Conditions: Portal Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4
Healthy volunteers: no

Brief summary:
The purpose of this trial is to investigate safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) after intravenous (IV) administration of FE 204205 in patients with cirrhotic portal hypertension.

Detailed description:
The trial aimed to evaluate the safety, tolerability, PK and PD of IV FE 204205 in cirrhotic patients with portal hypertension and was planned in 2 parts:

Part 1 of the trial was open-label where six subjects were planned to receive three ascending doses of FE 204205, given as infusion over 2 hours on three consecutive days.

Part 2 was planned as a randomised, placebo-controlled, double-blind investigation evaluating the effects of a single dose of FE 204205 on portal haemodynamics in 20 subjects who would have received either the maximum tolerated dose (as defined in Part 1) of FE 204205 (n=16) or placebo (n=4).

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: FE 204205 intervention 2: Placebo
Intervention descriptions: intervention 1: In Part 1 of the trial, each subject will receive increasing IV doses of FE 204205, given once daily as 2 hour infusion, on three consecutive days.

In Part 2 of the trial, each subject will receive a 2 hour IV infusion of the maximum tolerated dose of FE 204205 as defined in Part 1 of the trial. intervention 2: In Part 2 of the trial, each subject will receive a 2 hour IV infusion of placebo.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Protocol 
 
 
Title of trial:  
A placebo controlled, double-blind, randomised trial investigating safety, 
tolerability, pharmacodynamics, and pharmacokinetics after intravenous 
administration of FE 204205 in patients with cirrhotic portal hypertension 
NCT number: 
NCT02929407 
Sponsor trial code: 
000249  
Date:  
17 January 2017  
 
 
 
 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 1 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
CONSOLIDATED CLINICAL TRIAL PROTOCOL 
INCLUDING 
NON-SUBSTANTIAL PROTOCOL AMENDMENT 01, 19 OCT 2016, 
AND SUBSTANTIAL PROTOCOL AMENDMENT 02, 17 JAN 2017 
 
 
A placebo controlled, double-blind, randomised trial investigating safety, tolerability, 
pharmacodynamics, and pharmacokinetics after intravenous administration of FE 204205  
in patients with cirrhotic portal hypertension 
 
 
000249 
 
 
 
EudraCT Number: 
2016-001078-13 
IND Number: 
119,790 
Investigational Medicinal Product: 
FE 204205, solution for infusion 
Indication: 
Complications of cirrhotic portal hypertension 
Phase: 
1b 
Name and Address of Sponsor: 
Ferring Pharmaceuticals A/S 
Clinical Research & Development, 
Experimental Medicine 
Kay Fiskers Plads 11,  
2300 Copenhagen S, 
Denmark 
Telephone number: 
+45 8833 8834 
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. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 2 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
SYNOPSIS 
 
TITLE OF TRIAL 
A placebo controlled, double-blind, randomised trial investigating safety, tolerability, 
pharmacodynamics, and pharmacokinetics after intravenous administration of FE 204205 in 
patients with cirrhotic portal hypertension 
SIGNATORY INVESTIGATOR(S) 
 
TRIAL SITE(S) 
University of Barcelona, Hospital Clínic, Spain. 
PLANNED TRIAL PERIOD 
First patient first visit:  Q4 2016 
Last patient last visit:  Q1 2018 
CLINICAL PHASE 
1b 
BACKGROUND AND SCIENTIFIC JUSTIFICATION FOR CONDUCTING THE TRIAL 
Complications of portal hypertension, including ascites, hepatorenal syndrome, and variceal 
bleeding, are leading causes of morbidity and mortality in cirrhosis. Cirrhosis is a common cause of 
death in adults worldwide. It results in approximately one million deaths per year worldwide, 
170 000 per year in Europe, and 35 000 per year in the USA. Cirrhosis is the main indication for 
5500 liver transplants each year in Europe. 
Patients suffering from cirrhotic portal hypertension have an abnormally high splanchnic blood 
flow due to increased hepatic resistance and splanchnic arterial vasodilation. These circulatory 
disturbances cause a decrease in the effective arterial blood volume and a compensatory activation 
of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the non-osmotic 
release of vasopressin, which in turn results in fluid retention and renal vasoconstriction. 
Terlipressin, a full V1A receptor agonist, has been shown to be effective in the management of 
several complications to cirrhotic portal hypertension. Terlipressin reduces the portal pressure and 
this effect is mediated by an arteriolar vasoconstriction in the splanchnic area. By counter-acting 
the splanchnic arterial vasodilation and increasing the effective arterial blood volume, thereby 
improving renal perfusion and glomerular filtration rates, terlipressin has been shown to improve 
renal function in patients with hepatorenal syndrome. There are also reports showing that 
terlipressin, by normalising the underlying circulatory derangements, is effective in the treatment of 
refractory ascites. The rationale for use of terlipressin for treatment of variceal bleeding is to 
produce splanchnic vasoconstriction and thereby reduce portal blood inflow and portal pressure, 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 3 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
thus decreasing portal-variceal flow and pressure. 
Existing V1A receptor agonists, such as terlipressin, are full agonists and may produce excessive 
vasoconstriction if not dosed carefully. The risk profile of V1A full agonists requires careful titration 
and monitoring to prevent the development of serious adverse events (SAEs) due to tissue hypoxia 
and ischemia. Thus, the major limitation of existing agents is a risk of excess vasoconstriction, 
restricting their use to short term applications in inpatient settings under close monitoring by 
specialists. 
FE 204205 is a novel, selective vasopressin 1a receptor (V1A) partial agonist in clinical 
development intended for the treatment of complications to cirrhotic portal hypertension. In 
comparison to full V1A receptor agonists, the V1A partial agonist FE 204205 is expected to have a 
substantially improved therapeutic index due to a lower maximal effect and lower risk for excessive 
vasoconstriction. In animal studies FE 204205 shows only approximately half of the maximal 
vasoconstriction produced by full agonists without any concomitant signs of ischemia (i.e. no 
increased lactate levels), which is assumed to result in adequate clinical vasoconstriction 
concomitant with the required safety. 
Results from two Phase I studies, in which healthy subjects received FE 204205 intravenously, 
indicate that the maximal effect on vasoconstriction, by means of blood pressure, is reached at a 
plasma concentration of approximately 1 ng/ml, achieved by an intravenous infusion of 0.1 mg over 
6 hours. The effect of the V1A partial agonist FE 204205 appears to be capped compared to a full 
V1A agonist, since increasing the dose 9-fold (from 0.1 mg to 0.9 mg over 6 hours) did not result in 
greater pharmacodynamic effects. Administration of 0.9 mg over 6 hours was well tolerated with an 
adverse events (AEs) profile related to the pharmacological effects of a V1A receptor agonist.  
Subcutaneous administration of FE 204205 resulted in the generation of an active metabolite (M1), 
characterised as a V1A full agonist, at equimolar concentrations to FE 204205. The subcutaneous 
administration caused more AEs and of higher intensity than intravenous administration, and the 
maximal tolerated subcutaneous dose of FE 204205 was defined as 0.1 mg. After intravenous 
administration the M1 metabolite was detected only at very low concentrations, ≤2% of the 
FE 204205 concentration, and is not expected to show any appreciable pharmacodynamic effects in 
in this trial.  
This is the first study with FE 204205 in patients with cirrhotic portal hypertension and the selected 
endpoints will focus on the evaluation of safety and tolerability of the treatment in general, the 
investigation of effects on portal and systemic haemodynamics, and the pharmacokinetics of 
FE 204205. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 4 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
OBJECTIVES 
• Safety and tolerability of single intravenous infusions of FE 204205 
• Pharmacological effect of FE 204205 on systemic and portal haemodynamics in patients 
with cirrhotic portal hypertension  
• Pharmacokinetics of FE 204205 after intravenous infusion 
• Relationship between pharmacokinetics and pharmacodynamics of FE 204205 
• Metabolites of FE 204205 in plasma and urine of patients 
• Exploratory assessment of effects of FE 204205 on soluble biomarkers and renal function 
variables 
ENDPOINTS 
• Type, frequency and intensity of adverse events (AEs) 
• Electrocardiogram (ECG) (intervals, rhythm, and morphology)  
• Clinical chemistry, haematology and urinalysis  
• Venous blood gases including lactate  
• Systemic haemodynamics: Blood pressures and heart rate by non-invasive measurements, 
pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure (PAP), right atrial 
pressure (RAP), mean arterial pressure (MAP), and cardiac output (CO) by pulmonary 
artery catherization. CO, MAP, and RAP will be used for calculation of the systemic 
vascular resistance (SVR) 
• Portal haemodynamics by hepatic vein catheterization: Free hepatic venous pressure 
(FHVP), wedged hepatic venous pressure (WHVP), and inferior vena cava pressure (IVC). 
WHVP and the FHVP will be used for calculation of the hepatic venous pressure gradient 
(HVPG) 
• Pharmacokinetics FE 204205: AUC, AUCt, %extrap AUC, Cmax, tmax, CL, Vz, t½, MRT, Ae, 
and CLR 
• Metabolites in plasma and urine 
• Blood and urinary biomarkers: Renin, aldosterone, norepinephrine, atrial natriuretic peptide 
(ANP), brain natriuretic peptide (BNP), urine creatinine, urine sodium, and urine osmolality  
METHODOLOGY 
This is a trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
FE 204205 in cirrhotic patients with portal hypertension and anticipated HVPG ≥12 mmHg. The 
trial is divided in two parts: 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 5 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Part 1 is an open-label investigation of safety, tolerability, pharmacokinetics and 
pharmacodynamics of increasing intravenous doses of FE 204205 and will include 6 patients. The 
first two patients will receive their respective first dose on separate days. Systemic and portal 
haemodynamics will be assessed by pulmonary artery and hepatic vein catheterization on Day 3. 
Each patient will receive three ascending doses of FE 204205, given once daily as 2-hour infusions 
on three consecutive days. Dose escalation on Days 2 and 3 will only commence provided that the 
increase in mean arterial pressure from baseline is <15 mmHg, absolute mean arterial pressure 
≤120 mmHg, systolic blood pressure ≤160 mmHg, diastolic blood pressure ≤100 mmHg, and heart 
rate ≥55 beats per minute at any of the vital signs assessments during the 4 hours after start of 
infusion on the previous day. If these criteria are not met, the same dose will be administered the 
next day. If the increase of dose results in non-tolerable effects, the preceding tolerated dose will be 
reverted to for the remaining administrations in that patient.  
For the first 3 patients, the initial treatment given on Day 1 will be a single dose of 0.01 mg 
FE 204205 followed by planned doses of 0.025 mg FE 204205 on Day 2 and 0.05 mg FE 204205 
on Day 3. For the remaining 3 patients, the planned single doses are 0.025 mg FE 204205 on Day 1, 
0.05 mg FE 204205 on Day 2 and 0.1 mg FE 204205 on Day 3. After the first 3 patients have 
completed all Visit 2 assessments, a Safety Review Committee (SRC) with at least one external 
expert will evaluate the safety, tolerability, and pharmacodynamics of the compound and will 
decide if the dosing regimen can be increased as planned, or if a modified (lower) dose regimen 
should be applied. 
 
 
A Safety Review Committee (SRC) with at least one external expert, will evaluate the safety, 
tolerability, and pharmacodynamics of the compound after the completion of Part 1 to recommend 
what dose of FE 204205 to evaluate in part 2. 
Part 2 is a placebo controlled, double-blind, randomised investigation evaluating the effects of a 
single dose of FE 204205 on portal haemodynamics and will include 16 patients receiving 
FE 204205 and 4 patients receiving placebo. Each patient will receive a 2-hour intravenous infusion 
of the maximum tolerated dose of FE 204205 as defined in Part 1, or placebo, on Day 1. Systemic 
and portal haemodynamics will be assessed by pulmonary artery and hepatic vein catheterization. 
 
Day -1
2
3
Visit 2
Residential stay
Treatment period
Eligibility
Day -21 to -1
Screening  
Visit 1
IV inf
2 h
1
IV inf
2 h
IV inf
2 h
4
Day 7 to 14
Visit 3
End of Trial
HVPG
Follow-up


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 6 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
 
NUMBER OF SUBJECTS 
Part 1 
6 patients. Subjects withdrawn prematurely in Part 1 will be replaced in order to achieve 6 subjects 
that complete all Visit 2-assessments. 
Part 2 
Approx. 20 patients in Part 2. At least 18 patients in Part 2 with HVPG ≥12 mmHg. Measures will 
be taken to reach a balanced ratio between genders (i.e. at least 1/4 of each gender) in the study. 
CRITERIA FOR INCLUSION / EXCLUSION 
Patients, 18-65 years of age, with cirrhotic portal hypertension and anticiptated HVPG ≥12 mmHg 
Inclusion criteria 
1. Signed written informed consent 
2. Male or female patient, 18-65 years of age with confirmed evidence of cirrhosis 
3. From medical history anticipated HVPG ≥12 mmHg  
4. Negative pregnancy test at Screening and on Day -1 
5. Agrees to use an adequate method of contraception during the study until the follow-up visit, if 
not abstinent. Adequate methods of contraception include condom with or without spermicidal 
gel (adequate only for male participants), intrauterine device, surgical sterilisation, vasectomy, 
oral contraceptive pill associated with inhibition of ovulation, depot progesterone injections 
6. Negative urine drug screen and alcohol urine test at Screening and on Day -1 
Exclusion criteria 
1. Patients with co-existing disease including but not restricted to significant organ failure, 
decompensated cirrhosis with a Child Pugh score >12 or requirement for organ support, and 
acute pancreatitis  
2. Type 1 hepatorenal syndrome 
3. Severe hyponatremia (serum sodium concentration <125 mEq/L) 
4. Acute-on-chronic liver failure 
5. Hepatic encephalopathy ≥grade 2 
Day -1
2
Visit 2
Residential stay
Treatment period
IV inf
2 h
1
HVPG 
Eligibility
Day -21 to -1
Screening  
Visit 1
Day 5 to 12
Visit 3
End of Trial
Follow-up


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 7 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6. Hepatocellular carcinoma outside the Milan criteria (<5 cm for a single lesion or less than 
3 lesions with the largest measuring ≤3 cm) 
7. Bacterial infection within 7 days prior to dosing 
8. Gastrointestinal bleeding within 6 weeks prior to dosing. 
9. Severe renal impairment i.e. estimated creatinine clearance < 30mL/min calculated according to 
the The Modification of Diet in Renal Disease (MDRD) study equation  
 
