Clinical trial NCT02802228
Conditions: Portal Hypertension Liver Cirrhosis
Sponsor: Cumberland Pharmaceuticals
Start date: 2017-03-06; Completion date: 2018-07-17
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This placebo-controlled study will assess the safety and efficacy of a 90-day course of treatment with ifetroban for portal hypertension in cirrhotic patients

Detailed description:

Arms: arm 1: 90 day course of oral ifetroban following intravenous loading dose arm 2: 90 day course of placebo following intravenous dose of 5% dextrose in water (D5W)
Interventions: intervention 1: Ifetroban intervention 2: Placebo
Intervention descriptions: intervention 1: thromboxane prostanoid receptor antagonist delivered as infusion and oral capsule intervention 2: matched placebo delivered as infusion and oral capsule

Protocol documents:
Prot_SAP_000.pdf: 
IND 125794 
5.3.5.1 Clinical Study Protocol  
Cumberland Pharmaceuticals Inc. 
Ifetroban Injection and Capsules 
CPI_IFE-005; Protocol Amendment 02_24Jul2017 
 
Page 1 
 
CLINICAL STUDY PROTOCOL 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT 
STUDY TO ASSESS THE SAFETY AND EFFICACY OF IFETROBAN FOR 
THE TREATMENT OF PORTAL HYPERTENSION IN CIRRHOTIC 
PATIENTS 
 
Study Number: CPI-IFE-005 
 
 
Protocol Version 
 
Version Number:  
Amendment 02 
Final:  
 
24 JULY 2017  
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you which is 
indicated as privileged or confidential. 
 
 
 
RESPONSIBLE PERSONNEL 


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Sponsor - Medically Responsible Person 
 Sponsor’s Coordinating Office 
 
  
Todd Rice, MD 
 Leo Pavliv, R.Ph 
Director, Medical Affairs 
 Executive 
VP, 
Operations 
and 
Chief 
Development Officer 
Cumberland Pharmaceuticals Inc. 
 Cumberland Pharmaceuticals Inc. 
2525 West End Avenue, Suite 950 
 2525 West End Avenue, Suite 950 
Nashville, TN 37203 
 Nashville, TN 37203 
USA 
 USA 
 
  
Tel.: 
615-255-0068  
 Tel.: 
615-255-0068  
Fax.: 866-438-2372 
 Fax.: 866-438-2372 
 
 lpavliv@cumberlandpharma.com 
 
  
 
  
Sponsor’s Clinical Operations  
 Coordinating Investigator 
 
  
Jerry Fox, DVM 
 Don Rockey, MD 
Manager, Clinical Affairs 
 Professor and Chairman, Department of 
Medicine 
Cumberland Pharmaceuticals Inc. 
 Medical University of South Carolina 
2525 West End Avenue, Suite 950 
 96 Jonathan Lucas Street 
Nashville, TN 37203 
 Suite 803, MSC 623 
USA 
 Charleston, SC 29425 
 
 Telephone: 843-792-1020 
Tel.: 
615-255-0068  
 rockey@musc.edu 
Fax.: 866-438-2372 
  
jfox@cumberlandpharma.com 
  
 
  
 
 
 


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Ifetroban Injection and Capsules 
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1 
INVESTIGATOR’S STATEMENT 
I have read and agree to Amendment 02, dated 24Jul2017, of Protocol CPI-IFE-005, “A 
randomized, double-blind, placebo-controlled pilot study to assess the safety and efficacy of 
ifetroban for the treatment of portal hypertension in cirrhotic patients”. I am aware of my 
responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP), local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to these 
guidelines and to appropriately direct and assist the staff under my control, who will be involved 
in the study. 
 
Principal Investigator 
Signature: 
 
 
 
 
 
 
<<name>> 
 
Date of Signature 
 
<<address>> 
 
 
 
 
<<phone>> 
 
Sponsor Signature 
Signature: 
 
 
 
 
 
 
Todd Rice, MD 
 
Date of Signature 
 
Director, Medical Affairs  
 
 
Signature: 
 
 
 
 
 
 
Leo Pavliv, R.Ph 
 
Date of Signature 
 
Executive Vice President, Operations & Chief Development Officer 


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Ifetroban Injection and Capsules 
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SYNOPSIS 
Name of Sponsor: 
Cumberland Pharmaceuticals 
Inc. 
Finished Product: 
Ifetroban Sodium Injection and  
Oral Capsule 
Active Ingredient: 
Ifetroban Sodium 
Title of Study: A randomized, double-blind, placebo-controlled pilot study to assess the safety 
and efficacy of ifetroban for the treatment of portal hypertension in cirrhotic patients 
Coordinating Center: Medical University of South Carolina 
Expected Study Duration: 12 months 
Phase of Development: II 
Objectives: 
To evaluate the following in cirrhotic patients with portal hypertension that are treated with 
ifetroban: 
 Safety 
 Portal pressure 
 Serum liver enzymes 
 Surrogate markers of liver fibrosis and inflammation 
 Occurrence of variceal bleeds 
Methodology: This is a multicenter, double-blind randomized study to evaluate the efficacy and 
safety of ifetroban treatment in patients with cirrhosis.  
Number of subjects (planned): Thirty patients: 20 assigned to ifetroban; 10 on placebo 


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Diagnosis and main criteria for inclusion: 
1. Cirrhosis defined by histology or historical mean HVPG > 7 mm Hg, or confirmed by 
liver stiffness measurement (LSM) above diagnostic threshold (15 kPa for Vibration 
Controlled Transient Elastography (VCTE) or 6.7 kPa for Magnetic Resonance 
Elastography (MRE) AND evidence of splenomegaly or collaterals OR platelet count 
below 150 x 103 with AST>ALT  
2. At least two stable baseline values for AST, ALT, ALP and bilirubin taken at screening 
and between 15 and 90 days prior.  Stable is defined as values having a difference < 40 
U/L for AST and ALT, < 60 U/L for ALP and < 3.0 mg/dL for total serum bilirubin  
3. Baseline mean hepatic venous pressure gradient between 8 and 18 mmHg, inclusive 
Main criteria for exclusion:  
4. Less than 18 or more than 70 years of age 
5. Portal or splenic thrombosis 
6. Transjugular intrahepatic shunt (TIPS) 
7. Active GI/variceal hemorrhage within the last 60 days 
8. Hemodialysis 
9. Child-Pugh score > 12, calculated within 30 days of enrollment 
10. MELD-Na score > 20 
11. Platelet count < 60 x 103/µL 
12. History of bleeding diathesis or risk factors based on patient or familial history, other than 
cirrhosis and its sequelae 
13. Current acute kidney injury (AKI), chronic kidney disease (CKD) or hepatorenal 
syndrome (HRS) or a baseline SCr > 2.0 mg/dL 
14. MI in the 90 days prior to enrollment 
15. Current need for endothelin receptor antagonists, somatostatin analogues or prostanoids, 
treatment for viral hepatitis, anticoagulant or antiplatelet drugs. 
Investigational Medicinal Product (IMP), dose and mode of administration: Loading IV 
infusion of 150 mg ifetroban or placebo, followed by 250 mg ifetroban or placebo taken orally 
each day for 90 days 
Duration of treatment: 90 days 
Criteria for evaluation: 
SAFETY EVALUATION 
 Incidence and severity of adverse events 
EFFICACY EVALUATION 
 Hepatic Venous Pressure Gradient  
 AST/ALT levels 
 Aspartate Aminotransferase/Platelet Ratio Index (APRI) 
 measurements of fibrosis and inflammatory biomarkers 
 incidence and severity of variceal bleeds 
Statistical methods: Statistics will be descriptive. Continuous safety and efficacy data will be 
summarized in tables comparing proportions or percentages of patients in the active treatment 
group with those of the placebo patients. Standard deviation or standard error will also be 
calculated. All treated patients will be included in the safety analysis population.  
 


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TABLE OF CONTENTS  
1 
INVESTIGATOR’S STATEMENT ............................................................................. 3 
2 
SYNOPSIS .................................................................................................................. 4 
3 
TABLE OF CONTENTS ............................................................................................. 6 
 
LIST OF TABLES ....................................................................................................... 8 
4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................. 9 
5 
INTRODUCTION ..................................................................................................... 11 
5.1 
Background Information ....................................................................................... 11 
5.2 
Stage of Development ........................................................................................... 12 
5.3 
Patient Population .................................................................................................. 12 
5.4 
Trial Rationale ....................................................................................................... 12 
5.5 
Risk-Benefit Assessment ....................................................................................... 12 
6 
STUDY OBJECTIVES .............................................................................................. 13 
6.1 
Study Endpoints ..................................................................................................... 13 
7 
STUDY DESCRIPTION ........................................................................................... 14 
7.1 
Study Design ......................................................................................................... 14 
7.2 
Randomization and Blinding Conditions and Methods ......................................... 14 
7.2.1 
Randomization ................................................................................................... 14 
7.2.2 
Unblinding Conditions and Procedures ............................................................. 15 
7.3 
Drugs and Dosages ................................................................................................ 15 
7.3.1 
Identification and Description of Test Agents ................................................... 15 
7.3.1.1 
Ifetroban Injection .......................................................................................... 15 
7.3.1.2 
Oral Ifetroban Capsules ................................................................................. 16 
7.3.1.3 
Oral Placebo Capsules ................................................................................... 16 
7.3.2 
IMP Preparation and Dosing Instructions .......................................................... 16 
7.3.2.1 
Ifetroban or Placebo Injection ........................................................................ 16 
7.3.2.2 
Oral Ifetroban or Placebo ............................................................................... 17 
7.3.3 
Drug Accountability Procedures ........................................................................ 18 
7.4 
Selection of Study Population ............................................................................... 19 
7.4.1 
Inclusion Criteria ............................................................................................... 19 
7.4.2 
Exclusion Criteria .............................................................................................. 19 
7.5 
Prior and Concomitant Therapy ............................................................................ 21 
7.5.1 
Excluded Medications/Procedures/Therapy ...................................................... 21 


