Clinical trial NCT03107091
Conditions: Cirrhosis Ascites Hepatic
Keywords: Terlipressin Terlipressin acetate
Sponsor: BioVie Inc.
Start date: 2017-07-15; Completion date: 2019-04-25
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Low-dose continuous infusion of terlipressin will be administered to six cirrhotic patients with refractory ascites.

Detailed description:
Terlipressin continuous infusion will be adminstered via an ambulatory pump initially for 7 days in a clinical pharmacology unit. Serial blood draws for pharmacokinetic analysis will be performed to determine steady state concentration of both terlipressin and 8-lysine-vasopressin during infusion. After establishing safety and tolerance of infusion for 7 days, patients will be transitioned to an outpatient setting where they will be treated with terlipressin continuous infusion for an additional 21 days, monitored daily by home care nurses.

A total of 6 patients will be treated. Monitoring will include successful management of ascites, with reduction in paracentesis procedures and decreased ascites fluid volume, further supported by improvement in renal function.

Arms: arm 1: Continuous infusion of terlipressin starting at 2 mg/day over 7 days in-house and if tolerated continue treatment in the ambulatory setting for 21 days
Interventions: intervention 1: Terlipressin acetate continuous infusion
Intervention descriptions: intervention 1: Low-dose continuous infusion of Terlipressin administered via ambulatory pump over 28 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
NCT 03107091 
Continuous Infusion Terlipressin for Patients With Cirrhosis and Refractory Ascites 
November 17, 2018 
 


Continuous infusion Terlipressin 
For cirrhotic patients with refractory ascites 
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Protocol CIT-001 
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Company Confidential 
Document CIT-016-001 
 
 
 
 
Protocol Edition #6 
 
 
 
 
Safety and pharmacodynamic activity of low-dose terlipressin delivered by continuous 
intravenous infusion in patients with cirrhosis and refractory ascites requiring recurrent large 
volume paracentesis 
 
 
 
 
 
 
 
 
 
 
 
IND Number: 128582 
Sponsor: BioVie Inc 


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SIGNATURES OF AGREEMENT FOR PROTOCOL REVISION 
 
Incorporates: 
 
Amendment #1  Dated April 6, 2017 [Document CIT-021-001] 
 
Amendment #2  Dated Apr. 20, 2017 [Document CIT-022-001] 
 
Amendment #3  Dated Aug. 14, 2017 [Document CIT-023-001] 
 
Amendment #4  Dated Oct. 24, 2017  [Document CIT-024-001] 
 
Amendment #5  Dated April 1, 2018  [Document CIT-025-001] 
 
Amendment #6  Dated November 17, 2018  [Document CIT-025-001] 
 
 
 
 
 
Clinical Investigator 
Date 
Institution:   
 
 
 
 
 
 
SIGNATURES OF AGREEMENT FOR PROTOCOL REVISION BY THE SPONSOR, 
BIOVIE INC. 
 
 
 
BioVie Inc. Consulting Medical Director 
November 17, 2018 
Patrick D. Yeramian MD 
Yeramian@comcast.net 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ....................................................................................... 8 
2. 
SYNOPSIS .................................................................................................................... 11 
3. 
INTRODUCTION ....................................................................................................... 15 
4. 
OBJECTIVES .............................................................................................................. 17 
4.1. PRIMARY OBJECTIVES ............................................................................................ 17 
4.2. EXPLORATORY OBJECTIVES ................................................................................... 17 
5. 
MATERIALS AND METHODS ................................................................................ 18 
5.1. STUDY DESIGN ....................................................................................................... 18 
5.2. STUDY SITES .......................................................................................................... 19 
5.3. STUDY POPULATION ............................................................................................... 19 
5.3.1. Patient Screening and Enrollment ...................................................... 19 
5.3.2. Criteria for Inclusion .......................................................................... 19 
5.3.3. Criteria for Exclusion ......................................................................... 20 
5.4. METHOD OF ASSIGNING TREATMENT NUMBERS TO PATIENTS ................................ 22 
5.5. REPLACEMENT OF PATIENTS ................................................................................... 22 
5.6. DESCRIPTION OF CLINICAL SUPPLIES ....................................................................... 22 
5.7. LABELING OF CLINICAL SUPPLIES ........................................................................... 23 
6. 
STUDY PLAN AND PROCEDURES ........................................................................ 25 
6.1. SCHEDULE OF OBSERVATIONS AND PROCEDURES ................................................... 25 
6.2. ETHICS AND REGULATORY CONSIDERATIONS ......................................................... 29 
6.3. SCREENING AND PRE-TREATMENT PERIOD ............................................................. 29 