10. History of underlying chronic heart disease, including but not restricted to heart failure NYHA 
class III or IV, angina pectoris, or myocardial infarction 
11. Diagnosed ongoing hypertension 
12. Symptomatic peripheral vascular disease including Raynaud’s syndrome 
13. Diagnosed chronic obstructive pulmonary disease (COPD) 
14. Severe grade 3 anemia, i.e. Hb < 8.0 g/dL (< 4.9 mmol/L) 
15. Use of vasopressin or terlipressin within 7 days prior to dosing 
16. Permanent use of beta-blocker or a long-acting so called nitro-dilator, or if temporary use within 
7 days prior to dosing 
17. Use of treatments for hepatitis B or C virus within 6 months of randomisation or anticipated use 
during the trial period 
18. Positive serology for human immunodeficiency virus (HIV)-1 or HIV-2 
19. Women being pregnant or breastfeeding at screening and Day -1 
20. Hypersensitivity towards any component of FE 204205 formulation 
21. Sensitivity to contrast media  
22. Intake of an investigational medicinal product within the last 8 weeks preceding screening or 
longer if judged by the investigator to possibly influence the outcome of the current study 
23. Body mass index (BMI) <18 or >35 kg/m2 
24. Abuse of alcohol or drugs within 6 months prior to screening 
25. Mental incapacity or language barrier precluding adequate understanding or co-operation 
26. Previously included in this trial 
27. Considered by the investigator to be unsuitable to participate in the study for any other reason 
MEDICINAL PRODUCTS 
Investigational medicinal products (IMP) 
FE 204205: 10 mg/mL in 10 mM acetate buffer, pH 4.5, with mannitol to isotonicity 
Placebo: Sodium chloride 0.9% 
Non-investigational medicinal products (non-IMP) 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 8 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Sodium chloride 0.9% for dilution of IMP 
Midazolam 
Mepivacaine 
Iodine 
DURATION OF TREATMENT 
In part 1, each patient will receive three ascending doses of FE 204205, given once daily as 2-hour 
infusions on three consecutive days. In part 2, each patient will receive a single 2-hour intravenous 
infusion of FE 204205 or placebo. 
TRIAL PROCEDURES / ASSESSMENTS 
Part 1: 
Before inclusion into the study, all patients will undergo a general physical examination, including 
vital signs, ECG and laboratory assessments including haematology, clinical chemistry, and 
urinalysis. 
Patients will come for a residential stay, lasting between Day -1 to Day 4. Each patient will receive 
three ascending doses of FE 204205, given as 2-hour infusions over three consecutive days. During 
the treatment period, adverse events, vital signs, ECG, body weight, and clinical laboratory 
parameters will be assessed. Blood samples for measurement of biomarkers and plasma 
concentrations of FE 204205 and metabolites will be collected at specified time-points. Urine 
collection will be performed at specified timepoints for analysis of urinary output, urinary 
biomarkers and excretion of FE 204205 and metabolites. Patients will be confined to the clinic 
during the treatment period and will be carefully monitored for adverse events and effects on 
systemic haemodynamics. Systemic and portal haemodynamics will be assessed by pulmonary 
artery and hepatic vein catheterization with measurements performed before, during, and 
immediately after the intravenous infusion on Day 3. Catheterization of the hepatic vein and the 
pulmonary artery is a moderately invasive technique and will be carried out under mild sedation 
with midazolam and local anaesthesia.  
HVPG will be the primary pharmacodynamic parameter and assessments will be performed pre-
dose, and at 1 and 2 hours after start of the intravenous administration. HVPG is the golden 
standard for evaluation of portal hypertension in patients with cirrhosis. A balloon-tipped catheter is 
placed in the right or middle hepatic vein and the FHVP and WHVP are measured, the latter is 
when the vein is occluded by the balloon. All measurements will be performed at least in duplicate 
(the average will be used for the endpoint), and permanent tracings will be obtained with a 
multichannel recorder and adequately calibrated transducers. The HVPG is calculated as the 
difference between the WHVP and the FHVP. Hepatic vein catheterization is a safe procedure and 
is used routinely in clinical practice in patients with chronic liver disease. In association with the 
hepatic vein catheterization, inferior vena cava pressure (IVC) will be measured pre-dose and at 2 
hours after start of the intravenous administration. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 9 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Immediately before and after the hepatic vein catheterization (i.e. pre-dose and at 2 hours after start 
of the intravenous administration) a Swan-Ganz catheter will be introduced into the pulmonary 
artery for measurements of systemic haemodynamics (pulmonary capillary wedge pressure 
[PCWP], pulmonary artery pressure [PAP], right atrial pressure [RAP], mean arterial pressure 
[MAP], and cardiac output [CO]). CO, MAP, and RAP will be used for calculation of the systemic 
vascular resistance [SVR]. 
A follow-up visit will be performed between Day 7 and Day 14. 
Part 2: 
Before inclusion into the study, all patients will undergo a general physical examination, including 
vital signs, ECG and laboratory assessments including haematology, clinical chemistry, and 
urinalysis.  
Patients will come for a residential stay, lasting between Day -1 to Day 2. Each patient will receive 
a 2-hour intravenous infusion of FE 204205 or placebo on Day 1. During the treatment period, 
adverse events, vital signs, ECG, body weight, and clinical laboratory parameters will be assessed. 
Blood samples for measurement of biomarkers and plasma concentrations of FE 204205 and 
metabolites will be collected at specified time-points. Urine collection will be performed at 
specified timepoints for analysis of urinary output, urinary biomarkers and excretion of FE 204205 
and metabolites. 
On Day 1, systemic and portal haemodynamics will be assessed by pulmonary artery and hepatic 
vein catheterization.  
A follow-up visit will be performed between Day 5 and Day 12. 
STATISTICAL METHODS 
Power 
Part 1: No formal sample size calculation has been made. However, the number of patients (6) is 
considered sufficient to provide adequate information about the safety and tolerability of 
FE 204205, and thus inform about the suitable dose to evaluate in part 2. 
Part 2: Since this is a first exploratory evaluation of the efficacy of FE 204205 on reducing portal 
pressure, the sample size and power calculations were performed by evaluation of the intra-group 
difference (before and after treatment with FE 204205). Assuming, based on the literature, a 
standard deviation (SD) of relative change from baseline of 12 %, a sample size of 14 patients on 
active treatment was deemed sufficient to detect a within-group 10 % reduction in HVPG, with α = 
0.05 and 1-β = 0.8. Taking into consideration that it occasionally can be technically challenging to 
assess HVPG, a total of approx. 20 patients (16 on FE 204205 and 4 on placebo) are targeted (4:1 
randomisation).  


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 10 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Statistical analyses 
The statistical analysis will include descriptive statistics reflecting the explorative nature of the 
study. In general, the data will be presented by dose level in Part 1 and by treatment group in Part 2. 
No single primary endpoint has been identified, and there will be no multiplicity adjustments for 
the statistical analysis comparisons performed. In Part 2, the statistical analyses are based on the 
assumption that a placebo effect is negliable, so the primary statistical analyses will be performed 
using analyses of covariance of the change and relative change from baseline in the 
pharmacodynamic parameters adjusting for the respective baseline values to assess the significance 
of comparisons with baseline within each group  (in the treatment group to assess the treatment 
effect and in the placebo group to assess the assumption of a negliable placebo effect). Secondary 
inferential statistics will be computed between placebo and active treatment using an analyses of 
covariance with treatment group as an additional factor. 
The pharmacodynamic and safety endpoints will be analysed for the safety analysis set. The PK 
analyses will be performed for the PP analysis set. 
HVPG will be derived as the average of the duplicte assessments, separately calculated for each 
scheduled assessment, of the difference between WHVP and FHVP (WHVP- FHVP). 
HVPG and other haemodynamic variables will be assessed as change from baseline to 1 and 2 
hours post dose separately analysed for each treatment group, and compared between groups. 
Non-compartmental pharmacokinetic analysis of FE 204205 will be performed. 
Changes in safety parameters will be evaluated by subject listings and descriptive statistics. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 11 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................. 2 
LIST OF TABLES ......................................................................................................................15 
LIST OF FIGURES.....................................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................16 
1 
INTRODUCTION .............................................................................................................18 
1.1 
Background.............................................................................................................18 
1.2 
Scientific Justification for Conducting the Trial ............................................................19 
1.3 
Benefit / Risk Aspects...............................................................................................19 
2 
TRIAL OBJECTIVES AND ENDPOINTS ..........................................................................20 
2.1 
Objectives...............................................................................................................20 
2.2 
Endpoints ...............................................................................................................21 
3 
INVESTIGATIONAL PLAN..............................................................................................22 
3.1 
Overall Trial Design .................................................................................................22 
3.1.1 
Trial Design Diagram ....................................................................................22 
3.1.2 
Overall Design and Control Methods ...............................................................22 
3.1.3 
Trial Schedule ..............................................................................................24 
3.2 
Planned Number of Trial Sites and Subjects .................................................................24 
3.3 
Interim Analysis ......................................................................................................24 
3.4 
Safety Review Committee (SRC) ...............................................................................24 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups ...................................24 
3.5.1 
Trial Design .................................................................................................24 
3.5.2 
Selection of Endpoints ...................................................................................25 
3.5.3 
Blinding ......................................................................................................25 
3.5.4 
Selection of Doses in the Trial ........................................................................25 
3.5.5 
Selection and Timing of Dose for Each Subject .................................................27 
3.5.6 
Selection of the Trial Population .....................................................................27 
3.5.7 
Withdrawal Criteria.......................................................................................27 
3.5.8 
Follow-up Procedures....................................................................................27 
4 
SELECTION OF TRIAL POPULATION ...........................................................................28 
4.1 
Trial Population .......................................................................................................28 
4.1.1 
Inclusion Criteria ..........................................................................................28 
4.1.2 
Exclusion Criteria .........................................................................................28 
4.2 
Method of Assigning Subjects to Treatment Groups ......................................................29 
4.2.1 
Recruitment .................................................................................................29 
4.2.2 
Randomisation .............................................................................................29 
4.3 
Restrictions .............................................................................................................29 
4.3.1 
Prior and Concomitant Therapies ....................................................................29 
4.3.2 
Prohibited Therapy .......................................................................................30 
4.3.3 
Other Restrictions .........................................................................................30 
4.4 
Withdrawal Criteria ..................................................................................................30 
4.5 
Stopping Criteria......................................................................................................30 
4.6 
Subject replacement .................................................................................................31 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 12 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5 
TREATMENTS.................................................................................................................32 
5.1 
Treatments Administered ..........................................................................................32 
5.1.1 
Investigational Medicinal Product ...................................................................32 
5.1.1.1 
Part 1 ..............................................................................................................................32 
5.1.1.2 
Part 2 ..............................................................................................................................32 
5.1.2 
Non-Investigational Medicinal Product ............................................................33 
5.2 
Characteristics and Source of Supply ..........................................................................33 
5.2.1 
Investigational Medicinal Products ..................................................................33 
5.3 
Packaging and Labelling ...........................................................................................33 
5.4 
Conditions for Storage and Use ..................................................................................33 
5.5 
Blinding / Unblinding ...............................................................................................34 
5.5.1 
Blinding ......................................................................................................34 
5.5.2 
Unblinding of Individual Subject Treatment......................................................34 
5.6 
Treatment Compliance ..............................................................................................34 
5.6.1 
Dispensing and Accountability........................................................................34 
5.6.2 
Assessment of Compliance.............................................................................34 
5.7 
Auxiliary Supplies ...................................................................................................35 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies .............................35 
6 
TRIAL PROCEDURES .....................................................................................................36 
6.1 
Part 1 .....................................................................................................................36 
6.2 
Part 2 .....................................................................................................................41 
7 
TRIAL ASSESSMENTS ....................................................................................................44 
7.1 
Assessments Related to Endpoints ..............................................................................44 
7.1.1 
Adverse Events ............................................................................................44 
7.1.2 
Vital Signs ...................................................................................................44 
7.1.3 
ECG ...........................................................................................................44 
7.1.4 
Clinical Laboratory Variables .........................................................................45 
7.1.5 
Venous Blood Gases including Lactate ............................................................46 
7.1.6 
Urinary Output, Urinary Biomarkers and Excretion of FE 204205 and 
Metabolites ..................................................................................................46 
7.1.7 
Blood Hormones/Biomarkers..........................................................................47 
7.1.8 
Metabolites in Plasma and Urine .....................................................................47 
7.1.9 
Pharmacokinetics..........................................................................................47 
7.1.10 Systemic Haemodynamics..............................................................................47 
7.1.11 Portal Haemodynamics ..................................................................................48 
7.1.12 Body weight ................................................................................................48 
7.2 
Other Assessments ...................................................................................................48 
7.2.1 
Demographic and Baseline Data......................................................................48 
7.2.2 
Physical Examinations...................................................................................48 
7.2.3 
Serology......................................................................................................48 
7.2.4 
Drug Screen and Alcohol Urine Test................................................................48 
7.2.5 
Pregnancy Test .............................................................................................49 
7.2.6 
Prior and Concomitant Medication ..................................................................49 
7.3 
Drug Concentration Measurements .............................................................................49 
7.4 
Handling of Biological Samples .................................................................................49 
8 
ADVERSE EVENTS..........................................................................................................50 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 13 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
8.1 
Adverse Event Definition ..........................................................................................50 
8.2 
Collection and Recording of Adverse Events ................................................................51 
8.2.1 
Collection of Adverse Events..........................................................................51 
8.2.2 
Recording of Adverse Events..........................................................................51 
8.3 
Adverse Events of Special Interest ..............................................................................54 
8.4 
Pregnancy and Pregnancy Outcome ............................................................................54 
8.5 
Serious Adverse Events.............................................................................................54 
8.5.1 
Serious Adverse Event Definition....................................................................54 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events ..........................55 
8.6 
Follow-up of Adverse Events and Serious Adverse Events .............................................57 
8.6.1 
Follow-up of Adverse Events with Onset during the Trial ...................................57 
8.6.2 
Collection of Serious Adverse Events with Onset after Last Visit in the Trial .........57 
9 
STATISTICAL METHODS ...............................................................................................58 
9.1 
Determination of Sample Size ....................................................................................58 
9.2 
Subject Disposition ..................................................................................................58 
9.3 
Protocol Deviations ..................................................................................................59 
9.4 
Analysis Sets ...........................................................................................................59 
9.4.1 
Full Analysis Set ..........................................................................................59 
9.4.2 
Per Protocol Analysis Set ...............................................................................59 
9.4.3 
Safety Analysis Set .......................................................................................59 
9.5 
Trial Population .......................................................................................................59 
9.5.1 
Demographics and other Baseline Characteristics ..............................................59 
9.5.2 
Medical History, Concomitant Medication and Other Safety Evaluations ..............59 
9.6 
Endpoint Assessments ..............................................................................................60 
9.6.1 
General Considerations ..................................................................................60 
9.6.2 
Endpoints ....................................................................................................60 
9.6.2.1 
Systemic and portal haemodynamics...........................................................................60 
9.6.2.2 
Electrocardiogram .........................................................................................................61 
9.6.2.3 
Clinical laboratory variables.........................................................................................61 
9.6.2.4 
Adverse events ..............................................................................................................61 
9.6.2.5 
Venous blood gases including lactate ..........................................................................62 
9.6.2.6 
Urinary output ...............................................................................................................62 
9.6.2.7 
Blood and urinary biomarkers ......................................................................................62 
9.6.2.8 
Pharmacokinetics ..........................................................................................................62 
9.6.3 
Other assessments .........................................................................................63 
9.6.3.1 
Physical examinations...................................................................................................63 
9.7 
Extent of Exposure and Treatment Compliance.............................................................63 
9.8 
Interim Analyses ......................................................................................................63 
10 
DATA HANDLING ...........................................................................................................64 
10.1 
Source Data and Source Documents............................................................................64 
10.2 
Electronic Case Report Form (eCRF) ..........................................................................64 
10.3 
Data Management ....................................................................................................65 
10.4 
Provision of Additional Information............................................................................65 
11 
MONITORING PROCEDURES ........................................................................................66 
11.1 
Periodic Monitoring .................................................................................................66 
11.2 
Audit and Inspection.................................................................................................66 
11.3 
Confidentiality of Subject Data ..................................................................................66 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 14 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
12 
CHANGES IN THE CONDUCT OF THE TRIAL ...............................................................67 
12.1 
Protocol Amendments...............................................................................................67 
12.2 
Deviations from the Protocol .....................................................................................67 
12.3 
Premature Trial Termination ......................................................................................67 
13 
REPORTING AND PUBLICATION ..................................................................................68 
13.1 
Clinical Trial Report.................................................................................................68 
13.2 
Confidentiality and Ownership of Trial Data ................................................................68 
13.3 
Publications and Public Disclosure .............................................................................68 
13.3.1 Publication Policy .........................................................................................68 
13.3.2 Public Disclosure Policy ................................................................................68 
14 
ETHICAL AND REGULATORY ASPECTS.......................................................................69 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .......................69 
14.2 
Regulatory Authority(ies) Authorisation / Approval / Notification ...................................69 
14.3 
End-of-Trial and End-of-Trial Notification ..................................................................69 
14.4 
Ethical Conduct of the Trial .......................................................................................69 
14.5 
Subject Information and Consent ................................................................................69 
14.6 
Subject Participation Card .........................................................................................70 
14.7 
Compliance Reference Documents .............................................................................70 
15 
LIABILITIES AND INSURANCE ......................................................................................71 
15.1 
ICH-GCP Responsibilities .........................................................................................71 
15.2 
Liabilities and Insurance ...........................................................................................71 
16 
ARCHIVING ....................................................................................................................72 
16.1 
Investigator File.......................................................................................................72 
16.2 
Trial Master File ......................................................................................................72 
17 
REFERENCES..................................................................................................................73 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 15 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
LIST OF TABLES  
Table 5-1 Planned doses of FE 204205, Part 1 .............................................................................32 
Table 5-2 Composition of IMP .................................................................................................33 
Table 6-1 Study Flow Chart, Part 1 ...........................................................................................39 
Table 6-2 Study Flow Chart, Part 2 ...........................................................................................42 
Table 7-1 Safety Laboratory Parameters....................................................................................46 
Table 9-1 SD of relative (%) and absolute change from baseline in HVPG .................................58 
 