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7.5.2 
Dietary and Fasting Requirements .................................................................... 21 
8 
EXPERIMENTAL PROCEDURES .......................................................................... 22 
8.1 
Overview – Schedule of Time and Events ............................................................ 22 
8.2 
Measurements and Evaluations ............................................................................. 24 
8.2.1 
Description of Key Study Assessments ............................................................. 24 
8.2.1.1 
Hepatic Venous Pressure Gradient (HVPG) Measurement ........................... 24 
8.2.1.2 
Platelet Function Assessment ......................................................................... 25 
8.2.1.3 
Serum Biomarkers for Fibrosis and Inflammation ........................................ 25 
8.2.1.4 
Incidence of Variceal Bleeds .......................................................................... 26 
8.2.1.5 
Safety Labs .................................................................................................... 26 
8.2.2 
Description of Screening/Baseline Period ......................................................... 27 
8.2.3 
Enrollment Confirmation and Procedures ......................................................... 28 
8.2.4 
Description of Treatment Period ....................................................................... 29 
8.2.4.1 
Day 1 .............................................................................................................. 29 
8.2.4.2 
Day 10 ............................................................................................................ 29 
8.2.4.3 
Day 45 ............................................................................................................ 30 
8.2.4.4 
Day 90 / Early withdrawal ............................................................................. 30 
8.2.4.5 
Follow-up ....................................................................................................... 31 
8.2.5 
Potential Drug-induced Liver Injury ................................................................. 31 
8.2.5.1 
Criteria for Initiating Protocol for Potential DILI Cases ............................... 31 
8.2.5.2 
Protocol for Potential DILI Cases .................................................................. 31 
9 
SUBJECT DISCONTINUATION ............................................................................. 33 
9.1 
Subject Discontinuation - General ......................................................................... 33 
9.2 
Subject Discontinuation - Protocol-specified Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................... 34 
9.3 
Procedures for Subject Discontinuation ................................................................ 34 
9.4 
Study or Site Termination ...................................................................................... 34 
10 
ADVERSE EVENTS ................................................................................................. 35 
10.1 
Definitions ............................................................................................................. 35 
10.1.1 
Adverse Event Definitions ................................................................................ 35 
10.1.2 
Adverse Event Assessment Definitions ............................................................. 37 
10.2 
Collection, Recording and Reporting of Adverse Events ...................................... 38 
10.3 
Study-Specific Guidance Pertaining to Adverse Events ....................................... 39 
10.3.1 
Variceal Bleeding ............................................................................................... 39 
10.3.2 
Cirrhosis Decompensation ................................................................................. 40 
10.3.3 
Clinical Bleeding Events ................................................................................... 40 


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10.4 
Subject or Study Discontinuation Due to Adverse Event ...................................... 40 
10.5 
Follow-up of Adverse Events ................................................................................ 41 
11 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 41 
11.1 
Sample Size Determination ................................................................................... 41 
11.2 
Subject Population(s) for Analysis ........................................................................ 41 
11.3 
Statistical Methods ................................................................................................ 42 
11.4 
Interim Analysis ..................................................................................................... 42 
12 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 42 
12.1 
Confidentiality ....................................................................................................... 42 
12.2 
Source Documents ................................................................................................. 42 
12.3 
Case Report Forms ................................................................................................ 42 
12.4 
Records Retention ................................................................................................. 43 
13 
STUDY MONITORING, AUDITING, AND INSPECTING ................................... 43 
13.1 
Study Monitoring Plan .......................................................................................... 43 
14 
ETHICAL CONSIDERATIONS ............................................................................... 43 
14.1 
Informed Consent .................................................................................................. 44 
14.2 
Protocol Compliance ............................................................................................. 44 
14.3 
Financial Disclosure .............................................................................................. 44 
14.4 
Study Files ............................................................................................................. 45 
15 
REFERENCES .......................................................................................................... 45 
16 
SUMMARY OF CHANGES ..................................................................................... 46 
 
 
LIST OF TABLES 
Table 8.1-1 
Schedule of Events ................................................................................................ 23 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation Definition 
AE 
adverse event/experience 
AERD 
aspirin exacerbated respiratory disease 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
APRI 
aspartate aminotransferase/platelet ratio 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC-ROC 
area under the curve of the receiver operator characteristics 
BUN 
blood urea nitrogen 
C 
celsius 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
cm 
centimeter 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
D5W 
5% dextrose in water 
DILI 
Drug-induced liver injury 
dL 
deciliter 
EGD 
esophagogastroduodenoscopy  
ET 
early termination 
EU 
European Union 
F 
fahrenheit 
FDA 
Food and Drug Administration 
FHVP 
free hepatic venous pressure 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 


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Abbreviation Definition 
Hg 
mercury 
HRS 
hepatorenal syndrome 
HSC 
hepatic stellate cells 
HVPG 
hepatic venous pressure gradient 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
intravenous 
kPa 
kilopascal 
LSM 
Liver stiffness measurement 
MedDRA 
medical dictionary for regulatory activities 
MELD 
model end stage liver disease 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mm Hg 
millimeter mercury 
MRE 
Magnetic Resonance Elastography 
PT-INR 
Prothrombin time – international normalized ratio 
RNA 
ribonucleic acid 
ROTEM 
rotational thromboelastometry  
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SCr 
serum creatinine 
TEG 
thromboelastography 
TIPS 
transjugular intrahepatic portosystemic shunt 
Tmax 
time to maximum concentration 
TPr 
thromboxane prostanoid receptor  
TxA2 
thromboxane A2 
US 
United States of America 
USP 
United States Pharmacopeia 
VCTE 
Vibration Controlled Transient Elastography 
WHVP 
wedged hepatic venous pressure 
 


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5 
INTRODUCTION 
This study is to be performed in accordance with Good Clinical Practice (GCP), the ethical 
principles that have their origin in the Declaration of Helsinki, Title 21 of the Code of Federal 
Regulations Parts 50, 56 and 312, and the International Conference on Harmonization E6. 
5.1 
Background Information 
Cirrhosis is a potentially life-threatening condition that occurs when the liver is damaged by 
fibrotic scarring. Fibrosis can impair the flow of portal blood through the hepatic sinusoids and 
result in hypertension in the portal vasculature. One of the major complications from portal 
hypertension is the development of gastrointestinal varices. Bleeding due to varices specifically in 
the esophagus accounts for one third of the deaths related to portal hypertension. The median 
survival period in humans following diagnosis of cirrhosis is six years (La Vecchia 1994; Pagliaro 
1994). Currently little effective therapy is commercially available for treatment of portal 
hypertension.  
In the study of portal hypertension, there is key interest in mediators such as thromboxane A2 
(TxA2), F2-isoprostanes, nitric oxide, and endothelin-1 as well as the thromboxane receptor (TPr) 
which has TxA2 and F2-isoprostanes as two of its main ligands. F2-isoprostanes have been shown 
to mediate and promote fibrosis via TPr activation in hepatic stellate cells (HSC) from rats treated 
with cirrhosis-inducing carbon tetrachloride (Acquaviva 2013). HSCs play a significant role in the 
progression of cirrhosis by increasing the amount of extracellular matrix in the hepatic 
parenchyma.   
In addition to the fibrotic processes, many of these same mediators have a more immediate effect 
on the blood flow through the hepatic sinusoids. TxA2 serves as a vasoconstrictor, while nitric 
oxide vasodilates in the healthy liver (Yokoyama 2005). However, in the cirrhotic liver, studies in 
rats have revealed an increase in the hepatic production of TxA2 which would then further increase 
portal hypertension via vasoconstriction (Graupera 2003; Rodriguez-Vilarruplas 2012).  Also, the 
compensatory feedback between TxA2 as a vasoconstrictor and nitric oxide as the inhibitory 
vasodilator seems to disappear in the cirrhotic liver (Yokoyama 2005).            
Blockade of thromboxane-mediated signaling in the TPr has revealed an anti-fibrotic effect in two 
rat models of cirrhotic disease (Rosado 2013). Additionally, interrupting this signaling pathway 
lowered portal pressure suggesting a reduction in hepatic vascular resistance.    
Clinical trials utilizing antagonists of other potent vasoconstrictors of the hepatic portal system 
(e.g. endothelin-1) have been completed with little success, suggesting that TxA2 signaling may 
be of particular importance (Tripathi 2006). Therefore, the current study is being conducted to 


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collect safety and efficacy data from the use of the TPr antagonist, ifetroban, in patients with portal 
hypertension. 
5.2 
Stage of Development  
This is a Phase II exploratory study to determine the safety of oral ifetroban compared to placebo 
in patients with portal hypertension. The efficacy of oral ifetroban compared to placebo in reducing 
portal pressure and liver fibrosis will also be explored. 
5.3 
Patient Population 
Adult patients with liver cirrhosis, confirmed by liver biopsy, laboratory features, and/or 
elastography findings will be considered for study participation. Portal pressures are measured by 
the hepatic venous pressure gradient (HVPG) method during screening. A HVPG reading greater 
than 5 mm Hg defines portal hypertension, while higher HVPG values > 10 mm Hg suggest 
patients that are at a significant risk of developing gastrointestinal varices. This study will select 
patients with a baseline mean HVPG of > 8 mm Hg as they will have significant disease 
progression to be candidates for the study of an effect to the investigational treatment.  Patients 
with baseline mean HVPG values over 18 mm Hg will be excluded as a surgical intervention may 
be indicated at this severity of disease.     
5.4 
Trial Rationale 
Antagonism of the TPr has shown beneficial results in preclinical studies of cirrhosis with portal 
hypertension. The current standard of care for treatment of portal hypertension focuses on 
management of symptoms, including mechanical hemostasis of varices, pharmacologic support 
with B-blockers and surgical relief of the increased portal pressure with the transjugular 
intrahepatic portosystemic shunt (TIPS) procedure. By antagonizing the TPr, administration of 
ifetroban may treat this condition at a more foundational level, allowing both short- and long-term 
relief of portal hypertension and cirrhosis through a reduction in vasoconstriction and fibrosis. 
The intervention will be administered in both an intravenous and an oral form. The initial dose of 
ifetroban is intravenous and a potential immediate effect due to vasodilation will be studied; 
subsequently, oral dosing will continue at home for 3 months during which time the disease will 
be further monitored.         
5.5 
Risk-Benefit Assessment 
Clinical history with the use of ifetroban in patients with cardiovascular disease or cardiac risk 
factors, and in patients with hepatorenal syndrome (HRS) or aspirin exacerbated respiratory 
disease (AERD) has not identified any major risks with ifetroban use. Adverse events seen more 


