each strata.
When an “active” slot is pulled a “coin flip” approach will be taken in order to select which active 
dose is selected.  These probabilities will change monthly.  These RAR probabilities will adjust for 
the 3 strata factors. The balancing approach for the RAR is described in Section “Balance 
Weighting.”


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Part 2:  
In Part 2 of the trial there will be only one target active arm and placebo. During this part 
randomisation is done using random blocks of 2, 4, or 6 with equal randomisation (1:1) within each 
site, for each of the 8 strata.
The individual lists created at each stage of randomisation will be discontinued at the end of its 
stage, with the new lists within site being used.
Balance Weighting 
The adaptive randomisation algorithm creates a vector of probabilities for the four active treatment 
arms.  This is a “global” probability for the arms, meaning it is over all strata.  This section 
describes the balancing of the adaptive randomisation across the different strata to maintain, as well 
as possible, the balance of the 8 strata within active treatment arms, while achieving the needed 
adaptive randomisation.  
The 8 strata used to balance the randomisation are based on the two-way classification of 
mechanical ventilation (MV) (Yes/No), Creatinine (Low/High), and norepinephrine/noradrenaline 
(NA) use (Low/High). We present the method for modifying the global adaptive randomisation
probabilities to create different randomisation probabilities for each strata that will honor the goals 
of the response adaptive randomisation as well as the goal of balancing the strata in the treatment 
arms.
The outline of the approach at any interim point of the trial is:
1    The response adaptive randomisation probabilities are provided from the efficacy analysis. 
Label these %1, %2, %3, and %4, for the four active doses.
2    The odds-ratio of a stratum, for each arm, relative to all other arms, is calculated for the 
previously randomised patients.
3    Within each stratum the response adaptive randomisations are modified by the odds-ratios 
from the previous randomisations to create new odds for each arm that are strata specific.
4    The probabilities within each strata are normalized and used for randomisation.
The details of the balancing algorithm are presented below and an example data set is presented.
We label the 8 strata as s=1,…,8. For the previous randomisations, let Nsa be the number of stratum 
s randomised to arm a. The marginals of each stratum and/or arm are labeled with a + symbol.  


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The odds-ratio (modified by adding 0.5 to each cell for handling 0 counts) of the previous patients 
being randomised to arm a, within stratum s is labeled ORsa:
ORsa &
Nsa
N∋a ( Nsa
)
∗
+
,−
.
/0
Ns∋( Nsa
)
∗
N∋∋( N∋a ( Ns∋∋Nsa
)
∗
+
,−
.
/0
.
The global odds of randomising to each arm (%a/1–%a) for new patients is modified by the previous 
odds-ratio of randomisation to create the new randomisation probabilities by stratum for balancing 
future patients. The modified odds of randomising to arm a, within stratum s is
% a
1( % a
+
,−
.
/0
1
ORsa
+
,−
.
/0 .
These odds create unique probabilities for each arm, within each stratum. 
00
/
.
−−
,
+
00
/
.
−−
,
+
(
∋
00
/
.
−−
,
+
00
/
.
−−
,
+
(
sa
a
a
sa
a
a
OR
OR
1
1
1
1
1
%
%
%
%
These are normalized (across a stratum to sum to 1) to form a probability distribution for arms 
within a stratum: 
)
∗
1
&
00
/
.
−−
,
+
00
/
.
−−
,
+
(
∋
00
/
.
−−
,
+
00
/
.
−−
,
+
(
00
/
.
−−
,
+
00
/
.
−−
,
+
(
∋
00
/
.
−−
,
+
00
/
.
−−
,
+
(
&
4
1
1
1
1
1
1
1
1
1
1
1
s
Stratum
in 
a
Arm
Pr
b
sb
b
b
sb
b
b
sa
a
a
sa
a
a
OR
OR
OR
OR
%
%
%
%
%
%
%
%


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As an illustrative example, assume the high dose has not been opened (and the new randomisation
probability %4 is 0). Example of previous randomisations are presented in Table 2:
Table 2:
Example of randomisations to each arm within each stratum.
Strata
Arms
Total
a=1
a=2
a=3
1
5
5
5
15
2
9
1
5
15
3
2
2
2
6
4
1
0
0
1
5
15
18
20
53
6
2
8
8
18
7
7
8
9
24
8
3
4
1
8
Total
44
46
50
140
The odds-ratios of each arm, within each stratum, ORsa, are presented in Table 3:
Table 3:
The odds-ratio of arm a, within each stratum, s, with the 0.5 factor added to each 
cell
Strata
Arms
a=1
a=2
a=3
1
1.09
1.02
0.90
2
3.42
0.18
0.90
3
1.09
1.02
0.90
4
3.32
0.51
0.45
5
0.79
1.08
1.15
6
0.28
1.69
1.48
7
0.88
1.02
1.09
8
1.28
1.92
0.32
Assuming the global response adaptive randomisation probabilities are %1=0.33, %2=0.50, and 
%3=0.17, the modified randomisation probabilities for each arm within each stratum are presented in 
Table 4.