LIST OF FIGURES 
Figure 3-1 Overall study design for each patient in Part 1.............................................................22 
Figure 3-2 Overall study design for each patient in Part 2.............................................................22 
 
 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 16 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
List of Abbreviations 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical classification system 
CO 
Cardiac output 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EudraCT 
 European Union Clinical Trial Database 
FHVP 
Free hepatic venous pressure 
FPFV 
First patient first visit 
GCP 
Good clinical practice 
GMP 
Good manufacturing practice 
HVPG 
Hepatic venous pressure gradient 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
IVC 
Inferior vena cava 
LLOQ 
Lower limit of quantification 
LPLV 
Last patient last visit 
MAP 
Mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
Non-IMP 
Non-investigational medicinal product 
PAP 
Pulmonary artery pressure 
PCWP  
Pulmonary capillary wedge pressure 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per protocol 
RAP 
Right atrial pressure 
SAE 
Serious adverse event 
SRC 
Safety review committee 
SVR 
Systemic vascular resistance 
WHVP 
Wedged hepatic venous pressure 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 17 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
 
 
Definition of Terms  
Definition of general terms 
Enrolled 
When subject and Investigator have signed the Informed Consent form 
Included 
When the subject has received the first dose of IMP 
Pre-dose 
Before dosing on a day of dosing 
Treatment period 
Part 1: Time from start of infusion on Day 1, until 24 hours after the last 
administration. 
Part 2: Time from administration until 24 hours after administration  
 
 
Pharmacokinetic terms and definitions 
AUC 
Area under the concentration-time curve to infinity 
AUCt 
Area under the concentration-time curve from time zero up 
to time t, where t is the last time point at which the 
concentration is above the lower limit of quantification 
% Extrap AUC 
Percentage of AUC that is due to extrapolation from the 
last measurable concentration 
Cmax 
Maximum concentration observed 
tmax 
Time of maximum observed concentration (Cmax) 
CL 
Total systemic clearance 
CLR 
Renal clearance 
Vz 
Volume of distribution associated with the terminal phase 
λz 
First-order rate constant associated with the terminal (log-
linear) portion of the concentration-time curve 
t½  
Elimination half-life 
MRT 
Mean residence time 
Ae 
Cumulative amount of FE 204205 excreted unchanged in 
the urine 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 18 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
1 
INTRODUCTION 
1.1 
Background 
Complications of portal hypertension, including ascites, hepatorenal syndrome, and variceal 
bleeding, are leading causes of morbidity and mortality in cirrhosis. Cirrhosis is a common cause of 
death in adults worldwide. It results in approximately one million deaths per year worldwide, 
170 000 per year in Europe, and 35 000 per year in the USA. Cirrhosis is the main indication for 
5500 liver transplants each year in Europe (1). 
Patients suffering from cirrhotic portal hypertension have an abnormally high splanchnic blood 
flow due to increased hepatic resistance and splanchnic arterial vasodilation. These circulatory 
disturbances cause a decrease in the effective arterial blood volume and a compensatory activation 
of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the non-osmotic 
release of vasopressin, which in turn results in fluid retention and renal vasoconstriction (2). 
Terlipressin, a full V1A receptor agonist, has been shown to be effective in the management of 
several complications to cirrhotic portal hypertension (3). Terlipressin reduces the portal pressure 
and this effect is mediated by an arteriolar vasoconstriction in the splanchnic area. By counter-
acting the splanchnic arterial vasodilation and increasing the effective arterial blood volume, 
thereby improving renal perfusion and glomerular filtration rates, terlipressin has been shown to 
improve renal function in patients with hepatorenal syndrome (4). There are also reports showing 
that terlipressin, by normalising the underlying circulatory derangements, is effective in the 
treatment of refractory ascites (5). The rationale for use of terlipressin for treatment of variceal 
bleeding is to produce splanchnic vasoconstriction and thereby reduce portal blood inflow and 
portal pressure, thus decreasing portal-variceal flow and pressure (3). 
Existing V1A receptor agonists, such as terlipressin, are full agonists and may produce excessive 
vasoconstriction if not dosed carefully. The risk profile of V1A full agonists requires careful titration 
and monitoring to prevent the development of serious adverse events (SAEs) due to tissue hypoxia 
and ischemia. Thus, the major limitation of existing agents is a risk of excess vasoconstriction, 
restricting their use to short term applications in inpatient settings under close monitoring by 
specialists. 
FE 204205 is a novel, selective vasopressin 1A receptor (V1A) partial agonist in clinical 
development intended for the treatment of complications to cirrhotic portal hypertension. FE 
204205 have a peptide sequence that comprises one V1A agonist part linked to a V1A antagonist 
part, resulting in a molecule with partial V1A agonist properties, thereby improving the therapeutic 
index by a lower maximal effect and lower risk for excessive vasoconstriction. In animal studies 
FE 204205 shows only approximately half of the maximal vasoconstriction produced by full 
agonists without any concomitant signs of ischemia (i.e. no increased lactate levels).  
Results from two Phase I studies, in which healthy subjects received FE 204205 intravenously, 
indicated that it acts as a partial V1A agonist, resulting in adequate clinical vasoconstriction 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 19 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
concomitant with the required safety. The the maximal effect on vasoconstriction, by means of 
blood pressure, was reached at a plasma concentration of approximately 1 ng/ml, achieved by an 
intravenous infusion of 0.1 mg over 6 hours. The effect of FE 204205 appears to be capped 
compared to a full V1A agonist, since increasing the dose 9-fold (from 0.1 mg to 0.9 mg over 6 
hours) did not result in greater pharmacodynamic effects. Administration of 0.9 mg over 6 hours 
was well tolerated with adverse events (AEs) as expected by a V1A receptor agonist.  
Subcutaneous administration of FE 204205 resulted, possibly due to local peptidase activity, in the 
generation of an active metabolite (M1) at equimolar concentrations to FE 204205. M1 is 
characterised as a V1A full agonist, and the subcutaneous administration caused more AEs and of 
higher intensity than intravenous administration, and the maximal tolerated subcutaneous dose of 
FE 204205 was defined as 0.1 mg. In contrast, after intravenous administration the M1 metabolite 
was detected only at very low concentrations, ≤2% of the FE 204205, and is not expected to show 
any appreciable pharmacodynamic effects in in this trial.  
This is the first study with FE 204205 in patients with cirrhotic portal hypertension and the selected 
endpoints will focus on the evaluation of safety and tolerability of the treatment in general, the 
investigation of effects on portal and systemic haemodynamics, and the pharmacokinetics of 
FE 204205.  
1.2 
Scientific Justification for Conducting the Trial 
This is the first study with FE 204205 in patients with cirrhotic portal hypertension, and the 
selected endpoints will focus on the evaluation of safety and tolerability of the treatment in general, 
the effects on portal and systemic haemodynamics, and the pharmacokinetics of FE 204205. 
1.3 
Benefit / Risk Aspects 
FE 204205 is a partial V1A vasoconstrictor and the pharmacological effects observed in healthy 
subjects include increased blood pressure. A possible benefit of participating in this study would be 
that FE 204205 shows good effect in decreasing the portal pressure, thus rendering the patient a 
positive, albeit possibly temporary, clinical outcome. 
However, the mechanism of action may also pose some risks. Effects observed in healthy subjects 
include peripheral vasoconstriction, decreased organ perfusion, bradycardia, and decreased cardiac 
output. The observed AEs included abdominal pain, increased bowel activity, nausea, increased 
blood pressue, and decreased heart rate.  
In the one patient with cirrhosis dosed with FE 204205 to date (patient 
 in trial 000249), severe 
arterial hypertension and severe diarrhoea were reported. After review of the respective patient´s 
data, the Safety Review Committee concluded that it would be safe to continue the trial with a 
modified and lower dosing regimen as well as an increased frequency of blood pressure and heart 
rate monitoring (changes incorporated with Amendment 2). 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 20 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Based on the pharmacological effects of FE 204205, cardiovascular monitoring of the trial subjects 
will receive special attention. The trial is conducted in a hospital ward for patients with liver 
disease with close medical supervision. The Principal Investigator at the research clinic will 
ascertain that adequate facilities and procedures are available to handle emergency situations should 
they occur during the trial. The medical staff has extensive experience from trials with patients 
requiring invasive portal pressure measurements and intensive surveillance, and there are adequate 
procedures in place to handle adverse events in the trial subjects. Close monitoring of the subjects 
during drug infusions, including frequent blood pressure and heart rate measurements, will allow to 
stop the infusion immediately if needed. 
Measurements of hepatic venous pressure gradient  (HVPG) is a safe procedure and is used 
routinely in clinical practice in patients with chronic liver disease. The site is ward at the Hospital 
Clínic, University of Barcelona, and is located next to both medical and surgical intensive care 
wards. 
It is essential that FE 204205 is administered intravenously, since other routes of administration 
may cause degradation of the molecule resulting in the generation of the full agonist M1, as shown 
following subcutaneous administration in healthy subjects. Adequate procedures are in place, 
according to standard medical practice, to avoid extravasation, i.e. accidental injection or leakage of 
FE 204205 into the subcutaneous space or perivascular tissues. 
The above mentioned risks are addressed in the inclusion and exclusion criteria for the trial and will 
be closely monitored through safety laboratory evaluations, cardiovascular monitoring including 
vital signs and ECG, AE reporting, and by safety review committee (SRC) evaluations. The risk 
posed to the patients participating in the trail is deemed low and ethically justifiable. For more 
detailed information on FE 204205 please refer to the Investigator´s Brochure (6). 
2 
 TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
• Safety and tolerability of single intravenous infusions of FE 204205 
• Pharmacological effect of FE 204205 on systemic and portal haemodynamics in patients 
with cirrhotic portal hypertension 
• Pharmacokinetics of FE 204205 after intravenous infusion 
• Relationship between pharmacokinetics and pharmacodynamics of FE 204205 
• Metabolites of FE 204205 in plasma and urine of patients 
• Exploratory assessment of effects of FE 204205 on soluble biomarkers and renal function 
variables 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 21 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
2.2 
Endpoints 
• Type, frequency and intensity of AEs 
• Electrocardiogram (ECG) (intervals, rhythm, and morphology)  
• Clinical chemistry, haematology and urinalysis  
• Venous blood gases including lactate  
• Systemic haemodynamics: Blood pressures and heart rate by non-invasive measurements, 
pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure (PAP), right atrial 
pressure (RAP), mean arterial pressure (MAP), and cardiac output (CO) by pulmonary 
artery catherization. CO, MAP, and RAP will be used for calculation of the systemic 
vascular resistance (SVR) 
• Portal haemodynamics by hepatic vein catheterization: Free hepatic venous pressure 
(FHVP), wedged hepatic venous pressure (WHVP), and inferior vena cava pressure (IVC). 
WHVP and the FHVP will be used for calculation of the hepatic venous pressure gradient 
(HVPG) 
• Pharmacokinetics FE 204205: AUC, AUCt, %extrap AUC, Cmax, tmax, CL, Vz, t½, MRT, Ae, 
and CLR 
• Metabolites in plasma and urine 
• Blood and urinary biomarkers: Renin, aldosterone, norepinephrine, atrial natriuretic peptide 
(ANP), brain natriuretic peptide (BNP), urine creatinine, urine sodium, and urine osmolality 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 22 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Trial Design 
3.1.1 
Trial Design Diagram 
 
Figure 3-1 Overall study design for each patient in Part 1 
 
 
 
Figure 3-2 Overall study design for each patient in Part 2  
 
 
3.1.2 
Overall Design and Control Methods 
This is a trial investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of 
FE 204205 in cirrhotic patients with portal hypertension. The trial is divided in two parts: 
Part 1 is an open-label investigation of safety, tolerability, pharmacokinetics and 
pharmacodynamics of increasing intravenous doses of FE 204205 and will include 6 patients. 
Dosing will take place in a staggered fashion, with one patient completing dosing before the next 
patient will be dosed (i.e. with at least 3 days between administration of the first dose in one patient 
and the first dose in the next patient). Systemic and portal haemodynamics will be assessed by 
pulmonary artery and hepatic vein catheterization on Day 3. Each patient will receive three 
ascending doses of FE 204205, given once daily as 2-hour infusions on three consecutive days. 
Dose escalation on Days 2 and 3 will only commence provided that the increase in mean arterial 
Day -1
2
3
Visit 2
Residential stay
Treatment period
Eligibility
Day -21 to -1
Screening  
Visit 1
IV inf
2 h
1
IV inf
2 h
IV inf
2 h
4
Day 7 to 14
Visit 3
End of Trial
HVPG
Follow-up
Day -1
2
Visit 2
Residential stay
Treatment period
IV inf
2 h
1
HVPG 
Eligibility
Day -21 to -1
Screening  
Visit 1
Day 5 to 12
Visit 3
End of Trial
Follow-up