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commonly in patients receiving ifetroban compared to those in placebo arms include bradycardia 
and gastrointestinal events. The need for coronary artery bypass and coronary angioplasty 
procedures was also higher in the ifetroban treatment groups studied in cardiovascular trials. The 
mechanism of action of ifetroban (i.e. TPr antagonist resulting in inhibition of platelet aggregation) 
suggests the potential for an increased incidence of bleeding. The available clinical data have not 
demonstrated an increase in hemorrhagic events; however, subjects enrolled in ifetroban trials 
should be monitored for events such as spontaneous hemorrhage, decreased hemoglobin, and 
prolonged bleeding time.  Any hemorrhagic event occurring in this study is reported as an adverse 
event as directed in Section 10.3.  Additionally, platelet function testing is performed according to 
Section 8.2.1.2.Ifetroban has not been investigated in patients with portal hypertension, so no 
benefit is proven; however, as described above in 5.1 and 5.4, there is evidence that blocking the 
TPr may decrease portal hypertension via both acute and chronic mechanisms.            
6 
STUDY OBJECTIVES 
The exploratory objectives of this study are to evaluate the following in cirrhotic patients with 
portal hypertension that are treated with ifetroban: 
 Safety 
 Portal pressure 
 Serum liver enzymes 
 Surrogate markers of liver fibrosis and inflammation 
 Occurrence of variceal bleeds  
6.1 
Study Endpoints 
The study objectives will be assessed utilizing the following endpoints; see 8.2.1 for details of the 
assessments:  
 To evaluate the safety of ifetroban treatment in this population, the incidence and severity 
of adverse events will be compared between the ifetroban and the placebo groups.  
 To evaluate the effect of ifetroban treatment on portal pressure in this population, the 
change from baseline in the mean HVPG will be calculated at 15 minutes, 30 minutes and 
Day 90 following the completion of the first investigational medicinal product (IMP) dose 
and compared to placebo patients.     


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 To evaluate the effect of ifetroban treatment on serum liver enzymes in this population, the 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values on Day 45 
and Day 90 will be compared to baseline for ifetroban and placebo patients.   
 To evaluate the effect of ifetroban treatment on liver fibrosis and inflammation in this 
population, the change from baseline to Day 45 and Day 90 will be calculated for ifetroban 
and placebo patients in the following assessments: 
o Aspartate aminotransferase/platelet ratio (APRI) 
o Specified serum biomarkers 
 To evaluate the occurrence of variceal bleeds in this population, the incidence and severity 
of any variceal bleeds will be documented.  
7 
STUDY DESCRIPTION 
7.1 
Study Design 
 Phase II, randomized, double-blind, and placebo-controlled pilot study. 
 Thirty patients will be enrolled; twenty patients will be allocated to ifetroban and ten will 
receive placebo.   
 Each qualified subject will remain in the study for 90 days.  Enrollment for the entire study 
is expected to take twelve months.  
 A schedule of assessments is summarized in Table 8.1-1.  
7.2 
Randomization and Blinding Conditions and Methods 
7.2.1 
Randomization 
Randomization will be performed manually. The aim is to include twenty patients treated with 
ifetroban and ten patients with placebo. There is no stratification of patient sub-populations.  When 
the investigator confirms the eligibility of a subject and the intent to treat, he will advise the 
unblinded staff from his center to contact the unblinded sponsor representative. Email or phone 
correspondence is utilized and callers identify themselves with respect to their unblinded role on 
the study. The unblinded sponsor representative manually randomizes the subject, using the 
allocation list created prior to the study start, and communicates the assignment to the unblinded 
site personnel in writing (email or fax). The written records will be maintained at the site and at 
the sponsor to document the assignment for each subject.     


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7.2.2 
Unblinding Conditions and Procedures 
Breaking the blind for a subject should be considered only when knowledge of the treatment 
assignment is deemed essential by the subject’s physician for the subject’s care. Given that there 
are no antidotes for ifetroban, unblinding is not likely to lead to a change in treatment of the patient 
beyond holding or discontinuing the IMP. As such, unblinding should be a rare occurrence. 
If time permits, and if significant risk is not introduced to the patient, the investigator will contact 
the medical monitor at the sponsor to discuss the desire to unblind the treatment assignment. If 
agreement is reached that unblinding should occur, the blinded clinical monitor will mediate 
contact between the investigator and the unblinded sponsor contact, as needed, to disclose the 
treatment assignment. All discussions on this topic, including the treatment disclosure, if 
applicable, will be documented and filed in the study files.  
In emergency scenarios, the Investigator may contact the blinded clinical monitor directly who 
will then mediate communication with the unblinded sponsor contact.     
Any intentional or unintentional breaking of the blind at an investigative site must be reported to 
the Sponsor immediately.  
7.3 
Drugs and Dosages 
7.3.1 
Identification and Description of Test Agents 
7.3.1.1 
Ifetroban Injection 
Ifetroban injection is available for investigational use only. Ifetroban injection is packaged as a 
clear, colorless to light yellow liquid in 5 mL glass vials, each containing 50 mg ifetroban in a total 
volume of 5 mL (10 mg/mL). Ifetroban injection contains the following inactive ingredients: 
mono- and dibasic sodium phosphate, sodium chloride, and Sterile Water for Injection, United 
States Pharmacopeia (USP). 5% dextrose in water (D5W), which will be supplied by each site, 
will be used as the diluent for this study. 
The investigational labels on the ifetroban injection appear as follows: 
 
  
 
 
Ifetroban injection, 50 mg (10 mg/mL) 
Lot number: 1-FIN-1122    Volume: 5 mL 
Store at room temperature. 
Instructions: Use as directed. 
Caution: New Drug—Limited by United States Law to Investigational Use 
Cumberland Pharmaceuticals Inc., Nashville, TN 37203 


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7.3.1.2 
Oral Ifetroban Capsules 
Oral ifetroban is supplied as a capsule dosage form (size # 1, white opaque) for oral administration. 
The formulation consists of ifetroban, mannitol, microcrystalline cellulose, crospovidone, 
magnesium oxide, colloidal silicon dioxide, and magnesium stearate.  Capsules are filled into high 
density polyethylene bottles and sealed with screw-cap closures.  Capsules are only available at 
one strength of the sodium salt, i.e. 52.5 mg corresponding to a free-acid dose of 50 mg.  
7.3.1.3 
Oral Placebo Capsules 
Matching placebo capsules consist of microcrystalline cellulose, crospovidone, colloidal silicon 
dioxide, and magnesium stearate filled into size # 1, white opaque capsules. Capsules are filled 
into high density polyethylene bottles and sealed with screw-cap closures. 
The bottles of oral Ifetroban or placebo will contain the following information on the label:  
 
 
 
 
 
 
 
Additionally, each individual bottle will be labelled with a unique numeric code that identifies the 
contents to the unblinded sponsor representative.   
7.3.2 
IMP Preparation and Dosing Instructions 
Personnel at the site must be identified and documented by the Investigator as blinded or unblinded 
staff. A site-specific written process describing how the blind will be maintained during the 
preparation, administration and dispensing of IMP should be utilized. 
7.3.2.1 
Ifetroban or Placebo Injection 
As described in 8.2.3, the ifetroban or placebo injection will be prepared by the unblinded 
pharmacy based on the “provisional eligibility confirmation” of a new subject. If the subject is not 
ultimately confirmed as eligible, the prepared IMP will be discarded by the pharmacist and the 
process documented.  
PLACEBO OR IFETROBAN CAPSULES 50MG 
Quantity: 75 Capsules 
Instruction: Take capsules by mouth as directed. 
Store at controlled room temperature, 20oC – 25oC (68oF – 77oF) 
Caution: New Drug-Limited by Federal law to investigational use 
Cumberland Pharmaceuticals Inc. 


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 Enrolled subjects are to receive an initial intravenous infusion of IMP on Day 1, to be infused over 
15 minutes. The infusion is composed of 100 mL of 5% Dextrose in sterile water (D5W) for 
subjects assigned to placebo, or 150 mg (15 mL) of ifetroban diluted in 85 mL of D5W for ifetroban 
subjects. The ifetroban infusion is formulated by aseptically transferring a total of 15 mL of 
ifetroban injection from three 50 mg vials to a 100 mL bag of D5W after 15 mL of D5W are first 
removed and discarded. The 100 mL is infused over 15 minutes using the site’s standard processes. 
A label with the following information is adhered to the infusion bag by the unblinded pharmacist:  
 Placebo or 150 mg ifetroban injection  
 “Infuse intravenously over 15 minutes” 
 “Caution: New Drug—Limited by US Law to Investigational Use” 
Also, subject to the institution’s labeling methods for investigational medicine, it is suggested that 
the label also contain the following:  
 Subject identification number  
 Protocol number: CPI-IFE-005 
 Investigator Name  
Because ifetroban injection contains no bacteriostatic agents, vials are for single use only. Any 
unused portion of an ifetroban injection vial should be not be used for further dosing. All partially 
used vials should be retained for monitoring by the sponsor. 
Ifetroban infusion solutions should be infused as soon as practical after preparation, but no later 
than eight hours after preparation if left at room temperature. Alternatively, ifetroban infusion bags 
may be stored for up to 24 hours if stored between 2 – 8 ºC. Infusion bags should be protected 
from freezing.   
7.3.2.2 
Oral Ifetroban or Placebo   
Day 1 Dispensation 
According to the treatment assignment, the unblinded pharmacist receives individual bottle 
numbers from the unblinded sponsor representative for dispensation to the corresponding subject. 
Whereas the IMP infusion is dispensed based on “provisional eligibility confirmation” (7.3.2.1), 
oral IMP is only dispensed after eligibility is confirmed. Four bottles of placebo or ifetroban, each 
with 75 capsules (total of 300 capsules), are dispensed at Day 1.    