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Statistical Analysis Plan
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CONFIDENTIAL
Table 4:
The modified randomisation probabilities for each stratum 
Strata
Arms
a=1
a=2
a=3
1
0.31
0.50
0.19
2
0.11
0.73
0.16
3
0.31
0.50
0.19
4
0.12
0.60
0.28
5
0.38
0.47
0.15
6
0.56
0.33
0.11
7
0.35
0.49
0.16
8
0.27
0.34
0.39


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Appendix 8
Bias on Treatment Estimate for P&VFDs
The treatment estimates for the primary endpoint will be based on a comparison between all 
patients on all selepressin arms from both parts of the trial (pooled together and treated as a single 
arm), and all patients on the placebo arm from both parts of the trial.
Additionally, the primary analysis will be repeated for the selected arm only, i.e. comparing all 
patients on the selected arm (from part 1) from both parts of the trial (pooled), to all patients on the 
placebo arm from both parts of the trial.
To address the issue of a potential bias on the treatment estimates a variety of different scenarios 
were simulated (Table 5). The results are based on 3000 simulated trials of scenarios where all arms 
are equally effective and where the mortality benefits and P&VFD benefits for survivors 
correspond. For each simulated trial, the treatment effect estimates are simple classical point 
estimates from the raw patient data, e.g. the mortality treatment effect is estimated by the raw 
mortality rate in the placebo group, minus the raw mortality rate in the active group. 
Note that when investigating bias, it is not appropriate to restrict attention to simulated trials that 
are successful. Estimates from that approach will yield results that are larger than the simulated 
truths, and this is true for simple non-adaptive designs as well. In this trial the design is modified by 
removing all futility rules so that all simulated trials select an arm for Part 2 and enroll all 1800 
patients. Some of these simulated trials reach 800 patients with the placebo arm outperforming all 
active arms; in these Part 2 is begun with the least badly performing active arm.  
The table shows the true underlying benefit, the estimated benefits for the primary analysis (all 
selepressin arms from both parts of the trial compared to all patients on placebo from both parts of 
the trial), and the estimated benefits for the selected arm only (all patients on the selected arm from 
both parts of the trial compared to all patients on placebo from both parts of the trial).
The placebo arm was assumed to have a 25% mortality rate, a mean of 24 P&VFDs for survivors, 
and an overall mean of 18 P&VFDs (survivors and non-survivors).
If all active arms are included in the estimates (to correspond with the use of all active arms in the 
final van Elteren analysis as in the two middle columns), the estimates are unbiased and any 
differences from the truth are due to Monte Carlo variation. If only the selected arm is included in 
the estimates, there is some bias due to the fact that the selected arm must have performed relatively 
well in Part 1, the fact that Part 1 data are included in the estimates, and this bias is not completely 
neutralized by the introduction of a large sample of unbiased data in Part 2. The estimates of benefit 
in P&VFDs for survivors are nearly unbiased, while the relatively noisier mortality estimates have 
biases that can be on the same scale as the treatment effect. The largest bias is for the small 
mortality effect of 0.5%, where the design estimates an average effect of 0.77%, which is too small 
of a benefit to lead to a successful trial without a substantial effect on P&VFDs.  


Date: 20 Nov 2017
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Table 5:
Simulated treatment estimate bias for P&VFDs
  True benefit
Average estimated benefit (all 
selepressin arm)
Average estimated benefit 
(selected arm only)
Mortality
P&VFDs
(survivors)
Mortality
P&VFDs
(survivors)
Mortality
P&VFDs
(survivors)
0%
0 days
-0.03%
0.01 days
0.21%
0.06 days
0.5%
0.5 days
0.56%
0.51 days
0.77%
0.56 days
1.0%
1.0 days
0.98%
0.98 days
1.17%
1.05 days
1.5%
1.5 days
1.45%
1.46 days
1.63%
1.54 days
2.0%
2.0 days
1.92%
1.95 days
2.05%
2.03 days
3.0%
3.0 days
2.97%
2.97 days
3.10%
3.03 days
In both scenarios, treatment estimates are either unbiased or the treatment bias is negligible, and 
hence treatment estimates will not be adjusted for treatment bias.