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 23 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
pressure from baseline is <15 mmHg, absolute mean arterial pressure ≤120 mmHg, systolic blood 
pressure ≤160 mmHg, diastolic blood pressure ≤100 mmHg, and heart rate ≥55 beats per minute at 
any of the vital signs assessments during the 4 hours after start of infusion on the previous day. If 
these criteria are not met, the same dose will be administered the next day. If the increase of dose 
results in non-tolerable effects, the preceding tolerated dose will be reverted to for the remaining 
administrations in that patient.  
For the first 3 patients, the initial treatment given on Day 1 will be a single dose of 0.01 mg 
FE 204205 followed by planned doses of 0.025 mg FE 204205 on Day 2 and 0.05 mg FE 204205 
on Day 3. For the remaining 3 patients, the planned single doses are 0.025 mg FE 204205 on Day 1, 
0.05 mg FE 204205 on Day 2 and 0.1 mg FE 204205 on Day 3. After the first 3 patients have 
completed all Visit 2 assessments, a Safety Review Committee (SRC) will evaluate the preliminary 
safety, tolerability, and pharmacodynamics data of the FE 204205 and will decide if the dosing 
regimen can be increased as planned, or if a modified (lower) dose regimen should be applied (see 
Figure 3-3).  
HVPG will be the primary pharmacodynamic parameter and assessments will be performed before, 
during, and immediately after the intravenous administration on Day 3. Patients will be confined to 
the clinic during the treatment period and will be carefully monitored for adverse events and effects 
on systemic haemodynamics. 
A Safety Review Committee (SRC) will evaluate the safety, tolerability, and pharmacodynamics of 
the compound after the completion of Part 1 to recommend what dose of FE 204205 to evaluate in 
Part 2. 
Part 2 is a placebo controlled, double-blind, randomised investigation evaluating the effects of a 
single dose of FE 204205 on portal haemodynamics and will include 16 patients receiving 
FE 204205 and 4 patients receiving placebo. Each patient will receive a 2-hour intravenous infusion 
of the maximum tolerated dose of FE 204205 as defined in Part 1, or placebo, on Day 1. Systemic 
and portal haemodynamics will be assessed by pulmonary artery and hepatic vein catheterization. 
HVPG will be the primary pharmacodynamic parameter and assessments will be performed before, 
Figure 3-3: Suggested trial design for the 6 patients in Part 1. 
   *SRC = Safety Review Committee. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 24 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
during, and immediately after the intravenous administration. Patients will be confined to the clinic 
during the treatment period and will be carefully monitored for adverse events and effects on 
systemic haemodynamics. 
3.1.3 
Trial Schedule 
The first subject is expected to be enrolled in  Q4 2016 and the last follow-up visit is expected to 
take place in Q1 2018. The duration of the trial is expected to be approximately 1-1.5 years. The 
end of trial is defined as the follow-up visit for the last subject. 
3.2 
Planned Number of Trial Sites and Subjects 
The trial will be conducted at one site, University of Barcelona, Hospital clinic, Spain, including 
patients with cirrhotic portal hypertension, 6 patients in Part 1 completing all Visit 2-assessments, 
and approx. 20 patients in Part 2, at least 18 of which in Part 2 with HVPG ≥12 mmHg at baseline. 
3.3 
Interim Analysis 
No formal statistical interim analysis is planned.  
3.4 
Safety Review Committee (SRC) 
An SRC, comprising at least one external expert in addition to the Principal Investigator and the 
Ferring representatives, will evaluate the safety, tolerability and pharmacodynamics of the 
compound.  
Two scheduled meetings are planned: One SRC meeting will be held after the first 3 patients in Part 
1 have completed all Visit 2 assessments, where the SRC will recommend whether the doses can be 
increased as planned or if a modified (lower) dose regimen should be applied. Another SRC 
meeting will be held after all subjects in Part 1 have completed all Visit 2 assessments in order to 
determine the dose that will be used in Part 2 of the trial. Furthermore, unscheduled meetings can 
be demanded anytime for any reasonable cause by the sponsor or the Investigator, e.g. due to any 
unforeseen adverse events. In such a situation, the SRC will recommend whether the dosing should 
continue according to the pre-defined dosing schedule, be changed to a different dosing schedule, 
or whether dosing should be stopped. A working procedure for the SRC will be described prior to 
study initiation. 
3.5 
Discussion of Overall Trial Design and Choice of Control Groups 
3.5.1 
Trial Design 
The purpose of Part 1 is to assess safety, tolerability, and pharmacodynamics in the dose interval 
0.01-0.1 mg i.v. infusion over 2 hours, and thus determine the maximum tolerated dose within this 
dose interval. Part 1 is open-label since it comprises only one treatment arm, and it was neither 
regarded necessary nor ethically justifiable to include placebo treatment. The assessment of 
systemic and portal hemodynamics by pulmonary artery and hepatic vein catheterization on Day 3 
will enable a more precise evaluation of the hemodynamic effect at the maximum tolerated dose, 
compared to non-invasive vital signs assessments. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 25 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Part 2 is aiming at defining the anticipated maximal effects of a single intravenous dose of 
FE 204205 on portal haemodynamics. Part 2 of the trial is randomised and placebo-controlled in 
order to correct for the non-treatment related factors that otherwise may have an impact on the 
evaluation of FE 204205. All subjects will be randomly allocated to active treatment or placebo in a 
double-blind setting, i.e. the active or placebo treatment will not be revealed to the subjects or the 
personnel involved in the trial. The randomisation is standard procedure in studies with more than 
one treatment arm.      
3.5.2 
Selection of Endpoints 
Since this is the first study with FE 204205 in patients with cirrhotic portal hypertension the 
selected endpoints focus on the evaluation of safety and tolerability of the treatment in general, the 
pharmacokinetics of FE 204205, and investigation of the pharmacological activity including the 
pharmacodynamic reponse. 
HVPG is the golden standard for evaluation of portal hypertension in patients with cirrhosis. 
Measurements of HVPG is a safe procedure and it is used routinely in clinical practice in patients 
with chronic liver disease. The methodology and consistency of the HVPG measurements are 
crucial in the evaluation of treatment effects. This is ensured by all measurements being performed 
at one site with the same personnel. 
3.5.3 
Blinding 
Since all subjects in Part 1 receive the same treatment, Part 1 is open-labelled. 
Part 2 of the trial is double-blind, keeping all subjects and personnel involved in the trial blinded to 
the treatment received. Blinding is performed to reduce any bias concerning reporting and 
interpretation of e.g. AEs. If unblinding is deemed appropriate, the blinding for a patient need not 
kept once the patient have been treated and all data are entered in the eCRF. 
3.5.4 
Selection of Doses in the Trial 
The selection of doses and dose increments is based on the experiences from two studies in healthy 
subjects. The doses explored in healthy subjects, ranging between 0.03 to 0.9 mg IV infused over 6 
hours, were safe and well tolerated. The IV starting dose of 0.01 mg infused over 2 hours (=0.005 
mg/hr) corresponds to the infusion rate applied for the lowest dose level given to healthy subjects 
(0.03 mg IV infused over 6 hours = 0.005 mg/hr) and is expected to not exceed the exposure in 
healthy subjects by means of Cmax (expected Cmax: approximately 0.3 ng/mL). At this lowest dose 
level in healthy subjects (0.005 mg/hr IV over 6 hours), no relevant effects on blood pressure were 
observed. The observed decrease in pulse may have been due to reflex bradycardia and thus may 
indicate a pharmacodynamic effect. The dose level was safe and well tolerated in healthy subjects, 
and no gastrointestinal adverse events were reported.  
Compared to the first patient (#101) studied in trial 000249, the IV starting dose (introduced with 
Amendment 2) of 0.01 mg infused over 2 hours (=0.005 mg/hr) corresponds to an infusion rate that 
is 10 times lower than the one given to patient 
 (planned dose of 0.1 mg over 2 hours =0.05 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 26 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
mg/hr). Furthermore, the expected Cmax after 2 hours of infusion (~0.3 ng/mL) is 3 times below the 
plasma concentration observed in patient 
 (0.95 ng/mL after 30 min).  
In Part 1, provided that the dose on the preceding day is regarded safe and tolerable, the subsequent 
dose can be increased. The planned doses for the first 3 patients are 0.01 mg FE 204205 on Day 1, 
0.025 mg FE 204205 on Day 2 and 0.05 mg FE 204205 on Day 3. After the SRC has evaluated the 
preliminary data on safety, tolerability and pharmacodynamics of FE 204205 from the first 3 
patients, the planned doses for the remaining 3 subjects may be increased to maximum 0.025 mg 
FE 204205 on Day 1, 0.05 mg FE 204205 on Day 2 and 0.1 mg FE 204205 on Day 3 (see protocol 
section 3.4). Dose escalation in the subject on Days 2 and 3 will only commence provided that the 
increase in mean arterial pressure from baseline is <15 mmHg, absolute mean arterial pressure 
≤120 mmHg, systolic blood pressure ≤160 mmHg, diastolic blood pressure ≤100 mmHg, and heart 
rate ≥55 beats per minute at all of the vital signs assessments during the 4 hours after start of 
infusion on the previous day. If these criteria are not met, the same dose will be administered the 
next day. If the increase of dose results in non-tolerable effects, the preceding tolerated dose will be 
reverted to for the remaining administration in that subject. The highest planned dose of 0.1 mg 
infused over 2 hours (=0.05 mg/hr) corresponds to the infusion rate applied for the dose level of 0.3 
mg IV infused over 6 hours = 0.05 mg/hr) given to healthy subjects and is expected to not exceed 
the exposure in healthy subjects by means of Cmax (expected Cmax: approximately 3 ng/mL). At this 
dose level in healthy subjects (0.05 mg/hr IV over 6 hours), the mean arterial pressure increased 
(max. mean increase of +14 mmHg) and the pulse decreased. The dose level was safe and well 
tolerated in healthy subjects, as were dose levels up to 3 times higher (highest dose level studied in 
healthy subjects was 0.9 mg infused over 6 hours = 0.15 mg/hr). 
The highest planned dose of 0.1 mg infused over 2 hours (=0.05 mg/hr) that may be reached on  
Day 3 is the same that was assigned to patient 
 on Day 1. However, this dose level will only be 
reached in a patient in Part 1 who has already tolerated two lower dose levels of FE 204205 on Day 
1 and Day 2 and met the dose escalation criteria above. 
The chosen dose increments between dose levels (increasing by a factor of 2.5 from the starting 
dose, then maximum increase of factor 2 for the subsequent doses) are lower and thus more 
conservative then the ones used in the trials with healthy subjects, where a factor of ~3 was applied 
for the respective dose range from 0.005 mg/hr to 0.05 mg/hr. 
In Part 2 each patient will receive a 2-hour intravenous infusion of the dose of FE 204205 selected 
by the SRC, or placebo, on Day 1. The SRC will select the dose based on incidence and frequency 
of adverse events, safety laboratory data, ECG, systemic and portal haemodynamic parameters. The 
dose selected will be the maximum tolerated dose (MTD) or a lower dose. The MTD is defined as 
the dose level below the dose where one or more stopping criteria, as confirmed by a second 
measurement, are met in at least two subjects in Part 1. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 27 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
3.5.5 
Selection and Timing of Dose for Each Subject 
The administration of the investigational medicinal product (IMP) will commence in the morning 
during fasting conditions. 
3.5.6 
Selection of the Trial Population 
Subjects with cirrhotic portal hypertension and anticipated HVPG ≥12 mmHg, are chosen as trial 
population since this is the target population. Measures will be taken to reach a balanced ratio  
between genders (i.e. at least ¼ of each gender) in the trial. 
3.5.7 
Withdrawal Criteria 
The subject should be withdrawn if any signs of serious, or unexpected and unacceptable treatment 
emergent AEs occur, and may be withdrawn if the inclusion or exclusion criteria are violated 
during the conduct of the study. The subjects have the right to withdraw at any time for any reason 
without justification. In addition, a number of stopping criteria are defined, related to 
cardiovascular parameters (see Section 4.5). 
3.5.8 
Follow-up Procedures 
After the end-of-trial, the subject is referred to standard treatment according to medical need under 
the responsibility of the treating physician. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 28 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
4 
SELECTION OF TRIAL POPULATION 
4.1 
Trial Population 
Subjects, 18-65 years of age, with verified cirrhotic portal hypertension and anticipated HVPG 
≥12 mmHg. 
4.1.1 
Inclusion Criteria 
1. Signed written informed consent  
2. Male or female patient, 18-65 years of age with confirmed evidence of cirrhosis 
3. From medical history anticipated HVPG ≥12 mmHg  
4. Negative pregnancy test at Screening and on Day -1 
5. Agrees to use an adequate method of contraception during the study until the follow-up visit, if 
not abstinent. Adequate methods of contraception include condom with or without spermicidal 
gel (adequate only for male participants), intrauterine device, surgical sterilisation, vasectomy, 
oral contraceptive pill associated with inhibition of ovulation, depot progesterone injections 
6. Negative urine drug screen and alcohol urine test at Screening and on Day -1 
4.1.2 
Exclusion Criteria 
1. Patients with co-existing disease including but not restricted to significant organ failure, 
decompensated cirrhosis with a Child Pugh score >12 or requirement for organ support, and 
acute pancreatitis  
2. Type 1 hepatorenal syndrome 
3. Severe hyponatremia (serum sodium concentration <125 mEq/L) 
4. Acute-on-chronic liver failure 
5. Hepatic encephalopathy ≥grade 2 
6. Hepatocellular carcinoma outside the Milan criteria (<5 cm for a single lesion or less than 
3 lesions with the largest measuring ≤3 cm) 
7. Bacterial infection within 7 days prior to dosing 
8. Gastrointestinal bleeding within 6 weeks prior to dosing. 
9. Severe renal impairment i.e. estimated creatinine clearance < 30mL/min calculated according to 
the Modification of Diet in Renal Disease (MDRD) study equation  
10. History of underlying chronic heart disease, including but not restricted to heart failure NYHA 
class III or IV, angina pectoris, or myocardial infarction 
11. Diagnosed ongoing hypertension 
12. Symptomatic peripheral vascular disease including Raynaud’s syndrome 
13. Diagnosed chronic obstructive pulmonary disease (COPD) 
14. Severe grade 3 anemia, i.e. Hb < 8.0 g/dL (< 4.9 mmol/L) 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 29 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15. Use of vasopressin or terlipressin within 7 days prior to dosing 
16. Permanent use of beta-blocker or a long-acting so called nitro-dilator, or if temporary use within 
7 days prior to dosing 
17. Use of treatments for hepatitis B or C virus within 6 months of randomisation or anticipated use 
during the trial period 
18. Positive serology for human immunodeficiency virus (HIV)-1 or HIV-2 
19. Women being pregnant or breastfeeding at screening and Day -1 
20. Hypersensitivity towards any component of FE 204205 formulation 
21. Sensitivity to contrast media 
22. Intake of an investigational medicinal product within the last 8 weeks preceding screening or 
longer if judged by the investigator to possibly influence the outcome of the current study 
23. Body mass index (BMI) <18 or >35 kg/m2 
24. Abuse of alcohol or drugs within 6 months prior to screening 
25. Mental incapacity or language barrier precluding adequate understanding or co-operation 
26. Previously included in this trial 
27. Considered by the investigator to be unsuitable to participate in the study for any other reason  
4.2 
Method of Assigning Subjects to Treatment Groups 
4.2.1 
Recruitment 
Patients with cirrhotic portal hypertension will be recruited among the patients enlisted for 
treatment at hospital clinics in the Barcelona area. However, all treatments will be conducted at the 
University of Barcelona, Hospital Clinic. 
4.2.2 
Randomisation 
All subjects screened will be assigned a screening number. A subject number will be allotted to the 
subject according to a sequential subject number list in the order at which the subjects are found 
eligible. In Part 1, the subjects are not randomised. In Part 2, all subjects will be randomised to 
active treatment or placebo according to a computer-generated randomisation list provided by 
Global Biometrics, Ferring Pharmaceuticals A/S. Randomisation will be carried out on Day 1 
before administration of IMP. 
4.3 
Restrictions 
4.3.1 
Prior and Concomitant Therapies 
Concomitant medication with vasopressor substances, beta-blockers, or nitro-dilators is not 
allowed. Other concomitant medication may be administered at the discretion of the Investigator. 
Any concomitant medication will be recorded in the eCRF, together with the main reason for its 
prescription. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 30 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
4.3.2 
Prohibited Therapy 
Treatment with vasopressor substances (e.g. vasopressin, terlipressin, or catecholamines) or use of 
beta-blockers or a long-acting so called nitro-dilator, is not allowed. 
4.3.3 
Other Restrictions 
Subjects should abstain from drinking alcoholic beverages for 72 hours before the screening visit 
and all subsequent visits to the clinical investigation unit. In addition, subjects should abstain from 
beverages containing caffeine and alcoholic beverages during the residential stay in both trial parts. 
Intake of products containing poppy seeds (e.g., poppy cake) should be avoided for a period of at 
least 7 days before screening and admission to the clinic in both trial parts in order to avoid 
analytical interference with the drug screen for opiates. 
The subjects should abstain from strenuous physical activity that is not within the subject’s normal 
weekly routine for 48 hours prior to screening and from 48 hours prior to admission until the last 
safety examination in both trial parts. 
Subjects must not participate in another clinical trial during the course of the present trial. 
4.4 
Withdrawal Criteria 
The Investigator has the right and obligation to withdraw a subject should any signs of serious, or 
unexpected and unacceptable treatment emergent AEs occur. Furthermore, a subject may be 
withdrawn from the study if the inclusion or exclusion criteria are violated during the conduct of 
the study. 
Both the Investigator (with regard to his/her participation) and Ferring, reserves the right to 
discontinue the study at any time for safety reasons, such as signs of unacceptable adverse 
reactions, or mortality, or any other reasons jeopardising the justification of the study. Such a 
termination will be implemented in a time frame that is compatible with the subject’s well-being. If 
the study is prematurely terminated or suspended, the investigator should promptly inform the 
subjects and assure appropriate follow-up and treatment if required. Ferring Pharmaceuticals A/S 
will notify the Regulatory Authorities of any plans to terminate the study, and the Investigator will 
notify the Independent Ethics Committee (IEC). 
The subjects have the right to withdraw from the trial at any time for any reason, without the need 
to justify their decision. For any discontinuation, the Investigator will obtain all the required details 
and document the date of the premature termination and the main reason in the eCRF. If possible, 
follow-up assessments should be performed for subjects who are withdrawn after start of infusion. 
4.5 
Stopping Criteria 
The infusion will be interrupted and may be adjusted in the subject if any of the below stopping 
criteria occur, and halted for evaluation by the SRC when one or more criteria, as confirmed by a 
second measurement, are met in at least two subjects receiving the same treatment. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 31 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• Systolic blood pressure increased by 50% or more from the baseline and reaching 
>160 mmHg 
• Systolic blood pressure 180 mmHg or higher 
• Diastolic blood pressure 105 mmHg or higher 
• Mean arterial pressure 130 mmHg or higher 
• Heart rate 45 beats per minute or lower 
• Signs or symptoms of mesenteric or peripheral ischemia, or hypertensive crises. 
4.6 
Subject replacement 
Subjects withdrawn prematurely in Part 1 will be replaced in order to achieve 6 subjects that 
complete all Visit 2-assessments.  