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The bottle identification numbers do not disclose the contents of the bottle to unblinded staff.  
Therefore, for each dispensation, the numbers are recorded in the pharmacy records and also 
provided to the blinded treatment site staff for entry into the case report form. The subject is 
directed not to throw away any empty bottles or unused capsules and to bring all bottles with them 
to subsequent visits with the Investigator.    
Day 45 Dispensation 
At the Day 45 visit, any empty bottles are returned by the subjects and two new bottles, in addition 
to unused or partially-used bottles dispensed at Day 1, are sent home with the patient dispensed 
after bottle identification numbers for the new bottles are provided to the pharmacist by the 
unblinded sponsor contact. An additional new bottle may be dispensed in cases where the 
Investigator believes the quantity may be necessary to complete treatment through the final study 
visit. Bottle identification numbers for each dispensation are recorded in the unblinded pharmacy 
records. The subject is instructed to continue the same dosing regimen through Day 90.   
Dosing Instructions  
The subject is prescribed to begin taking their oral dose on Day 2, the day following their 
intravenous dose. Ifetroban and placebo should be taken at least 30 minutes before a meal or 6 
hours after a meal. Therefore, it is advisable to recommend the subject dose themselves each day 
soon after waking up.   
All subjects are to take five capsules once daily throughout the 90-day treatment period.  All 
capsules are taken in the same episode. In a double-blinded manner, ifetroban subjects will take 
five capsules of 50 mg ifetroban daily; placebo subjects will take five capsules of matched placebo 
per day. 
7.3.3 
Drug Accountability Procedures 
Ifetroban and placebo labeled for investigational use will be provided without charge by 
Cumberland Pharmaceuticals Inc. The investigator is required to keep complete and accurate 
records of the receipt, dispensation, disposal and return of all clinical trial drugs provided during 
the conduct of the study. Cumberland Pharmaceuticals will ensure maintenance of complete and 
accurate records of the receipt, dispensation, disposal or return of all trial drugs. 
Additional details regarding the monitoring of drug accountability and patient compliance with at-
home dosing is covered in 8.2.4.  


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7.4 
Selection of Study Population 
Determination of study eligibility will be made by the Investigator on the basis of the inclusion 
and exclusion criteria listed below. 
7.4.1 
Inclusion Criteria 
To be considered eligible to participate in this study, a patient must meet the following inclusions 
criteria: 
1) Adults with cirrhosis, defined as meeting at least one of the following:   
a) Histopathological diagnosis of liver cirrhosis 
b) Historical HVPG value > 7 mm Hg 
c) Liver stiffness measurement (LSM) greater than 
 15 kPa, if measured by Vibration Controlled Transient Elastography (VCTE), or 
 6.7 kPa, if measured by Magnetic Resonance Elastography (MRE) with at least one of 
the two following criteria:  
i) Evidence of splenomegaly or collateral portal-venous anastomoses on imaging or 
endoscopy without portal vein thrombosis 
ii) Platelet count below 150 x 103/µL and AST value greater than ALT  
 
2) At least two stable baseline values for each of the following variables: AST, ALT, ALP and 
bilirubin.  One value will be from the study screening period, and the other value(s) taken 
between 15 and 90 days prior to the screening labs.   Stable is defined as values having a 
difference < 40 U/L for AST and ALT, < 60 U/L for ALP and < 3.0 mg/dL for total serum 
bilirubin  
3) Baseline mean HVPG measurement > 8 and < 18 mm Hg 
7.4.2 
Exclusion Criteria 
To be considered eligible to participate in this study, a patient must not meet any of the following 
exclusion criteria: 
1. Be less than 18 years of age or greater than 70 years of age. 
2. Be pregnant, nursing, or planning to become pregnant. 
3. Have portal or splenic vein thrombosis.  Patients with portal or splenic vein thrombosis in 
their history may participate if there is more recent confirmation that there is no occlusion 
or that no thrombosis is detectable.    


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4. Previous transjugular intrahepatic shunt (TIPS) or portocaval shunt. 
5. Variceal or other gastrointestinal bleed in the two months prior to enrollment. 
6. Current or scheduled hemodialysis. 
7. Most recent Child-Pugh Score > 12, within 30 days of enrollment. 
8. Most recent MELD-Na score > 20, within 30 days of enrollment.  
9. Current acute kidney injury, chronic kidney disease, or most-recent baseline serum 
creatinine > 2.0 mg/dL.  
10. Active alcohol consumption (greater than an average of two drinks per day). 
11. Active hepatitis B virus (HBV) or hepatitis C (HCV) infection; current treatment, except 
suppression treatment for HBV, or plans to initiate treatment for HBV or HCV during study 
involvement; or eradication of HCV within previous 3 months.  
12. Platelet count < 60 x 103/µL 
13. Confirmed or suspected diagnoses of Vitamin A toxicity, extramedullary hematopoiesis, or 
Budd Chiari Syndrome. 
14. Use of endothelin receptor antagonists, somatostatin analogues or prostanoids in the last 
seven days or planned use during the study. 
15. Myocardial infarction in the 90 days prior to enrollment. 
16. History of bleeding diathesis OR any risk factors for bleeding based on patient or familial 
history, other than cirrhosis and its sequelae, or use of anticoagulant or antiplatelet drugs, 
including aspirin, in the last 14 days or planned use during the study. 
17. History of allergy or hypersensitivity to ifetroban. 
18. Have taken investigational drugs within 30 days before IMP administration. 
19. Inability to understand the requirements of the study, spoken English, or the need to abide 
by the study restrictions and to return for the required treatments and assessments. 
20. Be otherwise unsuitable for the study, in the opinion of the investigator. 


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7.5 
Prior and Concomitant Therapy 
Patients may enter the study while on a beta blocker but the patient must be on a stable dose for at 
least 30 days prior to enrollment, and the dose may not be altered or stopped during the Treatment 
Period. Beta-blocker-naïve patients may not initiate beta blocker therapy during the Treatment 
Period. 
Drugs from the statin class are allowed if the patient has been on a stable dose for three months 
and will continue on that dose throughout the study.   
7.5.1 
Excluded Medications/Procedures/Therapy 
Some concomitant medications are prohibited during study involvement as detailed below. As 
applicable, some medications must undergo a sufficient wash-out period before a subject can begin 
study treatment. 
The following drugs are not allowed to be taken between Day -14 and the end of study treatment:  
 Aspirin, other anti-platelet drugs, and anticoagulants  
The following drugs are not allowed to be taken between Day -7 and the end of study treatment: 
 Endothelin receptor antagonists, somatostatin analogues and prostanoids 
 Drugs from the nitrate class 
 Treatment protocols for HBV or HCV 
7.5.2 
Dietary and Fasting Requirements 
Food effect studies have demonstrated that high fat, protein or carbohydrate meals all have a 
similar effect of decreasing the maximum serum concentration (Cmax) (average of 80-90%), 
prolonging the time of maximum plasma concentration (Tmax) (8-12 fold), and decreasing the area 
under the concentration time-curves from time zero to infinity (AUC0-∞) of oral ifetroban (average 
of 25-35%) compared to the fasting state.  
For this study, ifetroban and placebo for ifetroban capsule should be taken at least 30 minutes 
before a meal or six hours after a meal.   


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8 
EXPERIMENTAL PROCEDURES 
8.1 
Overview – Schedule of Time and Events 
The study consists of a 14-day screening period, a 90-day treatment period where blinded 
investigational treatment is given as an initial intravenous (IV) dose, then daily doses of oral IMP. 
A 7-day follow-up completes the study. The schedule of events for the study, including allowable 
time windows appears in Table 8.1-1 below.  


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Table 8.1-1 
Schedule of Events 
Study Phase 
Screening 
Baseline 
Day 1 
Day 10 
Day 45 
Day 90 /  
Early Term 
Follow-up 
Allowable Windows 
Day -14 
to 
Hour 0 
Hour -6 
to 
Hour 0
 
+/- 3 
days 
+/- 5 
days 
From -5 to 
+0 days 
(Day 85-90)
6 to 8 days 
following Day 
90/ET visit
Demographic Data 
X 
 
 
 
 
 
 
Medical History 
X 
 
Review of 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
Pregnancy Test 
X 
 
Physical Exam 
X 
X
X
X
Hepatic Venous Pressure 
Gradient Measurements 
 
X 
- 15 minutes following start of IMP  
- 30 minutes following start of IMP     
 
 
X 
 
Serum Biomarker Sample 
Collection 
X 
 
 
 
X 
X 
 
Safety Labs 
X* 
X
X
X
Platelet Function Testing 
X 
 
 
X 
Repeat testing in cases of clinical 
bleeding events (Section 8.2.1.2)
HBV and/or HCV testing, 
if needed  
X 
 
 
 
 
 
 
VCTE, if needed  
X 
Vital Signs 
 
X 
after IV IMP completion 
X 
X 
X 
 
IMP dosing – intravenous 
 
Start of IV dose defines Hour 0 
 
IMP dosing - oral 
 
 
Once daily oral IMP dosing begins on Study Day 2 and continues 
through Day 90
 
Review of Drug 
Accountability 
 
 
 
X 
X 
X 
 
Con Med monitoring 
Continual 
 
Adverse Event monitoring 
 
 
Continual 
Phone Call 
* Per Inclusion Criterion #2, if historical ALT, AST, ALKP, and bilirubin are not available from between 15- and 90-days prior to the safety labs drawn during screening, an initial set of labs, reporting 
ALT, AST, ALKP, and bilirubin, will be required by the study prior to screening but following the subject’s consent.  In such a case, full safety labs per 8.2.1.5 will be assessed 15-90 days later during 
the 14-day screening window shown above.