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Date: 20 Nov 2017
E-Statistical Analysis Plan-21909; Ver.1.0
Supersedes: NA
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Statistical Analysis Plan Addendum
Ferring Pharmaceuticals
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
ADDENDUM
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
SEPSIS-ACT
Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial
000133
Investigational Product:
Selepressin; concentrate for solution for infusion
                                                             Placebo; sterile 0.9% sodium chloride solution
Indication:
Vasopressor-dependent Septic Shock
Phase:
2b/3
Author:
Date of issue:
November 20th - 2017
Version:
Final – Ver. 1.0
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals A/S or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorised officer of Ferring Pharmaceuticals A/S or 
another company within the Ferring Group


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Change log
Version
No.
Effective
Date
Reason for the Change / Revision
Supersedes
1
Nov 20-2017
Original SAP addendum
Not applicable


Date: 20 Nov 2017
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Signed agreement on Statistical Analysis Plan Addendum
The original analysis plan addendum was reviewed by,
!
 Global Biometrics, Ferring Pharmaceuticals 
A/S
!
 Global Clinical Operations, CDS, Medical Writing & 
Selepressin, , Ferring Pharmaceuticals A/S
!
 Medical Writing, Ferring Pharmaceuticals A/S
!
 Selepressin, Ferring Pharmaceuticals A/S
!
 Selepressin, Ferring Pharmaceuticals A/S
And reviewed and approved (signed electronically) by,
!
 Biometrics, Ferring Pharmaceuticals A/S


Date: 20 Nov 2017
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TABLE OF CONTENTS
1
Introduction.......................................................................................................................................... 5
1.1
Abbreviations............................................................................................................................ 5
2
Post-futility / Pre-unblinding Planned Analyses ............................................................................... 6
2.1
Primary Endpoint...................................................................................................................... 6
2.2
Organ Dysfunction.................................................................................................................... 6
2.2.1
Mechanical Ventilator-free Days up to Day 30 ........................................................... 6
2.2.2
Duration of Mechanical Ventilation up to Day 30....................................................... 6
2.2.3
Renal Replacement Therapy (RRT)-free Days up to Day 30 (excluding patients 
on RRT for chronic renal failure at time of randomisation) ........................................ 7
2.3
Morbidity/Mortality .................................................................................................................. 7
2.3.1
Intensive Care Unit (ICU)-free Days up to Day 30 ..................................................... 7
2.3.2
All-cause Mortality (Defined as the Fraction of Patients That Have Died, 
Regardless of Cause, by the end of Day 30, Day 90, and Day 180)............................ 7
2.4
Daily and Cumulative Urinary Output Until ICU Discharge (for a Maximum of 7 Days) ...... 7
2.5
Pulmonary Function (PaO2/FiO2) (in a subset of patients)...................................................... 7
2.6
Arterial Blood Gases and Acid/Base Status (PaO2, PaCO2, pH, SaO2, Bicarbonate, 
Base Excess), Lactate and Oxygen Saturation in Vena Cava Superior (ScvO2)...................... 7
2.7
Time to Out of Shock................................................................................................................ 7
2.8
Time to Out of Mechanical Ventilation .................................................................................... 8
2.9
Proportion of Patients maintaining Target MAP while on IMP................................................ 8
2.10
Episodes of Hypotension .......................................................................................................... 8
3
References............................................................................................................................................. 9


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1
Introduction
This document describes the statistical analyses for selepressin (FE202158) 000133 planned after 
the trial was stopped for futility, but before the blind was broken. It is an addendum to version 9.0 
of the statistical analysis plan.
1.1
Abbreviations
Abbreviations
Meaning of abbreviations in document
IMP
P&VFDs
Investigational medicinal product 
Vasopressor- and mechanical ventilator-free days