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 32 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5 
TREATMENTS 
A separate instruction will cover all procedures regarding handling, dilution, and administration of 
the IMPs. The manual will be provided to the clinical investigational unit before the start of the 
study. 
5.1 
Treatments Administered 
5.1.1 
Investigational Medicinal Product 
The IMPs in this trial are FE 204205 10 mg/mL and placebo (commercially available 0.9% sodium 
chloride). 
5.1.1.1 
Part 1 
In Part 1, each subject will receive three ascending doses of FE 204205, given once daily as 2-hour 
intravenous infusions on three consecutive days.  
Table 5-1 Planned dose regimen of FE 204205, Part 1 
(Doses to be infused i.v. over 2 hours and respective infusion rates) 
Treatment Day 
Dose 
(Patients 1-3) 
Dose 
(Patients 4-6) 
Day 1 
0.01 mg (0.005 mg/hr) 
0.025 mg (0.0125 mg/hr) 
Day 2 
0.025 mg (0.0125 mg/hr) 
0.05 mg (0.025 mg/hr) 
Day 3 
0.05 mg (0.025 mg/hr) 
0.1 mg (0.05 mg/hr) 
Planned doses and infusion rates are listed in Table 5-1. After the first 3 patients have completed all 
Visit 2 assessments, the SRC will evaluate the preliminary safety, tolerability, and 
pharmacodynamics data of the FE 204205 and will decide if the dosing regimen can be increased as 
planned, or if a modified (lower) dose regimen should be applied. A modified dosing regimen may 
be chosen by the SRC (also in unscheduled meetings, if deemed necessary by the Investigator or 
Sponsor) as long as the modified planned infusion rates do not exceed the infusion rates given in 
Table 5-1, and as long as the modified increments between the dosing days (from Day 1 to Day 2 
and from Day 2 to Day 3) do not exceed factor 2. 
 
5.1.1.2 
Part 2 
In Part 2, each subject will receive a single 2-hour intravenous infusion of FE 204205 or placebo. 
The SRC will evaluate the safety and tolerability of the compound after the completion of Part 1 to 
determine the maximum tolerated dose within the administered dose range of FE 204205, and 
recommend which dose to be investigated in Part 2. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 33 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5.1.2 
Non-Investigational Medicinal Product 
Commercially available 0.9% sodium chloride to be used for dilution of IMP will be supplied by 
the Sponsor. Commercially available midazolam for sedation, mepivacaine for local anaesthesia, 
and the contrast medium iodine will be provided by the site.  
5.2 
Characteristics and Source of Supply 
The IMPs are provided by Ferring Pharmaceuticals A/S and will be handled according to the 
principles of Good Manufacturing Practice (GMP). Ferring Pharmaceuticals A/S will provide the 
pharmacy at University of Barcelona, Hospital Clinic with IMP and non-IMP in amounts sufficient 
for the trial. 
5.2.1 
Investigational Medicinal Products 
The stock solution of FE 204205 is detailed in (Table 5-2). FE 204205 will be diluted with 0.9% 
sodium chloride to the desired concentrations. Commercially available 0.9% sodium chloride will 
be used as placebo. 
Table 5-2 
Composition of IMP 
 
FE 204205 
FE 204205 
10 mg/mL 
Sodium acetate buffer 
10 mM, pH 4.5 
Mannitol 
44.3 mg/mL 
Sodium chloride 
--- 
  
5.3 
Packaging and Labelling 
Packaging and labelling of the medicinal products will be performed under the responsibility of the 
IMP department at Ferring Pharmaceuticals A/S in accordance with GMP and national regulatory 
requirements.  
The IMP will be labelled according to Annex 13, EudraLex Volume 4 and national regulatory 
requirements. The label of the IMP will contain one self-adhesive tear-off portion to be affixed to 
the Subject dispensing log, or similar, maintained at the trial site. The IMPs will be labelled with a 
unique IMP number. 
5.4 
Conditions for Storage and Use 
Storage condition is stated at the labels of the IMP and non-investigational medicinal product (non-
IMP). The Investigator will ensure that the IMPs and non-IMP will be stored according to storage 
condition at the label, in a secure location with controlled access. The storage compartments shall 
be monitored regularly and the temperature shall be documented. Deviations in storage temperature 
must be reported to Sponsor without delay and the IMP must not be used until acceptance from the 
Sponsor is received. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 34 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5.5 
Blinding / Unblinding 
5.5.1 
Blinding 
Part 1 of the trial is open-labelled. In Part 2, all subjects, the Investigator, and all staff involved in 
the conduct of the trial will be blinded to the treatment received. The trial monitor will not be 
blinded, and no specific precautions will be taken to keep the pharmacist or personnel running the 
analyses of FE 204205 blinded. 
It is the responsibility of the pharmacy to ensure that the syringes used for infusion in Part 2 are 
identical and non-distinguishable.  
The pharmacy will receive the computer-generated randomisation list from Global Biometrics, 
Ferring Pharmaceuticals A/S.  
5.5.2 
Unblinding of Individual Subject Treatment  
An emergency decoding system will be available to the Investigator at University of Barcelona 
Hospital Clinic and to designated persons at Ferring Pharmaceuticals for each subject. Breaking of 
the blind for individual subjects in emergency situations is only permitted in case of a serious, 
unexpected, or other important AE, when the knowledge of the trial medication in question is 
required for therapeutic decisions and for the management of the subject. As far as the emergency 
permits, the need to break the blind will be agreed by the Investigator and Ferring. If the blinding is 
broken it must be documented by whom, reason and the date of unblinding. 
If it is necessary to unblind an individual subject’s treatment for the purposes of expedited reporting 
to the authorities and/or IEC, only those individuals within Ferring whose responsibility it is to 
report this information will know the identity of the trial medication. Every attempt will be made to 
try to keep all other trial and site personnel blinded throughout the course of the trial. 
Information on whether the blind has been broken for any subjects must be collected before the 
database is declared clean and is released to the statistician.  
If unblinding is deemed appropriate, the blinding for a patient need not kept once the patient have 
been treated and all data are entered in the eCRF. 
5.6 
Treatment Compliance 
5.6.1 
Dispensing and Accountability 
The Investigator will maintain a drug accountability logs or equivalent detailing the dates and 
quantities of study medication dispensed to, and used by, each subject, as well as the batch 
numbers. The Monitor will verify the drug accountability during the trial. 
5.6.2 
Assessment of Compliance 
The study medication will be administered by authorised staff at the clinical investigation unit. 
Compliance is assessed by recording the volume infused. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 35 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
5.7 
 Auxiliary Supplies 
University of Barcelona, Hospital Clinic, will use auxiliary supplies as instructed by Ferring 
Pharmaceuticals A/S. The materials will be provided from commercial lots and supplied by the site. 
No modification to the commercial state will be made. 
5.8 
Return and Destruction of Medicinal Products and Auxiliary Supplies 
Used IMP vials, sodium chloride infusion bags, and auxiliary supplies used for dilution and 
infusion will be destroyed at site according to local regulations and standard procedures at the site 
after the drug accountability has been verified by the Monitor and signed off by the Sponsor. 
Documentation on destruction will be forwarded to the Sponsor. 
Any unused IMP and sodium chloride will be returned for destruction, as instructed by IMP 
Department, Ferring Pharmaceuticals A/S, and in accordance with local requirements, after the 
drug accountability has been finalised, verified by the Monitor, signed off by the Investigator, and 
approved by the Sponsor. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 36 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6 
TRIAL PROCEDURES 
For each subject, the duration of the treatment period, including the screening period and the 
follow-up visit will not exceed 5 weeks. Assessments of concomitant medication and AEs will be 
performed throughout both study periods. 
FE 204205 or placebo will be administered as a continuous 2-hour intravenous infusion starting in 
the morning. The infusion may be paused or slowed down if tolerability issues arise. The patient 
will be monitored during the infusion, including assessment of pulse rate and blood pressure.  
6.1 
Part 1 
Each patient will receive three ascending doses of FE 204205, given once daily as 2-hour infusions 
on three consecutive days. 
Visit 1 (Screening, Day -21 to Day -1) 
At the screening visit each subject will be informed about the study and after signing the Informed 
Consent form assessments for eligibility will commence. The eligibility evaluation includes 
adherence to inclusion and exclusion criteria, collection of concomitant medication, demographic 
data and medical history, physical examination, urine drug screen, alcohol urine test, assessment of 
vital signs and 12-lead ECG, blood sampling for serology, pregnancy test, and clinical chemistry, 
haematology, and urine sampling for urinalysis (i.e. clinical laboratory parameters). 
Visit 2 (Residential stay, Day -1 to Day 4) 
Subjects found eligible will be asked to return for a treatment visit (residential stay). At the arrival 
to the clinic on the day before the first administration day (Day -1), a general eligibility check 
(inclusion/exclusion criteria, medical history, urine drug screen, alcohol urine test, assessment of 
vital signs and 12-lead ECG, pregnancy test, blood and urine sampling for clinical laboratory 
parameters) will be performed. A baseline assessment of venous blood gases including lactate will 
also be performed. 
The next day (Day 1) subjects will be dosed with a 2-hour continuous intravenous infusion of 
FE 204205 (for planned doses see Protocol Section 5.1.1.1). Before administration of FE 204205 
the subjects body weight will be assessed. Safety assessments including sampling for clinical 
laboratory parameters, assessment of vital signs, 12-lead ECG, venous blood gases including 
lactate, and urinary output will be performed at predetermined time-points (Table 6-1). Blood 
samples for pharmacokinetic determination, metabolites, biomarkers, and samples for urinary 
biomarkers and excretion of FE 204205 and metabolites will be collected at predetermined time-
points (Table 6-1).  
On Day 2 and Day 3 the subject will be administered ascending doses of FE 204205 through 2-hour 
continuous infusions. Before each administration of FE 204205 the subjects body weight will be 
assessed. Safety assessments including sampling for clinical laboratory parameters, assessment of 
vital signs, 12-lead ECG, venous blood gases including lactate, and urinary output will be 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 37 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
performed at predetermined time-points (Table 6-1). Blood samples for pharmacokinetic 
determination, metabolites, biomarkers, and samples for urinary biomarkers and excretion of 
FE 204205 and metabolites will be collected at predetermined time-points (Table 6-1). On Day 3, 
in addition to the same assessments performed on Day 2, systemic and portal haemodynamics will 
be assessed by pulmonary artery and hepatic vein catheterization with measurements performed at 
pre-determined time-points before, during and immediately after the intravenous infusion (Table 
6-1).  
HVPG is the golden standard for evaluation of portal hypertension in patients with cirrhosis. It is a 
moderately invasive technique and catherization of the patients will be carried out under mild 
sedation with midazolam and local anaesthesia. A balloon-tipped catheter is placed in the right or 
middle hepatic vein and the FHVP and WHVP are measured, the latter is when the vein is 
occulated by the balloon.  
After an overnight fast, the patients will be transferred to the Hepatic Haemodynamic Laboratory. 
Under mild sedation and local anesthesia, a venous catheter introducer will be placed using 
ultrasonographic guidance in the right jugular vein by the Seldinger technique. Under fluoroscopic 
control, a Swan-Ganz catheter will be advanced to the pulmonary artery for measurement of 
baseline (pre-dose) cardiopulmonary pressures and cardiac output by the thermal dilution method. 
After withdrawal of the Swan-Ganz catheter, a balloon-tipped catheter will be guided using 
fluoroscopy into the inferior vena cava and subsequently to the main right or middle hepatic vein 
for measurements of baseline (predose) FHVP, WHVP, and IVC. The HVPG results from the 
difference between WHVP (occluded) and FHVP. The adequacy of occlusion will be checked by 
gentle injection of a small amount of radiologic contrast medium after balloon inflation. All 
measurements will be performed at least in duplicate (the average will be used for the endpoint) and 
permanent tracings will be obtained with a multichannel recorder and adequately calibrated 
transducers. The catheter will be kept in the hepatic vein for assessments of FHVP and WHVP at 1 
and 2 hours after start of infusion of IMP. At withdrawal of the catheter (at 2 hours after start of 
infusion) IVC will be reexamined. Immediately after the removal of the balloon-tipped catheter, 
cardiopulmonary pressures and cardiac output will be reassessed (at 2 hours after start of infusion) 
using a Swan-Ganz catheter advanced to the pulmonary artery under fluoroscopic control. During 
the haemodynamic study all patients will be subjected to noninvasive monitoring by continuous 
display of heart rate, pulse oximetry, and respiratory rate, along with frequent blood pressure 
measurements. 
The subjects will be discharged from the clinic after the post-dose assessments (clinical laboratory 
parameters, vital signs, 12-lead ECG, body weight) on Day 4 (Table 6-1) have been performed. 
Visit 3 (Follow-up, Day 7 to Day 14) 
A follow-up visit will be performed 4-11 days after the last administration, and will be considered 
end of study. At this visit a physical examination, assessment of vital signs and 12-lead ECG 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 38 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
recording will be performed, pregnancy test, and samples for clinical laboratory parameters will be 
collected.  
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 39 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 6-1 
Study Flow Chart, Part 1 
Assessment 
Screening 
Treatment Period 
End of trial 
Visit No. 
Visit 1 
Visit 2 
Visit 3 
Procedures / Days 
-21 to -1 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Days 7-14 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
Medical history 
X 
X 
 
 
 
 
 
Clinical chemistry, haematology, 
urinalysis 
X 
X 
X1 
X1 
X1 
X1 
X 
Serology/virology 
X 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
Alcohol urine test 
X 
X 
 
 
 
 
 
Pregnancy test (serum) 
X 
X 
 
 
 
 
X 
12-lead ECG 
X 
X 
X2 
X2 
X2 
X2 
X 
Vital signs (non-invasive) 
X 
X 
X3 
X3 
X3 
X3 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Venous blood gas including lactate 
 
X 
X4 
X4 
X4 
 
 
Administration of FE 204205 
 
 
X 
X 
X 
 
 
Blood samples for PK and 
metabolites 
 
 
X5 
X5 
X5 
 
 
Hepatic vein and pulmonary artery 
catheterization 
 
 
 
 
X8 
 
 
Blood biomarkers 
 
 
X6 
X6 
X6 
 
 
Urine sampling for urinary output, 
urinary biomarkers and excretion of 
FE 204205 and metabolites 
 