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8.2 
Measurements and Evaluations 
8.2.1 
Description of Key Study Assessments 
8.2.1.1 
Hepatic Venous Pressure Gradient (HVPG) Measurement  
A recorder capable of generating permanent tracings (paper and/or electronic) must be used for 
this study. Following standard medical process regarding sedation, aseptic preparation of the 
venous access site and catheter care, initial venous access is established through a route and method 
chosen by the Investigator or qualified designee. Ultimately, a balloon-tipped catheter is placed in 
the main right hepatic vein under fluoroscopic guidance until the tip is approximately 5 cm from 
the vena cava. The succeeding steps are then followed to record the hepatic venous pressure 
gradient:  
1. The balloon is inflated and dye is injected to confirm complete occlusion of the catheterized 
vein. Dye that circumvents the balloon or is shunted to other venous return will require the 
catheter to be repositioned.   
2. The inflated catheter is left in place for approximately 45 seconds while pressure is 
recorded and stabilized [wedged hepatic venous pressure (WHVP)]. 
3. The balloon is completely deflated and the catheter is retrieved proximally until the tip is 
approximately 2 cm from the vena cava.  
4. Pressure recordings continue for approximately 45 seconds [free hepatic venous pressure 
(FHVP)]. 
5. After 1 minute, the catheter is advanced distally to its original position and the balloon 
inflated.  
6. Steps 2-4 are repeated at least two additional times.   
7. The hepatic venous pressure gradient is measured as the difference between the stable 
WHVP reading and the subsequent stable FHVP reading. At the Baseline and Day 90 time 
points, pressure gradients will be recorded until three HVPG values are all within 1 mm 
Hg of each other. .  For the +15 and +30 minute recordings, there will not be sufficient time 
to repeat more than three readings, so the initial three individual HVPG values will be 
accepted.   
The three  valid HVPG values, plus the mean, are recorded in the study case report form for each 
time point.   


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8.2.1.2 
Platelet Function Assessment 
Platelet function will be measured during screening and at Day 10 by rotational 
thromboelastometry (ROTEM) in study centers that have the ability to perform ROTEM.  In other 
centers, thromboelastography (TEG) will be utilized for the same purpose.  A citrated blood sample 
is drawn from all patients and the center’s laboratory standard procedures are followed.  At a 
minimum, the maximum amplitude (or maximum clot firmness) of the clot profile is measured to 
assess platelet function; however, other values reflecting clotting time, clot formation time, 
fibrinolysis, etc. will be collected in the case report.  
During the treatment or follow-up period, in any subject that exhibits a clinical bleed, as directed 
in protocol Section 10.3, a repeat ROTEM or TEG analysis will be performed at the initial onset 
of the bleeding episode, preferably prior to any associated treatment intervention.  The same 
technology (ROTEM or TEG) that was employed in the screening process will be used in cases of 
bleeding during the treatment phase of the study.       
8.2.1.3 
Serum Biomarkers for Fibrosis and Inflammation 
Serum will be collected from blood draws at Baseline, Day 45 and Day 90/Early-termination for 
measurement at a central laboratory of specialized biomarkers of hepatic fibrosis and 
inflammation. Approximately 10 mL of whole blood will be drawn at each time point.  
Comparative levels of many various cytokines like the interleukins, transforming growth factors, 
chemokines, and others have been correlated with the extent of fibrosis and inflammation 
confirmed on liver biopsy (Deng 2015). Therefore, the levels of key biomarkers may assist in the 
grading of liver disease or monitoring of treatment progress and avoid the risks and more-intensive 
effort behind liver biopsies. Additionally, there is evidence that other biomarkers may predict a 
patient’s HVPG and provide information about the presence or probability for varices without 
performing an esophagogastroduodenoscopy (EGD) (Buck 2014). Data showed that 86% of 
cirrhosis patients with HVPG below 12 mm Hg could be correctly identified without EGD.       
Details about the sample preparation are detailed in the laboratory manual.   
Additionally, the platelet count and AST results from the Safety Labs (8.2.1.4) at Baseline, Day 45 
and Day 90 are used to calculate the Aspartate Aminotransferase/Platelet Ratio (APRI). The APRI 
is easily calculated from readily-available lab parameters, yet is a good estimator of hepatic 
fibrosis. In a prospective study, the ability of the APRI to accurately score fibrosis in HVC patients 
compared to liver biopsy was deemed good to excellent with and area under the curve of the 
receiver operator characteristics (AUC-ROC) of 0.889 (Snyder 2006).        


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8.2.1.4 
Incidence of Variceal Bleeds 
The occurrence and details of any variceal bleeds during the treatment period will be captured in 
a dedicated module of the Case Report Form (CRF) and occurrences will be reported as endpoints 
in the study results. If the bleed meets the criteria of an adverse event, it will also be captured as 
an adverse event according to standard GCP reporting processes.   
Variceal bleeding is defined for this study as the presence of either reported or witnessed 
hematemesis, melenemesis, melena, or bright red blood per rectum and a concomitant drop in 
hemoglobin of 1 gm/dL compared to baseline and no other source of bleeding.   
Additional diagnostics, including upper gastrointestinal endoscopy, will not be ordered by the 
study protocol; however, results from any standard of care procedures should be captured in the 
study records.  
Treatment for any bleeding will be ordered at the Investigator’s discretion according to standard 
of care.   
8.2.1.5 
Safety Labs 
Blood sample collection for safety laboratory assessments will be performed within protocol-
specified time periods and according to the site’s standard practices for drawing and processing 
samples. The following analytes are measured by the site’s local laboratory and evaluated by the 
investigator with respect to reference ranges provided by that lab: 
 
Hematology and coagulation 
o Complete blood count (CBC) with differential 
 Total white blood cell count 
 absolute counts for  
 neutrophils 
 lymphocytes 
 monocytes 
 eosinophils 
 basophils 
 platelet count 
 hematocrit 
 hemoglobin 
o PT-INR (International Normalized Ratio of Prothrombin Time) 
o aPTT (activated Partial Thromboplastin Time) 
 
Clinical biochemistry with electrolytes 


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o Sodium 
o Potassium 
o Chloride 
o Total carbon dioxide 
o Glucose 
o Blood urea nitrogen (BUN) 
o Serum creatinine (SCr)  
o Total bilirubin 
o Albumin 
o Total protein 
o Aspartate aminotransferase (AST) 
o Alanine aminotransferase (ALT) 
o Alkaline phosphatase (ALP) 
8.2.2 
Description of Screening/Baseline Period 
Before the initiation of study-specific screening assessments, the patient or legal authorized 
representative must be given a complete explanation of the purpose and evaluations of the study.  
Subsequently, the patient or legal authorized representative must sign and receive a copy of an 
Informed Consent Form that was approved by the center’s governing Institutional Review Board 
(IRB). Once informed consent has been obtained, the eligibility of the patient to participate in this 
study will be determined by the Investigator on the basis of the inclusion and exclusion criteria. 
Screening/Baseline Period assessments will also be performed according to the protocol to 
determine eligibility. Only eligible patients will be randomized to receive IMP.  
During the Screening/Baseline Period, the following evaluations will be performed to determine 
the patient’s eligibility for this study and document their baseline disease state; allowable time 
windows are described in Table 8.1-1: 
 Demographic data  
 Review and documentation of medical history. Subjects must be asked about patient or 
familial history of bleeding diathesis and any known risk factors for bleeding.  Resolved 
diseases or past procedures that are not significant to the disease under study should be 
captured if they occurred in the previous five years. Other history should be captured 
regardless of time reference.   
 A serum or urine pregnancy test will be performed on all women of child-bearing potential. 


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 A baseline physical examination will be performed for all significant body systems.    
 Safety labs will be drawn and processed according to standard local processes. Analytes to 
be measured are listed above in 8.2.1.4.  Per inclusion criterion #2 (See Section 7.4.1), 
historical lab values for ALT, AST, ALKP and bilirubin are required from between 15 and 
90 days prior to the safety lab values drawn during screening for comparison and 
confirmation of disease-state stability.  If no such lab values are available to the 
Investigator, an initial panel will be drawn following the obtaining of subject consent, and 
the screening assessments, including a full safety lab panel (See Section 8.2.1.5) will be 
performed 15 to 90 days later, within the defined screening period. 
 Additional serum will be collected for submission to the central lab for biomarker analysis 
as per the laboratory manual. 
 Active HBV and HCV must be ruled out prior to enrollment.  If the patient’s HBV status 
is unknown, a Hepatitis B surface antigen (HBsAg) test will be performed.  If the patient’s 
HCV status is unknown, an HCV antibody test and/or, if needed, an HCV RNA test will be 
performed.    
 Baseline HVPG measurements are performed within the 6 hours prior to first IMP 
administration. However, as detailed in 8.2.3 below, this screening measurement will likely 
be performed immediately prior to IMP administration.   
 Baseline vital signs are taken in the six hours prior to first IMP treatment: heart rate; 
respiration rate; body temperature; and indirect blood pressure.  
 If the subject has been diagnosed with cirrhosis, but by a method other than those listed in 
inclusion criterion #1 (See Section 7.4.1), a VCTE will be performed to confirm a diagnosis 
of cirrhosis as defined in this protocol.   
8.2.3 
Enrollment Confirmation and Procedures 
Because the final determination of subject eligibility is typically made after the baseline HVPG 
measurements which are immediately prior to the pending administration of the first dose of IMP, 
the ifetroban or placebo injection needs to be prepared before complete eligibility is confirmed to 
allow for pharmacy preparation time. The Investigator will order the preparation of IMP injection 
based on the “provisional eligibility confirmation” of a new subject. The unblinded pharmacist 
will obtain the treatment assignment directly from the unblinded sponsor representative at that 
time and prepare the infusion per the instructions in 7.3.2.1. If the subject is confirmed as eligible 
following the baseline HVPG assessment (i.e., mean HVPG > 8 mm Hg and < 18 mm Hg), the 