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2
Post-futility / Pre-unblinding Planned Analyses
2.1
Primary Endpoint
To explore whether there was a ‘learning curve’ effect of administering the drug, the primary 
analysis will be conducted without the first 3 patients at each site.
Due to trial logistics (e.g. preparation time for pharmacy etc.) or safety concerns, some patients 
may receive norepinephrine instead of the investigational medicinal product (IMP) during parts of 
the treatment period where they have a vasopressor need. To try to mimic the ‘near perfect’ 
conditions, where IMP is used as the primary vasopressor, the primary analysis will be conducted 
on a subset of the per-protocol analysis set in which patients who did not have norepinephrine
weaned before IMP (unless due to death), or patients in which IMP was not restarted within 6 hours 
upon restart of norepinephrine, will be excluded.
To evaluate the new septic shock criteria (1), the primary endpoint will be evaluated for patients 
with lactate <2 mmol/L at baseline (sepsis) and patients with lactate ≥2 mmol/L (septic shock), 
respectively.
The VASST trial identified a potential survival benefit using vasopressin as compared to 
norepinephrine in patients with less severe septic shock defined as a baseline norepinephrine dose 
of less than 15 μg/min. Similarly, to assess whether there was a potential benefit of selepressin in 
vasopressor- and mechanical ventilator-free days (P&VFDs) in patients with less severe septic 
shock, the treatment effect of the primary endpoint will be presented graphically, in order to 
visually inspect whether the average treatment effect is distributed evenly across the baseline 
norepinephrine levels (≤15 μg/min, >15 μg/min).  
To further assess if baseline norepinephrine impacts the treatment effect, the same analysis will be 
repeated for baseline norepinephrine levels (≤0.1μg/kg/min, ]0.1; 0.20 μg/kg/min], ]0.2; 0.30
μg/kg/min], ]0.3; 0.45μg/kg/min], ]0.45; 0.60μg/kg/min], >0.60μg/kg/min).  
To assess if there is a treatment duration effect, patients will be stratified by cumulative duration of 
IMP infusion (<1 day, [1; 3 days[, [3; 7 days[, ≥7 days) and the treatment effect of the primary 
endpoint will be presented graphically, in order to visually inspect whether the average treatment 
effect is distributed evenly across the duration of treatment with IMP.
2.2
Organ Dysfunction 
2.2.1
Mechanical Ventilator-free Days up to Day 30 
To assess if there is an effect of baseline lung function on the potential treatment effect of 
selepressin on lung function, the treatment effect of mechanical ventilator-free days will be 
presented graphically, in order to visually inspect whether the average treatment effect is distributed 
evenly across baseline PaO2/FiO2 levels (<100mmHg, [100; 200 mmHg[, [200; 300 mmHg[,≥300
mmHg).
2.2.2
Duration of Mechanical Ventilation up to Day 30 
The graphical presentation in section 2.2.1 will be repeated for duration of mechanical ventilation.


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2.2.3
Renal Replacement Therapy (RRT)-free Days up to Day 30 (excluding patients on 
RRT for chronic renal failure at time of randomisation) 
RRT-free days will also be evaluated using the new septic shock definition (1) as for the primary 
endpoint.
2.3
Morbidity/Mortality
2.3.1
Intensive Care Unit (ICU)-free Days up to Day 30 
ICU-free days will also be evaluated using the new septic shock definition as for the primary 
endpoint.
2.3.2
All-cause Mortality (Defined as the Fraction of Patients That Have Died, 
Regardless of Cause, by the end of Day 30, Day 90, and Day 180) 
Mortality will also be evaluated using both the new septic shock definition, and the baseline 
norepinephrine cut-offs as for the primary endpoint.
2.4
Daily and Cumulative Urinary Output Until ICU Discharge (for a Maximum of 
7 Days) 
Urinary output and cumulative urinary output analyses will be repeated for the two components that 
make up total output volume; spontaneous urine output and output fluids collected from drainages, 
suction devices and respiratory fluid loss estimation (if transpiration was performed).
2.5
Pulmonary Function (PaO2/FiO2) (in a subset of patients)
PaO2/FiO2 up to and incl. Day 7 will be evaluated as an area under the curve (AUC).
Linear interpolation will be used to derive the AUC (taking into account that not all patients will 
have measurements taken between 24 hours post baseline and Day 2). Patients dead or withdrawn 
will be set to missing. The cumulative PaO2/FiO2 will be compared between treatment arms using a 
repeated measures ANCOVA model with baseline PaO2/FiO2 as covariate, treatment, time and 
treatment by time interaction as factors, baseline PaO2/FiO2 by time interaction, and patient as the 
experimental unit. Estimated treatment differences (to placebo) along with a 95% confidence 
interval will be presented.
2.6
Arterial Blood Gases and Acid/Base Status (PaO2, PaCO2, pH, SaO2, Bicarbonate, 
Base Excess), Lactate and Oxygen Saturation in Vena Cava Superior (ScvO2)
Lactate up to and incl. Day 7 will be evaluated as for PaO2/FiO2 in section 2.5 above.
2.7
Time to Out of Shock
A Kaplan-Meier analysis will be performed for time to out of shock, defined as the first time where 
the patient has no vasopressor for at least 24 hours. Patients who die or are withdrawn while still on 
vasopressors and before first 24 hour vasopressor-free episode will be censored. The same applies 
for patients prematurely discontinued from IMP.


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2.8
Time to Out of Mechanical Ventilation
Time to out of mechanical ventilation will be defined and analyzed similarly as for time to out of 
shock in section 2.7 above.
2.9
Proportion of Patients maintaining Target MAP while on IMP
The proportion of patients maintaining target MAP while on IMP will be compared between 
treatment groups using a logistic regression model.
2.10
Episodes of Hypotension
The proportion of patients having one or more episodes of hypotension will be compared between 
treatment groups using a logistic regression model.
The cumulative duration of periods of hypotension will (ideally) be compared between treatment 
groups using a zero inflated negative binomial model. In case model assumptions do not hold, a 
permutation test will be used.


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3
References
1
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus 
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016. 315(8):801-810.