 
X7 
X7 
X7 
 
 
Body weight 
 
 
X9 
X9 
X9 
X9 
 
1 Blood samples for safety laboratory evaluations will be collected 6 hours after start of infusion on Days 1-3, and in the 
morning on Day 4. 
2 ECG will be collected pre-dose and at 1, 2, 3, and 6 hours after the start of the infusion on Days 1-3, and in the 
morning on Day 4. 
3 Vital signs comprising systolic and diastolic arterial blood pressure (including calculation of mean arterial pressure) 
and  pulse will be assessed pre-dose, every 5 min until 30 min after start of infusion, then every 10 min until 1 hour 
after start of infusion, then every 15 min until 2.5 hours after start of infusion and therafter 3, 4, and 6 hours after start 
of infusion on Days 1-3, and in the morning on Day 4. Temperature only pre-dose and 6 hours after after start of 
infusion on Days 1-3. 
4 Venous blood gas including lactate will be collected 3 hours after the start of the infusion on Days 1-3.  
5 Blood samples for measurement of plasma concentration of FE 204205 and metabolites will be collected pre-dose and 
at 0.5, 1, 2, 3 and 4 hours after the start of the infusion on Days 1-3. 
6 Blood samples for measurement of biomarkers will be collected pre-dose and at 3 hours after the start of the infusion 
on Days 1-3. 
7 Urinary output, urinary biomarkers and excretion of FE 204205 and metabolites will measured pre-dose and after each 
spontaneous void up to 8 hours after start of infusion on Days 1-3. 
8 Measurement of portal haemodynamics by hepatic vein catheterization will be performed pre-dose and at 1 and 2 
hours after start of the infusion on Day 3. Pulmonary artery catheterization will be performed pre-dose and at 2 hours 
after start of the infusion on Day 3. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 40 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9Body weight will be assessed pre-dose on Days 1-3, and in the morning on Day 4. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 41 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
6.2 
Part 2 
Each patient will receive a 2-hour intravenous infusion of FE 204205 or placebo on Day 1. 
Visit 1 (Screening, Day -21 to Day -1) 
At the screening visit each subject will be informed about the study and after signing the Informed 
Consent form assessments for eligibility will commence. The eligibility evaluation includes 
adherence to inclusion and exclusion criteria, collection of concomitant medication, demographic 
data and medical history, physical examination, urine drug screen, alcohol urine test, assessment of 
vital signs and 12-lead ECG, blood sampling for serology, pregnancy test, and clinical chemistry, 
haematology, and urine sampling for urinalysis (i.e. clinical laboratory parameters). 
Visit 2 (Residential stay, Day -1 to Day 2) 
Subjects found eligible will be asked to return for a treatment visit (residential stay). At the arrival 
to the clinic on the day before the administration day (Day -1), a general eligibility check 
(inclusion/exclusion criteria, medical history, urine drug screen, alcohol urine test, assessment of 
vital signs and 12-lead ECG, pregnancy test, blood and urine sampling for clinical laboratory 
parameters) will be performed. A baseline assessment of venous blood gases including lactate will 
also be performed. 
The next day (Day 1) subjects will be randomised to 2-hour continuous infusion of either 
FE 204205 or placebo. Before administration of either FE 204205 or placebo the subjects body 
weight will be assessed. Safety assessments including sampling of clinical laboratory parameters, 
assessment for vital signs, 12-lead ECG, venous blood gases including lactate, and urinary output 
will be performed at predetermined time-points (Table 6-2). Systemic and portal heamodynamics 
will be assessed by pulmonary artery and hepatic vein catheterization (for details see Part 1 Visit 2) 
at the predetermined time-points specified in Table 6-2. Blood samples for pharmacokinetic 
determination, metabolites, metabolite pattern, biomarkers, and samples for urinary biomarkers and 
excretion of FE 204205 and metabolites will be collected at predetermined time-points (Table 6-2).  
The subjects will be discharged from the clinic after the post-dose assessments (clinical laboratory 
parameters, vital signs, 12-lead ECG, body weight) on Day 2 have been performed. 
Visit 3 (Follow-up, Day 5 to Day 12) 
A follow-up visit will be performed 4-11 days after the administration, and will be considered end 
of study. At this visit a physical examination, assessment of vital signs and 12-lead ECG recording 
will be performed, pregnancy test, and samples for clinical laboratory parameters will be collected 
(Table 6-2).  
 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 42 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 6-2 
Study Flow Chart, Part 2 
Assessment 
Screening 
Treatment Period 
End of trial 
Visit No. 
Visit 1 
Visit 2 
Visit 3 
Procedures / Days 
-21 to -1 
Day -1 
Day 1 
Day 2 
Days 5-12 
Informed consent 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
Randomisation 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
Physical examination 
X 
 
 
 
X 
Medical history 
X 
X 
 
 
 
Clinical chemistry, haematology, 
urinalysis 
X 
X 
X1 
X1 
X 
Serology/virology 
X 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
Alcohol urine test 
X 
X 
 
 
 
Pregnancy test (serum) 
X 
X 
 
 
X 
12-lead ECG 
X 
X 
X2 
X2 
X 
Vital signs (non-invasive) 
X 
X 
X3 
X3 
X 
Adverse events 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
Venous blood gas including lactate 
 
X 
X4 
 
 
Administration of IMP 
 
 
X 
 
 
Blood samples for PK and metabolites 
 
 
X5 
 
 
Blood samples for metabolite pattern 
 
 
X9 
 
 
Hepatic vein and pulmonary artery 
catheterization 
 
 
X6 
 
 
Blood biomarkers 
 
 
X7 
 
 
Urine sampling for urinary output, 
urinary biomarkers and excretion of 
FE 204205 and metabolites 
 
 
X8 
 
 
Body weight 
 
 
X10 
X10 
 
1 Blood samples for safety laboratory evaluations will be collected 6 hours after start of infusion on Day 1, and in the 
morning on Day 2. 
2 ECG will be collected pre-dose and at 1, 2, 3, and 6 hours after the start of the infusion on Day 1, and in the morning 
on Day 2. 
3 Vital signs comprising systolic and diastolic arterial blood pressure (including calculation of mean arterial pressure) 
and  pulse will be assessed pre-dose, every 5 min until 30 min after start of infusion, then every 10 min until 1 hour 
after start of infusion, then every 15 min until 2.5 hours after start of infusion and therafter 3, 4, and 6 hours after start 
of infusion on Day1, and in the morning on Day 2. Temperature only pre-dose and 6 hours after start of infusion on 
Day 1.  
4 Venous blood gas including lactate will be collected 3 hours after the start of the infusion on Day 1. 
5 Blood samples for measurement of plasma concentration of FE 204205 and metabolites will be collected pre-dose and 
at 0.5, 1, 2, 2.5, 3, 4 and 5 and after the start of the infusion on Day 1. 
6 Measurement of portal haemodynamics by hepatic vein catheterization will be performed pre-dose and at 1 and 2 
hours after start of the infusion on Day 1. Pulmonary artery catheterization will be performed pre-dose and at 2 hours 
after start of infusion. 
7 Blood samples for measurement of biomarkers will be collected pre-dose and at 3 hours after the start of the infusion 
on Day 1. 
8 Urinary output, urinary biomarkers and excretion of FE 204205 and metabolites will measured pre-dose and after each 
spontaneous void up to 8 hours after start of infusion. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 43 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9Blood samples for metabolite pattern will be collected pre-dose and at 3 hours after the start of infuion on Day 1 
10Body weight will be assessed pre-dose on Day 1and and in the morning on Day 2. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 44 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7 
TRIAL ASSESSMENTS 
7.1 
Assessments Related to Endpoints 
Actual sampling times for assessments will be recorded in the eCRF. 
In the event that the infusion is stopped prior to two hours after start, all subsequent assessments 
related to endpoints should be performed as if the infusion stopped at 2 hours, i.e. PK sampling in 
Part 1 at infusion stop and 1 and 2 hours after stop, vital signs in Part 1 at infusion stop and 0.25, 
0.5, 1, 2, and 4 hours after stop, etc. 
7.1.1 
Adverse Events 
AEs will be recorded during the trial period from the obtaining the informed consent to the follow-
up visit for both Part 1 and Part 2. For further information on definitions and reporting of AEs and 
SAEs, see Section 8. 
7.1.2 
Vital Signs 
Vital signs comprising systolic and diastolic arterial blood pressure (including calculation of mean 
arterial pressure) and pulse will be assessed at screening, on Day -1, pre-dose, every 5 min until 30 
min after start of infusion, then every 10 min until 1 hour after start of infusion, then every 15 min 
until 2.5 hours after start of infusion and thereafter 3, 4, and 6 hours after start of infusion on Days 
1-3, and in the morning of Day 4 as well as at the follow-up visit in Part 1. Body temperature will 
be measured pre-dose and 6 hours after start of infusion on Days 1-3 in Part 1. 
In Part 2, vital signs will be assessed at screening, on Day -1, pre-dose, every 5 min until 30 min 
after start of infusion, then every 10 min until 1 hour after start of infusion, then every 15 min until 
2.5 hours after start of infusion and thereafter 3, 4, and 6 hours after start of infusion on Day 1, in 
the morning of Day 2, and at the follow-up visit. Body temperature will be measured pre-dose and 
6 hours after start of infusion on Day 1. 
Systolic and diastolic blood pressure will be measured after the subject has been in supine position 
for at least 5 minutes. All recordings will be performed using validated standard equipment. 
Clinically significant abnormal findings will be reported as AEs. Additional vital signs assessments 
may be collected by the Investigator for safety reasons. 
7.1.3 
ECG 
12-lead ECGs will be recorded at screening, Day -1, pre-dose and 1, 2, 3, and 6 hours after start of 
infusion of FE 204205 on Days 1-3, in the morning of Day 4, and at the follow-up visit in Part 1. 
In Part 2, 12-lead ECGs will be recorded at screening, Day -1, pre-dose and 1, 2, 3, and 6 hours 
after start of infusion on Day 1, in the morning of Day 2, and at the follow-up visit. 
The ECGs will be recorded with a validated ECG device. The parameters HR, PR interval, RR, 
QRS, QT, and QTc(F) (i.e. QT correction according to the Fridericia formula QTcF= QT/RR0.33) 
will be assessed. ECG recordings will capture at least four QRS complexes, i.e. 3 evaluable RR 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 45 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
intervals. The Investigator or a designate will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. Any occurrence of de- or re-polarisation disorders, 
arrhythmic disorders or other abnormalities will be assessed and any changes compared to the pre-
medication record will be commented. Clinically significant abnormal findings will be reported as 
AEs. Additional ECGs may be collected by the Investigator for safety reasons. 
7.1.4 
Clinical Laboratory Variables 
Clinical chemistry, and haematology 
In Part 1, blood samples for safety laboratory evaluations of clinical chemistry and haematology 
parameters (Table 7-1) will be collected at screening, on Day -1, 6 hours after start of intravenous 
infusion of FE 204205 on Days 1-3, in the morning of Day 4, and at the follow-up visit. 
In Part 2, blood samples for safety laboratory evaluations of clinical chemistry and haematology 
parameters (Table 7-1) will be collected at screening, on Day -1, 6 hours after start of intravenous 
infusion on Day 1, in the morning of Day 2, and at the follow-up visit. 
The actual sampling times will be recorded. The clinical chemistry, and haematology analyses will 
be performed locally. Clinically significant abnormal findings will be reported as AEs. 
Urinalysis 
Urine samples for safety laboratory evaluation of urinalysis parameters (Table 7-1) will in Part 1 be 
collected at screening, on Day -1, 6 hours after the start of the intravenous infusion of FE 204205 
on Days 1 to 3, in the morning of Day 4, and at follow-up. 
In Part 2, urinalysis samples will be collected at screening, on Day -1, 6 hours after the start of the 
intravenous infusion on Day 1, in the morning of Day 2, and at follow-up.  
Urinalysis will be performed locally from a sample of mid-stream urine by means of a dip-stick 
test. In case any result of the dipstick is abnormal, a new urine test will be performed. In case any 
result of the dipstick is abnormal and clinically significant, a new urine test will be performed. If 
the abnormal result is confirmed, further examination may be initiated at the discretion of the 
Investigator. Clinically significant abnormal findings will be reported as AEs.  


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 46 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Table 7-1 
Safety Laboratory Parameters 
Clinical Chemistry 
Haematology 
Urinalysis 
Alanine aminotransferase 
Haematocrit 
Protein 
Albumin 
Haemoglobin 
Glucose 
Alkaline phosphatise 
Mean cellular volume (MCV) 
Bilirubin 
Aspartate aminotransferase 
Mean corpuscular haemoglobin content (MCH) 
pH 
Glucose 
Mean corpuscular haemoglobin concentration (MCHC) 
Nitrite 
Calcium 
Platelet count 
Ketone 
Chloride 
Red blood cell count 
Urobilinogen 
Cholesterol 
Reticulocytes 
Blood 
C-reactive protein 
White blood cell count with differential count  
Leukocytes 
Creatinine 
Neutrophils, lymphocytes, eosinophils, and basophils 
Specific gravity 
Gamma-glutamyltransferase 
Monocytes, large unclassified cells 
 
Phosphate 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin 
 
 
Triglycerides 
 
 
Troponin I  
 
 
Urea (blood urea nitrogen) 
 
 
 