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infusion will continue as planned. If the subject does not meet the HVPG requirement, they are 
considered a screen failed subject and their prepared infusion is discarded by the pharmacy and 
the process documented. 
8.2.4 
Description of Treatment Period  
8.2.4.1 
Day 1 
Hour 0 of the treatment period is defined as the time when the intravenous infusion of IMP is first 
initiated. According to the site’s standard procedures, the 100 mL infusion volume will be 
administered over a 15-minute period. As soon as allowable after the completion of the infusion, 
an assessment of the mean HVPG will be made according to the procedure detailed in 8.2.1.1. 
Additional assessments will be initiated at both 15 and 30 minutes following the start of the IMP 
infusion.    
The subject will be dispensed a quantity of 300 IMP capsules (4 bottles of 75 capsules each) with 
instructions to begin a daily dose of 5 capsules (total 250 mg ifetroban or placebo) on the morning 
following the infusion. Drug administration at home should generally occur in the morning, but, if 
this does not happen on a given day, the dose should still be given at a later point during that day 
so that no dose is missed. All five capsules are taken in the same episode.  Subjects are instructed 
to note any missed days of oral IMP and report those to study staff.  Missed doses are not to be 
taken on a subsequent day.   
Enrolled subjects will be trained on how to identify petechial, ecchymosis, and other signs of 
bleeding and they will be directed to discontinue further study medication and contact the 
Investigator immediately to report any such symptoms.    
8.2.4.2 
Day 10 
Subject will have a clinic visit on Day 10 (+/- 3 days) for a safety follow-up evaluation. The visit 
will consist of a physical examination, including inspection for any symptoms of platelet 
dysfunction, vital sign measurement, and local lab assessment of safety labs, including a platelet 
function assessment by ROTEM or TEG. Consistent with the entire treatment period, changes in 
concomitant medications and any spontaneously-reported adverse events will be recorded.       
The subject must bring all bottles of IMP to the visit. The blinded study coordinator performs a 
drug compliance evaluation and calculates the percentage of compliance based on the amount of 
capsules missing since the Day 1 dispensation. If compliance is not 100%, the subject is re-
educated on the proper dosing regimen and the importance of being fully compliant with study 
drug administration. A plan to follow-up additionally with the subject (e.g., by phone or other 


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communications) may be devised.  If the Investigator has any concern over the subject being able 
to maintain a drug compliance between 90% and 110%, the Investigator will discuss continued 
study participation or possible study withdrawal with the subject.    
8.2.4.3 
Day 45 
At Day 45 (+/- 5 days), an interim treatment-period visit is performed for the standard safety 
evaluations (physical exam including inspection of symptoms of platelet dysfunction, vital signs, 
and safety labs) and serum is collected and prepared for central laboratory submission for 
biomarker analysis. Additionally, the subject is directed to bring the drug bottle(s) dispensed on 
Day 1 to the visit along with any unused capsules. Full drug accountability is performed by the 
study staff, compliance is calculated, and any treatment compliance issues are discussed between 
the Investigator and the subject. If the Investigator has any concern over the subject being able to 
maintain a drug compliance between 90% and 110%, the Investigator will discuss continued study 
participation or possible study withdrawal with the subject. Compliance is recorded in the CRF so 
values outside of the allowable 90 to 110% range are not recorded separately as protocol deviations 
in the CRF.       
Unless the subject withdraws from the study voluntarily or under direction by the Investigator, the 
subject is dispensed 150 additional IMP capsules with instructions to continue treatment.  Two 
bottles are sent home with the subject in addition to any capsules that were brought by the subject 
to the Day 45 visit.   
In total, between the Day 1 and Day 45 Visits, each subject will be dispensed six bottles of 75 
capsules each.      
8.2.4.4 
Day 90 / Early withdrawal  
The subject is directed to take the final oral dose of IMP at home on the day prior to their scheduled 
Day 90 Visit. All drug bottles and unused medication is brought to the visit by the patient. Safety 
assessments (physical exam including inspection of symptoms of platelet dysfunction, vital signs, 
and safety labs) are performed in addition to the collection and processing of serum for central 
analysis of biomarkers. The subject is again prepared for hepatic vein pressure measurements and 
HVPG measurements are recorded during the visit. Finally, complete drug accountability is 
performed and compliance calculated by the site staff.       


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8.2.4.5 
Follow-up 
A phone call is made by the study staff between 6 and 8 days following the Day 90/Early 
termination visit.  The subject is asked about their medical status to assess for any spontaneously 
reported adverse events.   
8.2.5 
Potential Drug-induced Liver Injury 
Subjects in this study are enrolled with confirmed pre-existing hepatic disease; therefore, published 
guidelines (http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf) for monitoring 
potential drug-induced liver injury (DILI) are available but do not apply to the same degree.  
A modified protocol is followed when patients in the treatment or follow-up phases show evidence 
of possible DILI and need to be monitored or have their study treatment modified accordingly.   
8.2.5.1 
Criteria for Initiating Protocol for Potential DILI Cases  
Any subject meeting any one of the following criteria during the treatment or follow-up phase 
will enter the protocol (See Section 8.2.5.2 below) for potential DILI cases:  
 An elevation of ALT or AST greater than 2 X the baseline value for that patient 
 An elevation of total bilirubin greater than 1.5 X the baseline value for that patient 
 Any increase in bilirubin seen in conjunction with suspect hypersensitivity signs or 
symptoms such as fever, rash, eosinophilia, nausea, vomiting, or right upper quadrant 
pain mandates that the subject enter the monitoring protocol, but also discontinue study 
drug immediately.    
8.2.5.2 
Protocol for Potential DILI Cases 
All assessments made during the monitoring of potential DILI cases will be captured in the CRF.   
Initial Evaluation 
Any subject that meets a criterion in Section 8.2.5.1 should have liver enzymes and bilirubin levels 
repeated within 48 hours to confirm the abnormalities and detect if they are increasing or 
decreasing.  At that unscheduled visit, the following assessments will be performed and additional 
information collected: 
 Physical Exam with detailed assessment of symptoms 
 History of concomitant drug use (including nonprescription medications and 
supplements), alcohol use, recreational drug use, and special diets. 


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 History of exposure to environmental chemical agents 
A diagnostic plan should be formulated and initiated by the Investigator, if appropriate based on 
history, physical exam findings and laboratory results, to rule out additional potential causes of 
liver disease such as acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease.   
Monitoring 
At a minimum, liver enzyme and serum bilirubin testing should be performed initially 2-3 times 
weekly until abnormalities stabilize or the trial drug has been discontinued and the subject is 
asymptomatic.  The scope and frequency of monitoring can then be modified as appropriate.    
 
Decision to Stop Study Drug 
There is no strict guidance on when to stop study drug in a patient with pre-existing liver disease 
that is demonstrating some possible signs of drug-induced liver injury.  Section IV.A.5 of the 
following guidance may be used for reference and assistance: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf  
 
The Medical Monitor should be consulted as well in the decision to continue or discontinue study 
drug.  
  
The decision to discontinue or temporarily interrupt study drug treatment should generally be 
based on the following factors:  
 Stability or directional changes of ALT, AST, and bilirubin  
 Elapsed time during which values have remained higher than baseline 
 The degree to which the baseline ALT, AST and bilirubin were high relative to the upper 
limit of normal 
Please note that Section 8.2.5.1 directs the study drug to be stopped for cases of elevated bilirubin 
with concurrent symptoms such as fever, rash, eosinophilia, nausea, vomiting, or right upper 
quadrant pain.  
 
Follow-up 
All trial subjects showing possible DILI should be followed until all abnormalities return to normal 
or to the expected baseline state given the pre-existing liver disease.   


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9 
SUBJECT DISCONTINUATION  
9.1 
Subject Discontinuation - General  
Subjects will be encouraged to complete the study; however, they may voluntarily withdraw at any 
time and for any reason. The Investigator will describe in the CRF the reason for the subject’s 
choice to discontinue.   
A subject may be removed from the study for the following reasons; in each case, the decision to 
discontinue should be confirmed following consultation between the Investigator and Sponsor: 
 Adverse event (AE): If a subject experiences an AE for which continued study participation 
presents an unacceptable consequence or risk to the subject, the subject may be 
discontinued under the Investigator’s judgement. See also Section 9.2. 
 Subject non-compliance: A subject’s past, current, or anticipated inability to comply with 
study visits, clinical trial medication or other processes required by the protocol may lead 
to the decision to discontinue the subject from the study. The subject’s compliance in taking 
oral medication at home should be within 90 and 110% at all visits.    
 Enrollment violation: If it is realized after the initiation of investigational treatment (or 
placebo) that a subject did not meet all eligibility requirements, the Sponsor and 
Investigator will discuss whether it is safe, ethical, and scientifically sound to keep the 
subject in the study or to discontinue the subject.   
 Concurrent Treatment: If a subject initiates a procedure or medication that may interfere 
with their study conduct or for which study involvement may pose a significant risk to the 
prescribed therapy, the subject may be discontinued. This also includes the use of therapies 
restricted by the protocol in Section 7.5.     
 TIPS or shunt procedure during the treatment period.  
 Liver transplant during the treatment period.   
 Other reasons: Following discussion between the Sponsor and Investigator, subjects may 
be discontinued from the study for reasons other than those listed above. 


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9.2 
Subject Discontinuation - Protocol-specified Common Terminology 
Criteria for Adverse Events (CTCAE) 
Subjects encountering adverse events meeting either of the criteria below will be discontinued 
from study drug but continued to be monitored for safety.  The Investigator will plan to remain 
blinded and consult with the sponsor’s Medical Monitor and a decision will be made and 
documented regarding continued patient monitoring and criteria under which study drug would be 
re-initiated or additional efficacy assessments would be performed.    
 Any grade 4 or higher adverse event defined by CTCAE (See Section 10.1.2 for guidance) 
 Any grade 3 adverse event that is classified by the Investigator as possibly or probably 
related to study drug 
See also Section 10.4 regarding the unblinded review of safety data if multiple subjects have 
significant AEs.   
9.3 
Procedures for Subject Discontinuation 
If a subject is permanently withdrawn from study drug prior to completion of the full treatment 
period, a Day 90 visit, as described above should be performed if the subject consents and there is 
no additional risk to the patient by performing the assessments. Following the visit, reasonable 
efforts should be made to monitor the subject for AEs, as appropriate.  
Subjects that are discontinued may be replaced, as needed. The decision will be made on a case-
by-case basis by the study sponsor.   
9.4 
Study or Site Termination 
If conditions arise during the study that indicate that the study should be halted or that the study 
center should be terminated, this action may be taken after appropriate consultation among the 
Sponsor, Investigator, Medical Monitor, and Study Monitor.   
Conditions that may warrant termination of the study include, but are not limited to, the following: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
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 See also Section 10.4 regarding enrollment termination due to AEs. 
A study conducted at a single study site or a single study site in a multicenter study may also 
warrant termination under the following conditions: 
 Failure of the Investigator to enroll subjects into the study at an acceptable rate 
 Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
 Submission of knowingly false information from the research facility to the Sponsor, Study 
Monitor, or appropriate regulatory authority 
 Insufficient adherence to protocol requirements 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonization (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, Section 4.12, ICH E6 4.13, ICH E6 5.20, and ICH E6 5.21. 
10 
ADVERSE EVENTS 
Information about AEs, whether spontaneously reported by the subject, discovered by the 
Investigator by questioning/review of diary records or detected through physical examination, 
laboratory test or other means, will be collected and recorded on the adverse event form and 
followed-up as appropriate. Information about serious adverse events should be reported to the 
Sponsor within 24 hours of obtaining knowledge of the event.  
10.1 
Definitions 
10.1.1 
Adverse Event Definitions 
Adverse events are defined according to ICH Harmonized Tripartite Guideline E2A. 
Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a trial product 
whether it has a causal relationship with the study treatment or not.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 


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The following are not considered an AE: 
 Pre-planned procedure (documented as concomitant illness on the CRF at screening) unless 
the condition for which the procedure was planned has worsened from the first trial related 
activity after the subject has signed the informed consent form. 
 Pre-existing conditions found during and as a result of screening procedures. 
Serious adverse event (SAE) 
An AE that meets any of the following criteria:  
 results in death  
 is immediately life-threatening (this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it was more severe)  
 requires in-patient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability or incapacity 
 is a congenital anomaly or birth defect 
 is judged medically important in the opinion of the Investigator (this refers to an event that 
may not be immediately life-threatening or result in death or hospitalization, but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed. 
Non-serious adverse event 
Any adverse event that does not meet the definition of an SAE. 
Unexpected adverse event 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed.  
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 


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10.1.2 
Adverse Event Assessment Definitions 
Anticipated 
Anticipated events include known consequences of an underlying disease or the condition under 
investigation, events anticipated from any background regimen, events common in the study 
population, or re-emergence or worsening of a condition relative to pretreatment baseline. 
Severity 
The reported event terms and severity grading of each event reported in this study adhere to the 
Common Terminology Criteria for Adverse Events (CTCAE) grading criteria, which is 
coordinated by the National Cancer Institute of the National Institutes of Health. 
Resources including quick references, governance documents and data files of adverse events can 
be found here: http://evs.nci nci.nih.gov/ftp1/CTCAE/About.html  
The Investigator, with support from the study monitor, will report adverse events using the lowest 
level terms, as identified by the Medical Dictionary for Regulatory Activities (MedDRA) 
http://www.meddra.org/, whenever possible.   
The severity of each event adheres to the severity grades established by CTCAE: 
Grade 1  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.   
Grade 3  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living.  
Grade 4  Life-threatening consequences; urgent intervention indicated.  
Grade 5  Death related to AE. 
The investigator will determine the severity for each individual event utilizing the following 
guidance; 
listed 
here 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf:      
Relationship/Relatedness 
The causal relationship between an adverse event and the trial product is assessed by the 
investigator using the following definitions: 


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Probable: Good reasons and sufficient documentation to assume a causal relationship. 
Possible: A causal relationship is conceivable and cannot be dismissed  
Unlikely: The event is most likely related to an etiology other than the trial product. 
An adverse event is considered causally related to the use of the trial product when the relationship 
assessment is probable or possible. Events assessed as unlikely related to the use of trial product 
will be considered as having no relationship to treatment. 
Outcome 
The outcome of an adverse event is assessed by the investigator using the following definitions: 
Recovered: Fully recovered, or by medical or surgical treatment the condition has returned to 
the level observed at the first trial-related activity after the subject signed the informed consent. 
Recovering: The condition is improving and the subject is expected to recover from the event. 
This term should only be used when the subject has completed the trial. 
Recovered with sequelae: As a result of the AE the subject suffered persistent and significant 
disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with sequelae 
should be classified as an SAE. 
Not recovered: The subject’s condition has not improved and the symptoms are unchanged 
Unknown: The subject’s condition is unknown. This term should only be used when no other 
definition is possible e.g., the subject is lost to follow-up. 
10.2 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an adverse event must be collected and reported from the first 
trial-related activity after the subject signs the informed consent and until, for example, last subject 
contact/visit/end of post-treatment follow-up period.  
At each contact with the trial center, the subject must be asked about adverse events in an objective 
manner like: “Have you experienced any problems since the last contact?” 
Adverse events according to the definition, either observed by the investigator or reported by the 
subject, must be recorded by the investigator and evaluated.  Adverse events must be recorded in 
the case report forms. For serious adverse events, the SAE form must also be filled in. 


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The investigator should record the diagnosis, if available. If no diagnosis is available, the 
investigator should record each sign and symptom as individual adverse events.  
Serious Adverse Events 
The investigator must report initial information on all serious adverse events within 24 hours of 
obtaining knowledge of the event.  
Furthermore, the investigator must complete and transmit, as applicable, the adverse event and 
SAE forms within five days of obtaining knowledge of the SAE. The monitor must be informed 
accordingly. 
The Investigator will inform the health authorities and independent ethics committees (IECs)/IRBs 
in accordance with local requirements in force and the International Conference on Harmonization 
(ICH) guidelines for GCP and the European Union (EU) Directive 2001/20/EC / Food and Drug 
Administration (FDA) Title 21 Code of Federal Regulations, Part 312.32 (5). 
Adverse Events Starting after Trial Completion 
Adverse events occurring after trial completion, which the investigator considers to be related to 
the investigational medicinal product must be reported to the sponsor.  
10.3 
Study-Specific Guidance Pertaining to Adverse Events 
Patient interactions, including examinations, tests, procedures and treatments that are ordered 
based on the occurrence of cirrhosis decompensation or hemorrhagic events are captured in the 
CRF in the Concomitant Treatment, Platelet Function, Unscheduled Visits, and/or Comments 
Modules.    
10.3.1 
Variceal Bleeding 
In most cases, an occurrence of a gastrointestinal hemorrhage during the treatment phase will meet 
the definition of an adverse event. Since variceal bleeds are an endpoint of the study, specific 
details surrounding such an occurrence are collected on a dedicated module of the CRF.  However, 
the same event is also added to the Adverse Event module of the CRF so that safety listings for the 
study are complete. 
Incidences of variceal bleeds will also follow the protocol for general bleeding as directed below 
in Section 10.3.3.    


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10.3.2 
Cirrhosis Decompensation 
All events that are considered decompensation events related to cirrhosis meet the definition of an 
adverse event and are captured accordingly.  The following are recognized decompensation events:  
 Ascites 
 Hepatorenal syndrome (HRS) 
 Spontaneous bacterial peritonitis (SBP) 
 Hepatic encephalopathy (HE) 
 Gastric or esophageal variceal bleeding 
Of these events, only the occurrence of variceal bleeding is an endpoint of the study and is 
captured in a dedicated CRF module in addition to the AE module.  All other decompensation 
events will be captured in the AE module and monitored closely.   
 
10.3.3 
Clinical Bleeding Events 
Immediately following a diagnosis of a clinical bleed during the treatment or follow-up periods, 
and, if possible, prior to any resulting medical intervention, a whole blood sample is collected in a 
sodium citrate tube and the sample is evaluated for platelet function by either ROTEM or TEG 
technology, as described in Section 8.2.1.2.   
Any clinical presentation of a hemorrhagic event, including variceal bleeding, procedural 
complications and hematomas, is reported as an AE and monitored closely.  Depending on the 
clinical presentation and available test results, possible event terms may include a clinical term 
(e.g., post-procedural bleeding) or a laboratory-based term (e.g., thrombocytopathy, 
thrombocytopenia, etc.) according to the Investigator’s assessment.   
As noted in 10.3.1, variceal bleeding will also be reported in a dedicated CRF module.   
10.4 
Subject or Study Discontinuation Due to Adverse Event 
In the event that three or more patients experience a grade 3 (CTCAE) or above from one system 
organ class, regardless of the events’ relative attribution to study drug by the Investigator, 
additional enrollment will be halted immediately and an unblinded safety review of patient data 
will be initiated according to the study’s safety plan.  The outcome of this review will be 
documented and communicated to the Investigators.  Potential outcome may include termination 
of the study, modification of the protocol, or resuming of the protocol without modification.        


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10.5 
Follow-up of Adverse Events 
Follow-up of Non-Serious Adverse Events 
All adverse events classified as non-serious adverse events that are both severe and possibly or 
probably related to the investigational medicinal product should be followed until the subject has 
recovered. 
For cases of chronic conditions, follow-up until “recovered” is not required.  After the subject has 
completed the trial, these cases can be closed with the outcome “recovering” or “not recovered”. 
All other non-serious adverse events must be followed until the outcome of the event is 
“recovering” (for chronic conditions), “recovered” or until, for example, last subject 
contact/visit/end of post-treatment follow-up period, whichever comes first, and until all queries 
related to the adverse event have been resolved. 
Follow-up of Serious Adverse Events 
All adverse events classified as serious should be followed until the outcome of the event is 
“recovered”, “recovered with sequelae”, “death” and until all queries have been resolved. For cases 
of chronic conditions and cancer, follow-up until “recovered”, “recovered with sequelae” or 
“death” is not required. After the subject has completed the trial, these cases can be closed with 
the outcome “recovering” or “not recovered”. 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
There is no statistical analysis plan for this study and a biostatistician was not consulted in the 
study design. Results will be analyzed and reported descriptively.  
11.1 
Sample Size Determination 
Formal sample size calculations were not performed. Twenty active, and ten placebo subjects will 
be enrolled in this study and results will be presented descriptively.   
11.2 
Subject Population(s) for Analysis 
All data will be listed by subject. Continuous data will be summarized in tables comparing 
proportions or percentages of patients in each treatment group. Standard deviation or standard error 
will also be calculated. The safety population consists of all subjects who were enrolled and 
received at least a partial dose of IMP; no treated subjects will be excluded from the safety analysis 
population. For the efficacy analyses on this pilot study, patients will be evaluated according to the 
treatment they received.   