 
7.1.5 
Venous Blood Gases including Lactate 
Samples for analysis of blood gases (O2 and CO2) and lactate will be collected on Day -1, 3 hours 
after start of infusion on Days 1-3 in Part 1, and on Day -1 and 3 hours after start of infusion on 
Day 1 in Part 2.  
Additional samples may be collected at the discretion of the Investigator. 
7.1.6 
Urinary Output, Urinary Biomarkers and Excretion of FE 204205 and Metabolites 
In Part 1, the urinary output will be recorded pre-dose and after each spontaneous void up to 8 
hours after start of infusion on Days 1-3. The urine collected will be analysed for biomarkers (urine 
creatinine, urine sodium, and urine osmolality), and amount of FE 204025 and its metabolites (see 
Section 7.1.8). 
In Part 2, the urinary output will be recorded pre-dose and after each spontaneous void up to 8 
hours after start of infusion on Day 1. The urine collected will be analysed for biomarkers (urine 
creatinine, urine sodium, and urine osmolality), and amount of FE 204025 and its metabolites (see 
Section 7.1.8). 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 47 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.1.7 
Blood Hormones/Biomarkers  
Blood samples for measurement of biomarkers i.e. reninand aldosterone will be collected pre-dose 
and at 3 hours after start of each infusion for Part 1 and renin, aldosterone, norephinephtine, atrial 
natriuretic peptide, and brain natriuretic peptide will be collected pre-dose and at 3 hours after start 
of the infusion for Part 2. 
The analysis of the biomarkers will be performed at the University of Barcelona, Hospital Clinic. 
7.1.8 
Metabolites in Plasma and Urine 
Metabolites will be analysed in blood collected pre-dose, and at 1, 2, 3, 4, and 6 hours after the start 
of infusion on Days 1-3 in trial Part 1. In Part 2, blood for analysis of metabolites will be collected 
pre-dose, 0.5, 1, 2, 3, 4, 5 and at 6 hours after the start of infusion on Day 1. 
Blood samples for metabolite pattern will be collected pre-dose and at 3 hours after start of infusion 
on Day 1 in trial Part 2. 
Metabolite analysis will be performed for urine samples taken pre-dose and after each spontaneous 
void up to 8 hours after start of infusion on Days 1-3 (Part 1) and Day 1 (Part 2). 
The analysis of metabolites will be performed under the responsibility of the Bioanalysis 
Department, Ferring Pharmaceuticals A/S, by means of liquid chromatography coupled mass 
spectrometry (LC-MS). The analysis will be performed within EU. 
7.1.9 
Pharmacokinetics 
Blood samples for measurement of plasma concentration after the intravenous administration of 
FE 204205 will be collected pre-dose, and at 0.5, 1, 2, 3, and 4 hours after the start of infusion on 
Days 1-3 in trial Part 1. The actual sampling time will be recorded in the eCRF. 
In Part 2, samples for FE 204205 plasma concentration measurements will be collected pre-dose, 
and at 0.5, 1, 2, 2.5, 3, 4, and 5 hours after the start of infusion on Day 1. The actual sampling time 
will be recorded in the eCRF. 
7.1.10 
Systemic Haemodynamics 
In Part 1 will systemic haemodynamis be assessed by measuring blood pressure and heart rate with 
non-invasive methods at screening, on Day -1, pre-dose and, 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 hours 
after start of infusion on Days 1-3, and in the morning of Day 4 as well as at the follow-up visit (see 
Section 7.1.2). In addition, PCWP, PAP, RAP, MAP and CO will be measured by a Swan-Ganz 
catheter introduced into the pulmonary artery pre-dose, and 2 hours after start of infusion on Day 3. 
CO, MAP, and RAP will be used for calculation of SVR. 
In Part 2, blood pressure and heart rate will be measured with non-invasive methods at screening, 
on Day -1, pre-dose and, 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 hours after start of infusion on Day 1, and 
in the morning of Day 2 as well as at the follow-up visit (see Section 7.1.2). In addition, PCWP, 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 48 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
PAP, RAP, MAP and CO will be measured by a Swan-Ganz catheter introduced into the pulmonary 
artery pre-dose, and 2 hours after start of infusion on Day 1. CO, MAP, and RAP will be used for 
calculation of SVR. 
7.1.11 
Portal Haemodynamics 
Measurements of portal haemodynamics to assess FHVP, WHVP, and IVC will be performed by 
hepatic vein catheterization pre-dose and at 1 and 2 hours after start of infusion on Day 3 in Part 1 
and on Day 1 in Part 2. IVC will be measured pre-dose and at 2 hours after start of infusion only. 
All measurements will be performed at least in duplicate (the average will be used for the 
endpoint), and permanent tracing will be obtained with a multichannel recorder and adequately 
calibrated transducers. The HVPG is calculated as the difference between the WHVP and FHVP. 
Measurement of HVPG is a safe procedure and is used routinely in clinical practice in patients with 
chronic liver failure.  
7.1.12 
Body weight 
Body weight for the assessment of any effect on possible ascites will be performed in Part 1 
predose on Days 1-3 and in the morning on Day 4. In Part 2 it will be performed predose and in the 
morning on Day 2. 
7.2 
Other Assessments 
7.2.1 
Demographic and Baseline Data 
Information about gender, date of birth, body weight, height, BMI, and medical history will be 
collected at the screening visit for each subject. 
7.2.2 
Physical Examinations 
A physical examination will be performed at screening, to determine eligibility, and at the follow-
up visit for both Part 1 and Part 2. The full physical examination comprises examination of general 
appearance, central and peripheral nervous system, head and neck (including ears, eyes, nose, 
mouth and throat), cardiovascular system, respiratory system, gastrointestinal system, lymphatic 
system, urinary system, skin and musculoskeletal system. 
7.2.3 
Serology 
Determination of HIV-1 and HIV-2 antibodies, hepatitis B surface-antigen, and hepatitis C virus 
antibodies will be performed at screening for eligibility purposes.  
7.2.4 
Drug Screen and Alcohol Urine Test 
To ensure that drugs are not abused, a urine dip-stick drug screen and an alcohol urine test will be 
performed at screening, and on Day -1 in both Part 1 and Part 2. 
The drug screening will be performed from fresh mid-stream urine for the determination of 
amphetamines,  benzodiazepines, cannabinoids, cocaine, ecstasy,  opiates,  and methadone. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 49 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
7.2.5 
Pregnancy Test 
In women, serum β-hCG will be determined at screening, on Day -1 and at follow-up in both Part 1 
and Part 2, using validated standard methods. 
7.2.6 
Prior and Concomitant Medication 
Information about prior and concomitant medication will be collected for each subject throughout 
the study. 
7.3 
Drug Concentration Measurements 
Analysis of plasma and urine concentrations of FE 204205, metabolite concentrations, and 
metabolite patterns will be performed  under the responsibility of the Department of Bioanalysis at 
Ferring Pharmaceuticals A/S by means of a validated tandem mass spectrometry based (LC-
MS/MS) method. The analysis will be performed within EU. 
7.4 
Handling of Biological Samples 
A detailed description of all sample collections and shipment procedures will be included in a 
separate laboratory manual. The Sponsor or third party(ies) will store the blood samples up to 
2 years after reporting of the trial. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 50 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
8 
ADVERSE EVENTS 
8.1 
Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject 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 by the Investigator [note: pre-existing conditions diagnosed through 
assessments and examinations at the screening visit or during the screening period 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. 
Pre-treatment Adverse Event 
A pre-treatment adverse event is any untoward medical occurrence arising or observed between 
signing of informed consent and the first administration of the IMP. 
Treatment Emergent Adverse Event 
A treatment emergent adverse event is any AE 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 administration of the IMP and within the time of residual 
drug effect.  
The time of residual drug effect is the estimated period of time after the administration of the IMP, 
where the effect of the product is still considered to be present based on pharmacokinetic (PK), 
pharmacodynamic (PD) or other substance characteristics. The residual drug effect is generally 
accepted to be 5 times the terminal half-life. The terminal half-life of FE 204205 is anticipated to 
within the range of 3 hours, i.e. in this study the residual drug effect is likely to be well within the 
time to the last assessment in both Part 1 and Part 2. Since this is the first time FE 204205 is 
administered to patients with cirrhotic portal hypertension, all AEs occurring from start of infusion 
on Day 1 up to the last assessment on Day 4 in Part 1 and Day 2 in Part 2 are regarded as treatment 
emergent. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 51 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Post-treatment Emergent Adverse Events 
A post-treatment emergent adverse event is any AE occurring after the time of residual drug effect 
of the IMP, i.e. after the last assessment on Day 4 in Part1, and after Day 2 in Part 2. 
8.2 
Collection and Recording of Adverse Events 
8.2.1 
Collection of Adverse Events 
The Investigator must monitor the condition of the subject throughout the trial from the time of 
obtaining informed consent until the last visit. 
The sources of AEs cover: 
• The subject’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 subject. 
• Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities. 
• Other information relating to the subject’s health becoming known to the Investigator (e.g. 
hospitalisation). 
8.2.2 
Recording of Adverse Events 
The Investigator must record all AEs in the Adverse Event Log provided in each subject’s eCRF 
with information about: 
• AE 
• Date and time of onset (time can be omitted, if applicable) 
• Intensity 
• Causal relationship to IMP 
• Action taken to 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. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 52 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
If a subject suffers from the same AE more than once and the subject recovers in between the 
events, the AEs should be recorded separately. If an AE changes 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. However, if an AE with onset before the first IMP administration (i.e. a pre-treatment 
adverse event) changes in intensity, this must be recorded as two separate events. The initial AE 
should be recorded with outcome “not yet recovered” and the date and time of outcome is when the 
intensity changed. The second AE should be recorded with date and time of onset when the 
intensity changed. 
Note the following: A procedure is not an AE; the reason for conducting the procedure is. 
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). 
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.  
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:  
• AEs that are uncommon but are known to be strongly associated with IMP exposure. 
• AEs that are not commonly associated with IMP exposure, but the event occurs in 
association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 53 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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. 
• AEs common in the trial population, which are also anticipated to occur with some 
frequency during the course of the trial, regardless of IMP exposure. 
Action Taken to IMP 
The action taken to the IMP in response to an AE must be classified as one of the following: 
• No change (medication schedule maintained or no action taken) 
• Withdrawn 
• Interrupted 
• Dose reduced 
• Dose increased. 
Other Action Taken 
AEs requiring therapy must be treated with recognised standards of medical care to protect the 
health and well-being of the subject. 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 AE, this medication should be entered in the Concomitant 
Medication Log. 
Date and Time of Outcome 
The date and time the subject recovered or died. 
Outcome 
The outcome of an AE must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering (the event is improving) 
• Not recovered 
• Fatal. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 54 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
8.3 
Adverse Events of Special Interest 
Taking into account the pharmacological profile of FE 204205, AEs related to exaggerated 
pharmacological effects, e.g. peripheral ischemia, increased blood pressure, and decreased cardiac 
output will be closely monitored. 
8.4 
Pregnancy and Pregnancy Outcome 
If a pregnancy occurs, the subject will be withdrawn from the study and Global Pharmacovigilance 
at Ferring Pharmaceuticals informed, using an SAE Report Form. Note, that pregnancy itself is not 
an SAE. The mother and the foetus will be followed up at least until the birth of the infant and one 
month after the birth of the infant. In general, the follow-up will include the course, duration and 
the outcome of the pregnancy and the infant. If a pregnancy results in an abnormal outcome which 
the Investigator and/or Ferring consider to be related to the IMP, this outcome will be treated as an 
expedited report. 
8.5 
Serious Adverse Events 
8.5.1 
Serious Adverse Event Definition 
Serious Adverse Events during the Trial 
 
An event is defined 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 subject 
enrolled in a trial is per se not an event, but an outcome. 
is life-threatening 
The term life-threatening refers to an AE in which the subject 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 subject 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 an SAE. Hospital admissions and/or 
surgical operations planned before trial inclusion are not considered adverse 
events, if the illness or disease existed before the subject 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. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 55 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
An event is defined a serious 
adverse event if it: 
Guidance 
is a congenital anomaly/birth 
defect 
Congenital anomaly/birth defect observed in any offspring of the subject 
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 subject 
or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of important medical events include AEs 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 subject exposed to a 
medicinal product. 
8.5.2 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported immediately to Ferring Global Pharmacovigilance as soon as it 
becomes known to the Investigator and not later than within 24 hours of their knowledge of the 
occurrence of an SAE. 
The Investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE. 
The SAE Report Form is included in the eCRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the eCRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the eCRF system, a paper SAE Report Form should 
be used and sent to Ferring Global Pharmacovigilance using the contact details below. 
Global Pharmacovigilance, Ferring Pharmaceuticals A/S 
E-mail: safety.mailbox@ferring.com 
Fax: 
 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log 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. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 56 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Additional information relevant to the SAE 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, such details 
such as subject’s name, address, and hospital ID number should be concealed and instead subject 
number should be provided. 
The Investigator will supply Ferring and the IEC with any additional requested information such as 
results of post-mortem examinations and hospital records. 
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. 
SAEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol, Investigator’s Brochure and labelling. 
Expedited Reporting 
All AEs that are serious, unexpected and considered related to the IMP judged by either the 
Investigator or Ferring require expedited reporting. The expectedness is assessed by Ferring 
according to the Investigator’s Brochure. 
All available information relevant to the evaluation of the SAE will be reported. SAEs will be 
considered reportable regardless of whether or not the IMP was used in accordance with the 
provisions in the Protocol and/or the Investigator’s Brochure. AEs that are serious but expected 
(related and/or unrelated to the IMP) are subject to expedited reporting in accordance with local 
requirements. 
Timelines 
Fatal or life-threatening serious, unexpected, related cases occurring in clinical investigations 
qualify for very rapid reporting. Regulatory agencies shall be notified (e.g., by telephone, facsimile 
transmission, or in writing) as soon as possible, but no later than 7 calendar days after first 
knowledge by the Sponsor that a case qualifies for expedited reporting, followed by a report that 
must be as complete as possible within 8 additional calendar days. 
Serious cases that are unexpected and related and are not fatal or life-threatening, must be 
submitted as soon as possible but no later than 15 calendar days after first knowledge by the 
Sponsor that the case meets the minimum criteria for expedited reporting. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 57 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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 subject is stable. 
After the subject’s last visit, the Investigator must follow-up on any AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the 
medical condition of the subject 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 Last Visit in the Trial 
If an Investigator becomes aware of an SAE after the subject’s last visit, and he/she assesses the 
SAE 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. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 58 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9 
STATISTICAL METHODS 
The Global Biometrics Department of Ferring Pharmaceuticals A/S will be responsible for the 
statistical analyses. All analyses will be detailed in a separate Statistical Analysis Plan. 
The pharmacokinetic parameters specified will be computed by the Department of Experimental 
Medicine, Ferring Pharmaceuticals A/S. Analysis of PK at end of study will be performed under the 
responsibility of Global Biometrics. 
9.1 
Determination of Sample Size 
Part 1: No formal sample size calculation has been made. However, the number of patients (six) is 
considered sufficient to provide adequate information about the safety and tolerability of 
FE 204205, and thus inform about the suitable dose to evaluate in part 2. 
Part 2: Since this is the first exploratory evaluation of the efficacy of FE 204205 on reducing portal 
pressure, the sample size and power calculations were performed by evaluation of the intra-group 
difference (before and after treatment with FE 204205). Assuming, based on the literature, a 
standard deviation (SD) of relative change from baseline of 12 % (see table below), a sample size 
of 14 patients on active treatment was deemed sufficient to detect a within-group 10 % reduction in 
HVPG, with α = 0.05 and 1-β = 0.8. Taking into consideration that it occasionally can be 
technically challenging to assess HVPG, a total of 20 patients (16 on FE 204205 and 4 on placebo) 
are targeted (4:1 randomisation).  
 
 Table 9-1 SD of relative (%) and absolute change from baseline in HVPG   
Reference 
Inv Drug  
SDs of %Change in HVPG 
SDs of Change in HVPG 
(mmHg)  
Escorsell et al. (7) 
Terlipressin  
9%, 12% 
 
Abraldes et al. (8) 
Simvastatin 
9%, 12% 
 
Berzigotti et al. (9) 
NCX-1000 
(~13 %) 
2.2 mmHg* (baseline 17.1 mmHg) 
Reverter et al. (10) 
Sapropterin 
(~14 %) 
2.2 mmHg* (baseline 16.0 mmHg) 
*derived from reported mean change, samples size and p-value (two-sided paired t)  
 
 
A reasonable estimate of the SD would be 12% (also assumed by Reverter et al. (10) in their power 
calculations)  
 