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11.3 
Statistical Methods 
In presenting data from this trial, continuous data will be summarized in tables listing the mean, 
standard deviation or standard error, median, and number of subjects in a group. Categorical data 
will be summarized in tables listing the frequency and the percentage of subjects in a group. These 
summaries will be presented separately for subjects in the Ifetroban and placebo treatment arms.  
11.4 
Interim Analysis 
No interim analyses are planned. 
12 
STUDY MANAGEMENT AND DATA COLLECTION 
12.1 
Confidentiality 
All information regarding the nature of the proposed investigation provided by the Sponsor or 
Study Monitor to the Investigator (with the exception of information required by law or regulations 
to be disclosed to the IRB, the subject, or the appropriate regulatory authority) must be kept in 
confidence by the Investigator. 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject number on CRFs and other study documents submitted to the Study Monitor. 
Documents that will not be submitted to the Study Monitor and that identify the subject (e.g., the 
signed informed consent document) must be maintained in strict confidence by the Investigator, 
except to the extent necessary to allow auditing by the appropriate regulatory authority, the Study 
Monitor, or Sponsor representatives. 
12.2 
Source Documents 
Source data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, tracings from the HVPG measurements, copies or transcriptions certified after 
verification as being accurate and complete, 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. The Monitor, representatives of the Sponsor and the applicable regulatory authority will be 
allowed access to source documentation. 
12.3 
Case Report Forms 
CRF forms will be available for data entry by the site through RedCAP™, a web-based, electronic 
data entry and reporting platform. Cases will be monitored remotely and on-site by the sponsor 


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according to a written Monitoring Plan and data will be retrieved by the monitor for data analysis 
at the sponsor.     
12.4 
Records Retention 
According to 21CFR312.62, all CRFs, as well as supporting documentation and administrative 
records, must be retained by the Investigator for a minimum of two years following notification 
that the appropriate regulatory authority has approved the product for the indication under study, 
notification that the entire clinical investigation will not be used in support of a marketing 
application, or notification that the marketing application was not approved. No study documents 
will be destroyed or moved to a new location without prior written approval from the Sponsor. If 
the Investigator relocates, retires, or withdraws from the clinical study for any reason, all records 
required to be maintained for the study should be transferred to an agreed upon designee, such as 
the Study Monitor, another Investigator, or the institution where the study was conducted. 
13 
STUDY MONITORING, AUDITING, AND INSPECTING 
13.1 
Study Monitoring Plan 
The investigator will permit study-related monitoring, audits and inspections by the IRB, the 
Sponsor and any applicable regulatory authority.  
The sponsor will adhere to a written Monitoring Plan in fulfilling the requirements of ICH/GCP 
guidelines and the CFR to monitor the execution of the study and the collection of data.  In general, 
the progress of the study will be monitored by using the following methods: 
 Periodic onsite visit(s) by the sponsor representative 
 Telephone communications among the Investigator, Clinical Monitor and/or Medical 
Monitor, as needed 
 Remote and on-site review by the sponsor representative of CRFs, clinical records and 
regulatory documents 
Details are described in the written monitoring plan.  
14 
ETHICAL CONSIDERATIONS 
This study will be conducted according to the standards of ICH, GCP Guidelines, IRB regulations, 
any applicable government regulations and procedures. This protocol and any amendments will be 
submitted to a properly constituted IRB for approval of the study conduct. 


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14.1 
Informed Consent 
Written informed consent must be obtained from each subject (or the subject’s legal 
guardian/representative) before performing any Screening/Baseline Period evaluations. The 
signed informed consent document will be retained by the Investigator, and a signed copy will be 
given to the subject or subject’s legal guardian/representative. The informed consent document, 
which is prepared by the Investigator, must have been reviewed and approved by the Sponsor and 
the Investigator’s IRB before the initiation of the study. The document must contain the 
20 elements of informed consent described in 21CFR50.25 and ICH E6 4.8. In addition, subjects 
of appropriate intellectual maturity should provide written informed assent, as determined by the 
institution’s IRB or local legal requirement. 
14.2 
Protocol Compliance 
Investigators must follow the IRB-approved protocol. If the Investigator intends to deviate from 
the protocol, the IRB and Sponsor should be informed prior to the deviation.  
In cases where the Investigator decides to deviate from the protocol in order to avoid an apparent 
immediate risk to a specific subject, the Investigator may proceed with emergency and appropriate 
treatment at his discretion and the IRB and Sponsor will be notified as soon as possible afterward. 
In addition, the Investigator will document in the subject’s CRF the reasons for the protocol 
deviation and the ensuing events. 
Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, assessment variable(s), the number of subjects treated, or the subject selection criteria. 
Such changes must be prepared as a protocol amendment by the Sponsor. A protocol amendment 
must receive IRB approval before implementation.   
In parallel with the IRB approval process, the protocol amendment will be submitted to the 
appropriate regulatory authority as an amendment to the regulatory submission under which the 
study is being conducted. If a protocol amendment requires changes in the informed consent 
document, the revised informed consent document prepared by the Investigator must be approved 
by the Sponsor, Study Monitor, and the IRB. 
14.3 
Financial Disclosure 
Each clinical site investigator will provide the Sponsor with sufficient, accurate financial 
information in accordance with local and federal regulations to allow the sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate regulatory 


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health authorities. Investigators are responsible for providing information on financial interest 
during the study and for one year after completion of the study in accordance with FDA policy 
(Title 21 CFR – PART 54 FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS 
Revised as of April 1, 2015). 
14.4 
Study Files 
Documentation verifying the Investigator’s legal and regulatory authority and acceptable scientific 
background to conduct the trial will be available at both the site and the sponsor before shipments 
of IMP are sent to the investigative center.   
Following study initiation, the Investigator will maintain adequate records to re-create and justify 
the complete conduct of the trial at a later date. Document inventory will adhere to ICH/GCP and 
CFR requirements and will include those pertaining to the Investigator’s qualifications, inventory 
and handling details of investigational products, and detailed medical and study histories for all 
subjects.    
15 
REFERENCES 
Acquaviva A, Vecchio D, Arezzini B, et al. 2013. Signaling pathways involved in isoprostane-
mediated fibrogenic effects in rat hepatic stellate cells. Free Rad Biol Med. 65:201-7.  
Buck M, Garcia-Tsao G, Groszmann RJ, et al. Novel inflammatory biomarkers of portal pressure 
in compensated cirrhosis patients. Hepatology. 2014; 59(3):1052-9.   
Deng YQ, Zhao H, Ma AL, et al. 2015. Selected cytokines serve as potential biomarkers for 
predicting liver inflammation and fibrosis in chronic hepatitis B patients with normal to mildly 
elevated aminotransferases. Medicine. 94(45): doi 10.1097. 
Graupera M, Gracia-Pagan, Pares M, et al. 2003. Cyclooxygenase-1 inhibition corrects endothelial 
dysfunction in cirrhotic rat livers. J Hepatology. 39: 515-21.  
LaVecchia C, Levi F, Lucchini F, et al. 1994. Worldwide patterns and trends in mortality from liver 
cirrhosis, 1955 to 1990. Annals of Epidemiology. 4(6):480-6. 
Pagliaro L, D‘Amico G, Malizia G, et al. Portal hypertension in cirrhosis; natural history. In:  
Bosch J, Broszmann R (eds) Portal hypertension: Pathophysiology and treatment. Blackwell 
Scientific, Cambridge: 72-92.    


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Rodriguez-Vilarruplas A, Lavina B, Garcia-Caldero H, et. al. 2012. PPARa activation improves 
endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J of Hepatology. 
56:1033-9. 
Rosado E, Rodríguez-Vilarrupla A, Gracia-Sancho J, et al. 2013. Terutroban, a TP-receptor 
antagonist, reduces portal pressure in cirrhotic rats. Hepatology. 00(00):1-12. 
Snyder N, Gajula L, Xiao SY. 2006. APRI: an easy and validated predictor of hepatic fibrosis in 
chronic hepatitis C. J Clin Gastroenterol. 40(6):535-42.  
Tripathi, D, Therapondos G, Ferguson JW, et al. 2006. Endothelin-1 contributes to maintenance of 
systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled 
trial. Gut. 55:1290-5. 
Yokoyama Y, Nimura Y, Nagino M, et al. 2005. Role of thromboxane in producing hepatic injury 
during hepatic stress.  Arch Surg. 140: 801-7.  
16 
SUMMARY OF CHANGES  
Protocol changes in Amendment 02, dated 20Jul2017, as compared to Amendment 01, dated 
28July2016 are as follows:  
 Changes are made throughout the protocol to differentiate between HVPG (a single result 
calculated from the difference of a wedged pressure reading and a free pressure reading) 
and mean HVPG (the average of three valid HVPG values).  
 The allowable difference in the values between the historical and the screening ALP in 
Inclusion Criterion #2 is increased from 40 to 60 U/L.  
 The upper range for Inclusion Criterion #3 is increased from 16 mmHg to 18 mmHg. 
 Exclusion Criterion #3 is updated to clarify that patients with a prior history of portal or 
splenic vein thrombosis are eligible to enroll if they are subsequently confirmed as having 
no occlusive portal or splenic vein thrombosis. 
 Exclusion Criterion #11 is revised to clarify that subjects taking chronic suppressive 
therapy for Hepatitis B Virus can be enrolled as long as their infection is not active.    
 The value at which a low platelet count excludes a subject, per Exclusion Criterion #12, 
is decreased from 80 x 103/µL to 60 x 103/µL.  


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 The allowable screening period is increased from seven to fourteen days.  
 The informed consent process is deleted from the Schedule of Events table.  The obtaining 
of informed consent must be performed prior to any study procedures and therefore does 
not need to be conducted within the 14-day screening period.  Therefore, the consenting 
process is not a screening procedure per se, but rather precedes screening.  
 Single HVPG readings are performed in sequence at Baseline and Day 90 rather than 
performing readings in triplicate.  The procedure is now finished when three sequential 
readings are within 1 mmHg of each other.   
 The Day 1 summary description of HVPG in Table 8.1-1 is updated to better adhere to the 
actual description in Section 8.2.4.1.      
 A provision is added to the protocol in Section 8.2.2 to allow for baseline values of ALT, 
AST, ALKP and bilirubin to be measured prior to the screening period in patients without 
available historical values in the required timeframe.  A footnote is also added to Table 
8.1-1.  
 The VCTE procedure is added to the screening assessments in Section 8.2.2 for patients 
that are diagnosed with cirrhosis, but not by any of the methods detailed by the protocol 
in the Inclusion Criteria (Section 7.4.1).  Table 8.1-1 is updated accordingly.  
 ROTEM or TEG assessments are added at Day 10.