9.2 
Subject Disposition 
All subjects screened and dosed in Part 1 and all subjects screened and randomised in Part 2 will be 
accounted for. All post-dosing and post-randomisation discontinuations will be summarised by time 
of, and reason for, discontinuation. The number of subjects screened but not found eligible will be 
stated in the report but otherwise not accounted for. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 59 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9.3 
Protocol Deviations 
The rating of protocol deviations will be decided on the basis of a review of the data before 
unblinding of the data and the declaration of ‘clean file’ and database lock. Major protocol 
deviation criteria will be specified in the statistical analysis plan. 
9.4 
Analysis Sets 
9.4.1 
Full Analysis Set  
The full analysis data set (FAS) comprises all subject that are dosed at least once and is analysed 
according to the actuel treatment received.  
9.4.2 
Per Protocol Analysis Set 
The per protocol (PP) analysis set comprises all dosed patients with no major protocol deviations 
and with HVPG ≥12 mmHg at baseline. For subjects encountering a major protocol deviation after 
study treatment has been initiated, data after the point at which the first deviation occurs will be 
excluded from all evaluations. Final decisions for exclusion of subjects/subject data from the PP 
analysis set will be made when a clean database is available to review ahead of database lock. The 
PP analysis set will be used for the PK analysis with the exception that specific subjects may be 
excluded if certain PK parameters cannot be estimated with sufficient precision (criteria for which 
will be further detailed in the Statistical Analysis Plan) 
9.4.3 
Safety Analysis Set 
The safety analysis set comprises all subjects that received at least one dose of IMP and is analysed 
according to the actual treatment received. 
9.5 
Trial Population 
Presentations will be based on the FAS and the PP datasets, if they are identical only the FAS 
dataset will be presented. 
9.5.1 
Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented 
separately for Part 1 and 2. For Part 2 also separately by treatment group to assess the degree of 
similarity achieved. 
9.5.2 
Medical History, Concomitant Medication and Other Safety Evaluations 
Medical history (recorded at the screening visit) will be coded using the latest version of the 
MedDRA. Prior and concomitant medication will be summarised by ATC classification 1st level 
(alphabetically), ATC classification 2nd level (in decreasing order of frequency). 
Concomitant medication and relevant medical history will be presented by descriptive statistics, by 
part and treatment. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 60 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
9.6 
Endpoint Assessments 
Endpoint assessment will be based on the FAS data set and the PP dataset. 
9.6.1 
General Considerations 
All endpoints (see Section 9.6.2) will be analysed using descriptive statistics, In general, the data 
will be presented by dose level and time point in part 1 and by treatment group and time point in 
Part 2. 
Inferential analyses on change and relative change from baseline in systemic and portal 
haemodynamic variables from Part 2 of the study will be conducted by using an Analyses of 
Covariance (ANCOVA) adjusting for the respective baseline value per treatment arm and time 
point. The focussing on mean change from baseline is based on the assumption the of a negligible 
placebo effect as reported in e.g. (7,8). Nevertheless, placebo-subtracted treatment effects will also 
be inferred (despite of limited power) using ANCOVA with treatment group as an additional factor. 
9.6.2 
Endpoints 
The following endpoints, without differentiation between primary and secondary endpoints, will be 
analysed:  
• Type, frequency and intensity of adverse events (AEs) 
• Electrocardiogram (ECG) (intervals, rhythm, and morphology)  
• Clinical chemistry, haematology and urinalysis  
• Venous blood gases including lactate  
• Systemic haemodynamics: Blood pressures and heart rate by non-invasive measurements, 
pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure (PAP), right atrial 
pressure (RAP), mean arterial pressure (MAP), and cardiac output (CO) by pulmonary 
artery catheterisation. CO, MAP, and RAP will be used for calculation of the systemic 
vascular resistance (SVR) 
• Portal haemodynamics by hepatic vein catheterization: Free hepatic venous pressure 
(FHVP), wedged hepatic venous pressure (WHVP), and inferior vena cava pressure (IVC). 
WHVP and the FHVP will be used for calculation of the hepatic venous pressure gradient 
(HVPG) 
• Pharmacokinetics: AUC, AUCt, % Extrap AUC, Cmax, tmax, CL, Vz, λz, t½, MRT, Ae and 
CLR 
• Metabolites in plasma and urine 
• Blood and urinary biomarkers: Renin, aldosterone, norepinephrine, atrial natriuretic peptide 
(ANP), brain natriuretic peptide (BNP), urine creatinine, urine sodium, and urine 
osmolality. 
9.6.2.1 
Systemic and portal haemodynamics 
Supine blood pressure, pulse, and body temperature (absolute values) will be summarised by 
treatment and time point. Shift tables will be presented for changes from baseline, and will be 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 61 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
summarised by treatment. Abnormal values will be flagged in a subject listing. PCWP, PAP, RAP, 
MAP, CO, and SVR will be summarised by treatment and time point. 
9.6.2.2 
Electrocardiogram 
All ECG data (heart rate, PR interval, RR, QRS, QT/QTc) will be listed for each subject and 
summarised by treatment and time point. In addition, ECGs will be categorised as “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant” (as judged by the 
Investigator) and summarised. 
9.6.2.3 
Clinical laboratory variables 
Clinical chemistry and haematology parameters will be summarised in terms of absolute values and 
changes from baseline to each scheduled post-baseline time point. Shift tables will be presented for 
changes in category (below, within, or above the normal range) from baseline, presented by 
treatment. Urinalysis parameters will be summarised by treatment and time point. 
9.6.2.4 
Adverse events 
Adverse events (AE) will be coded according to the latest version of MedDRA. All data will be 
listed by subject. Only treatment emergent AEs will be presented in summary tables. Separate data 
listing will be provided for AEs that are defined as pre-treatment or post-treatment emergent. 
Overview of treatment emergent adverse events 
A treatment emergent AEs (TEAE) overview summary table will be presented including for each 
treatment; the number of subjects reporting an AE, the percentage of subjects with an AE, and the 
number of events reported, for the following categories:  
• 
All AEs 
• 
Severe AEs 
• 
SAEs 
• 
Adverse drug reactions 
• 
AEs leading to withdrawal 
• 
Deaths 
Adverse drug reactions (ADRs) are defined as events considered being reasonably possibly related 
to the IMP as judged by the Investigator. 
Incidence of treatment emergent adverse events 
Treatment-emergent adverse events will be summarised by MedDRA system organ class (SOC) 
and preferred term (PT). The summary will display the total number of subjects reporting an AE, 
the percentage of subjects (%) with an AE, and the number of events reported. AEs will be 
presented by SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence (based 
on total across treatments). Summary tables will be prepared for: 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 62 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
• 
All TEAEs  
• 
TEAEs by causality 
• 
TEAEs by intensity 
• 
ADRs by SOC and PT 
• 
ADRs by intensity 
Missing values will be treated as missing except for causality, intensity, seriousness, and outcome 
of an AE, at which occurrence a “worst case” approach will be taken. Thus, if causality is missing 
the AE will be regarded as related to the IMP, if the intensity is missing the intensity of the AE will 
be regarded as severe, if seriousness is missing the AE will be regarded as an SAE, and if the 
outcome is missing and no date of outcome is present the outcome is regarded as “not yet 
recovered”. 
Separate listings will be provided for SAEs, deaths, and other significant AEs, if any. 
9.6.2.5 
Venous blood gases including lactate 
Venous blood gases and lactate will be summarised by treatment and time point. 
9.6.2.6 
Urinary output 
Urinary output will be summarised for the collection interval by treatment and time point. 
9.6.2.7 
Blood and urinary biomarkers 
Urine creatinine, urine sodium, and urine osmolality) will be summarised by treatment and time 
point. 
Blood biomarkers (renin, aldosterone, norepinephrine, ANP, and BNP will be summarised by 
treatment and time point. 
9.6.2.8 
Pharmacokinetics 
The pharmacokinetic analysis will be based on the PP analysis set and performed by Department of 
Experimental Medicine, Ferring Pharmaceuticals A/S. The pharmacokinetic parameters will be 
calculated by non-compartmental analysis (NCA) using the software Phoenix WinNonlin® 
(Pharsight Corporation, U.S.A.). Actual sampling time points relative to dosing (i.e. starting time of 
dose infusion) will be used for the NCA and on the individual plots of plasma concentration versus 
time. Scheduled time points will be used in the descriptive summaries and summary plots of the 
data. Plasma concentration values below lower limit of quantification (LLOQ) and missing values 
(e.g. no blood sample collected or no value obtained at analysis) will be excluded from the NCA. 
Values below LLOQ will be represented by ‘LLOQ/2 in summary tables and plots of the data. No 
formal analysis of “outliers” is planned. 
From the plasma and urine concentration-time data of FE 204205 the following parameters will be 
estimated, if possible: AUC, AUCt, % Extrap AUC, Cmax, tmax, CL, Vz, λz, t½, MRT, Ae and CLR.  
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 63 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
Selection of data points for calculation of t½ via λz will be based on the following considerations: 
• 
AUC will be calculated by the linear trapezoidal method 
• 
The automatic range selection used in Phoenix WinNonlin® will be used to propose an 
optimal number of time points to use for the calculation of λz. 
• 
At least three samples above LLOQ obtained during the log-linear elimination phase will be 
included in the calculation of the λz. 
• 
The final selection of samples for calculation of λz will be based on visual inspection of log 
concentration-time plots of individual profiles. 
Pharmacokinetic parameters will be presented by treatment (only for subjects receiving active 
treatment) with number of measurements, number of missing data, mean, standard deviation, 
median, minimum, maximum, geometric mean, and %CV (based on untransformed data) for 
geometric mean (for AUC and Cmax). For t½, the harmonic mean will be listed instead of the 
geometric mean. For tmax the geometric mean and the CV% will be omitted. 
9.6.3 
Other assessments 
9.6.3.1 
Physical examinations 
Physical examination at each scheduled visit will be listed by subject. 
9.7 
Extent of Exposure and Treatment Compliance 
Treatment compliance in terms of numbers of subjects that were dosed within each treatment 
regimen and the dose received will be presented for the PP and safety analysis sets. 
9.8 
Interim Analyses 
No interim analysis is planned. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 64 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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, subjects’ 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, subject 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 
Any trial specific source data will be described and defined in a Source Data Agreement form 
produced for this trial. 
10.2 
Electronic Case Report Form (eCRF) 
An eCRF system provided by Target Health Inc. will be used for data capture. The system is fully 
validated and access at all levels to the system is granted/revoked following Ferring and vendor 
procedures, in accordance with regulatory and system requirements. 
The eCRF system and the database will be hosted at Target Health Inc. After the trial database is 
declared clean and released to the statistician, a final copy of the database will be stored at Ferring 
within the SAS Drug Development system. 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 by Target Health Inc. The pdf-files will be stored on a CD and will be 
provided to the Investigator before access to the eCRF is revoked. The Investigator will 
approve/authorise the eCRF entries for each subject with an electronic signature which equals a 
handwritten signature. The signer must log in with his or her username and password and then re-
enter this password on the page(s) requiring a signature. The data will be entered into the sytem in a 
timely manner. 
Entry errors occurring in the eCRF will be corrected electronically. Such corrections/modifications 
will be automatically tracked by an audit trail detailing the date and time of the correction and the 
name of the person making the correction. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 65 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
10.3 
Data Management  
All data management activities will be specified in a Data Management Plan prepared under the 
responsibility of the Global Biometrics Department, Ferring Pharmaceuticals A/S. 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. Alla data management 
will be performed by Target Health Inc. under the responsibility of the Global Biometrics 
Department, Ferring Pharmaceuticals A/S. A study database will be created according to the data 
management standard operating procedures and data validation programmes will be developed to 
check for data completion and validity. 
Laboratory datawill be  transferred electronically to Target Health Inc. for inclusion in the study 
database according to laboratory data transfer specifications to be agreed between the individual 
laboratories and Target Health Inc. For medical coding of AEs, medical history, and concomitant 
medication the most recent versions of MedDRA and WHO Drug will be used. The coding will be 
performed by Ferring Pharmaceuticals A/S. When all data have been processed, queried resolved, 
medical coding completed and any issues from review of protocol deviations and data listings 
resolved, the database will be locked and any further update will be denied. A final quality 
assurance audit of the locked database will take place prior to transfer of the final database structure 
according to Ferring’s data transfer specifications. 
10.4 
Provision of Additional Information 
On request, the Investigator will provide Ferring with additional data relating to the trial, or copies 
of relevant source records, duly anonymised and protected in accordance with applicable 
requirements. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 66 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
11 
MONITORING PROCEDURES 
11.1 
Periodic Monitoring 
The Monitor will contact and visit the Investigator 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 Investigator will permit the 
Monitor direct access to all source data, including electronic medical records, and/or documents in 
order to facilitate data verification. The Investigator will co-operate with the Monitor to ensure that 
any discrepancies that may be identified are resolved. The Investigator is expected to be able to 
meet the Monitor during these visits. When the first subject is randomised at the trial site a 
monitoring visit will take place shortly afterwards.  
11.2 
Audit and Inspection 
The Investigator 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 inspectors or 
representatives from IECs 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 subjects must be informed by the Investigator and in the Informed Consent Documents that 
authorised Ferring representatives and representatives from Regulatory Authorities and IECs 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 Investigator should notify Ferring without any delay of any inspection by a Regulatory 
Authority or IEC. 
11.3 
Confidentiality of Subject Data 
The Investigator will ensure that the confidentiality of the subjects’ data will be preserved. In the 
eCRF or any other documents submitted to Ferring, the subjects 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 subject identification code 
and the signed Informed Consent Documents, will be maintained by the Investigator in strict 
confidence. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 67 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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 Investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IEC and Regulatory Authorities, in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to trial subjects may be 
implemented prior to IEC approval/favourable opinion. 
12.2 
Deviations from the Protocol 
If deviations from the protocol occur, the Investigator must inform the Monitor, and the 
implications of the deviation must be reviewed and discussed. Any deviation must be documented, 
either as 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 Investigator (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 Investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory Authorities and IEC will be informed. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 68 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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 Investigator.  
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 Investigator 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 
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the Investigator(s) offered authorship and Ferring.  
Authorship is granted based on the ICMJE criteria (see current official version: 
http/www.ICMJE.org). The total number of authors is based on the guideline from the relevant 
journal or congress. In the event of any disagreement in the content of a publication, both the 
Investigator’s and Ferring’s opinion will be fairly and sufficiently represented in the publication. 
Any external Contract Research Organisation or laboratory involved in the conduct of this trial has 
no publication rights regarding this trial. 
13.3.2 
Public Disclosure Policy  
It is the responsibility of Ferring to register the trial in appropriate public registry/registries 
according to applicable regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 69 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
14 
ETHICAL AND REGULATORY ASPECTS 
14.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
An IEC will review the protocol and any amendments and advertisements used for recruitment. The 
IEC will review the Subject Information Sheet and the Informed Consent form, their updates (if 
any), and any written materials given to the subjects. A list of all IECs to which the protocol has 
been submitted and the name of the committee chairmen will be included in the Clinical Trial 
Report. 
14.2 
Regulatory Authority(ies) 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 subject is 
exposed to any trial-related procedure, including screening tests for eligibility. 
14.3 
End-of-Trial and End-of-Trial Notification 
At the end of trial, the sponsor will notify the appropriate Regulatory Authority and IEC about the 
study completion. End of trial is defined as last subject last visit. In addition, a clinical summary 
report will be provided within one year of trial completion.  
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, in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements. 
14.5 
Subject Information and Consent 
The Investigator (or the person delegated by the Investigator) will obtain a freely given written 
consent from each subject after an appropriate explanation of the aims, methods, anticipated 
benefits, potential risks, and any other aspects of the trial which are relevant to the subject’s 
decision to participate. The trial subject must be given ample time to consider participation in the 
trial, before the consent is obtained. The Informed Consent Documents must be signed and dated by 
the subject and the Investigator who has provided information to the subject regarding the trial 
before the subject is exposed to any trial-related procedure, including screening tests for eligibility. 
The Investigator (or the person delegated by the Investigator) will explain that the subject is 
completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for his/her further care and without the need to justify his/her decision. 
The subject will receive a copy of the Subject Information and his/her signed Informed Consent 
form. 
If new information becomes available that may be relevant to the trial subject’s willingness to 
continue participation in the trial, a new Subject Information and Informed Consent form will be 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 70 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
forwarded to the IEC (and Regulatory Authorities, if required). The trial subjects will be informed 
about this new information and re-consent will be obtained. 
14.6 
Subject Participation Card 
The subject will be provided with a Subject Participation Card bearing the following information: 
• That he/she is participating in a clinical trial. 
• That he/she is treated with FE 2014205 (note: in case of a blinded trial, treatment allocation 
must not be revealed on the Subject Participation Card). 
• The name and phone number of the Investigator. 
• The name, address and phone number of Ferring (as required by local regulations). 
The subject will be asked to keep the Subject Participation Card in their possession at all times 
during the trial and to return it  at the last trial visit, if applicable. 
Additionally, each subject’s primary care physician will be notified of their participation in the trial 
by the Investigator, if the subject agrees and if applicable. 
14.7 
Compliance Reference Documents 
The Declaration of Helsinki, the consolidated ICH-GCP, the EU Clinical Trials Directive and other 
national law(s) in the country where the trial takes place shall constitute the main reference 
guidelines for ethical and regulatory conduct. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 71 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
15 
LIABILITIES AND INSURANCE 
15.1 
ICH-GCP Responsibilities 
The responsibilities of Ferring, the Monitor and the Investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial takes 
place. The Investigator is 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 subject in association with the IMP or the 
participation in the trial, Ferring has contracted an insurance which covers the liability of Ferring, 
the Investigator and other persons involved in the trial in accordance with applicable laws and 
regulations. 
 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 72 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
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 25 years 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 subject 
identification code which provides the sole link between named subject source records and 
anonymous eCRF data for Ferring. The Investigator must arrange for the retention of this Subject 
Identification Log and signed Informed Consent Documents for at least 25 years 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. 


Date: 17 Jan 2017 
E-Study Protocol-19790; Ver.4.0 
Supersedes: 3.0 
Page 73 of 73 
 
 
FE 204205 
Trial Code: 000249  
Sterile Solution - 10 mg,ml  
Clinical Trial Protocol 
Ferring Pharmaceuticals 
CONFIDENTIAL 
17 
REFERENCES 
1 
Tsochatzis E, Bosch J, Burroughs A. Liver cirrhosis. Lancet. 2014; 383:1749-1761. 
2 
Moller S, Henriksen JH, Bendtsen F. Extrahepatic complications to cirrhosis and portal 
hypertension: Haemodynamic and homeostatic aspects. Word J. Gastroenterol. 2014; 
20:15499-15517. 
3 
Gines P, Fernandez J, Durand F, Saliba F. Management of critically-ill cirrhotic patients. J. 
Hepatol. 2012; 56:Suppl 1:S13-24. 
4 
Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, Marinelli M, Solá E, 
Baccaro ME, Terra C, Arroyo V, Ginès P. Predictors of response to therapy with terlipressin 
and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology. 2010; 
51:219-226. 
5 
Fimiani B, Guardia DD, Puoti C, D Ádamo G, Cioffi O, Pagano A, Tagliamonte MR, Izzi 
A. The use of terlipressin in cirrhotic patients with refractory ascites and normal renal 
function: a multicentric study. Eur. J Int. Med. 2011; 22:587-590. 
6 
FE 204205 Investigator’s Brochure Edition 4 
7 
Escorsell ÀA, Bandi JC, Moitinho E, Feu F, Garcia-PagánPagan JC, Bosch J, Rodées J. 
J.Time profile of haemodynamic effects of terlipressin in portal hypertension.J. Hepatol. 
1997; 26: 621-627. 
8 
Abraldes JG, Albillos A, Bañnares R, Turnes J, Gonzáalesz R, Garcia-PagánPagan JC, 
Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal 
hypertension: A randomized controlled trial.GGastroenterology. 2009; 136: 1651-1658. 
9 
Berzigotti A, Bellot P, Gottardi AD, Garcia-Pagán JC, Gagnon C,Spénard J, Bosch J. NCX-
1000, a nitric oxide-Releasing derivative of UDCA, does not decrease portal pressure in 
patients with cirrhosis: Results of a randomized, double-blind, dose-escalating study. Am. J. 
Gastroenterol 2010; 105:1094-1101. 
10 
Reverter E, Mesonero F, Seijo S, Martinez J, Abraldes JG, Penãs B, Berzigotti A, Deulofeu 
R, Bosch J, Albillos A,Garcia-Peán JC. Effects of sapropterin on portal and systemic 
hemodynamics in patients with cirrhosis and portal hypertension: A bicentric double-blind 
placbo-controlled study. Am. J. Gastroenterol 2015; 110:985-992.