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6.3.1. Screening Procedures .................................................................................... 29 
6.3.2. Informed Consent .......................................................................................... 29 
6.3.3. Study Entry Visit ............................................................................................ 30 
6.3.4. Enrollment of Patients ................................................................................... 30 
6.3.5. Pre-Treatment Observation Period ............................................................... 30 
6.4. TREATMENT PERIOD ............................................................................................... 31 
6.4.1. Baseline - Admission ..................................................................................... 31 
6.4.2. In-House Treatment of Patients ..................................................................... 32 
6.4.3. Day 1-7 in-house monitoring ......................................................................... 34 
6.4.4. Discharge from GCRC .................................................................................. 34 
6.4.5. Ambulatory Treatment and Monitoring of Patients – Day 8-28 ................... 35 
6.4.6. Interim Visits at Day 14 and 28 ..................................................................... 36 
6.4.7. Follow-up Period ........................................................................................... 36 
6.5. RECOMMENDED CONCOMITANT MEDICATION ........................................................ 37 
6.6. PROHIBITED CONCOMITANT MEDICATIONS ............................................................ 38 
6.7. PHARMACOKINETICS OF TERLIPRESSIN ................................................................... 38 
6.8. INFLUENCE OF PARACENTESIS ON TERLIPRESSIN PHARMACOKINETICS .................. 39 
6.9. DIET ....................................................................................................................... 39 
6.10. PATIENT EDUCATION ............................................................................................ 39 
6.11. THERAPEUTIC PARACENTESIS DURING AND AFTER THE STUDY PERIOD ................. 40 
6.12. DATA COLLECTION AFTER THE STUDY PERIOD ..................................................... 40 
6.13. CRITERIA FOR WITHDRAWAL FROM STUDY ........................................................... 40 
6.14. PATIENT REPLACEMENT ........................................................................................ 41 


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6.15. DISCONTINUATION OF TREATMENT FOR ADVERSE EVENTS ................................... 42 
6.16. AES OF INTEREST .................................................................................................. 43 
6.17. MANAGEMENT OF AES AND TREATMENT DOSE MODIFICATION ............................ 44 
6.18. SAFETY MONITORING RULES ................................................................................ 45 
7. 
STATISTICS .................................................................................................................45 
7.1. JUSTIFICATION OF SAMPLE SIZE .............................................................................. 45 
7.2. SAMPLE SIZE ........................................................................................................... 46 
7.3. DESCRIPTION OF STATISTICAL METHODS ............................................................... 46 
7.3.1. Demographics, Baseline and Other Characteristics ..................................... 46 
7.3.2. Safety and Tolerability .................................................................................. 46 
7.3.3. Pharmacokinetics .......................................................................................... 47 
7.3.4. Evaluation of Pharmacokinetic Design ......................................................... 49 
7.3.5. Efficacy .......................................................................................................... 50 
8. 
SERIOUS ADVERSE EVENT REPORTING ...........................................................51 
8.1. DESCRIPTION OF ADVERSE EVENTS ........................................................................ 51 
8.2. RELATIONSHIP TO STUDY DRUG OR STUDY INTERVENTION .................................... 52 
8.3. DESCRIPTION OF AND PROCEDURAL REQUIREMENTS FOR SERIOUS ADVERSE 
EVENTS ................................................................................................................. 52 
8.4. REPORTING RESPONSIBILITY FOR SERIOUS AE ....................................................... 53 
8.5. REPORTING PROCEDURES ....................................................................................... 54 
9. 
ETHICAL ASPECTS ...................................................................................................55 
9.1. ETHICS AND GOOD CLINICAL PRACTICE ................................................................. 55 
9.2. CONFIDENTIALITY REGARDING STUDY SUBJECTS .................................................. 56 


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9.3. FINANCIAL DISCLOSURE ......................................................................................... 56 
9.4. SAFETY MONITORING COMMITTEE ......................................................................... 56 
9.5. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ...................... 57 
9.6. INFORMED CONSENT .............................................................................................. 58 
10. 
ADMINISTRATIVE REQUIREMENTS .................................................................. 60 
10.1. PROTOCOL AMENDMENTS ..................................................................................... 60 
10.2. MONITORING PROCEDURES ................................................................................... 61 
10.3. PROTOCOL DEVIATION AND VIOLATION ................................................................ 62 
10.4. INVESTIGATIONAL SITE TRAINING ........................................................................ 62 
10.5. RECORDING OF DATA AND RETENTION OF DOCUMENTS ....................................... 62 
10.6. CASE REPORT FORMS ............................................................................................ 64 
10.7. AUDITING PROCEDURES ........................................................................................ 64 
10.8. DISCLOSURE AND CONFIDENTIALITY .................................................................... 64 
10.9. DISCONTINUATION OF STUDY ............................................................................... 65 
11. 
DATA MANAGEMENT ............................................................................................. 65 
11.1. DATA COLLECTION ............................................................................................... 65 
11.2. DATA CLARIFICATION ........................................................................................... 66 
12. 
REFERENCES ............................................................................................................ 66 
13. 
APPENDIX 1: OVERDOSE INSTRUCTIONS ....................................................... 68 
14. 
APPENDIX 2 - INSTRUCTIONS FOR THE COLLECTION, HANDLING AND 
SHIPPING OF SAMPLES ....................................................................................................... 69 
14.1. COLLECTION OF BLOOD SAMPLES ......................................................................... 69 
14.2. PROCESSING AT SITE ............................................................................................. 69 


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14.3. SHIPPING OF SAMPLES FOR CENTRAL ANALYSIS ................................................... 69 
15. 
APPENDIX 3 – BLOOD PRESSURE MEASUREMENT ....................................... 72 
16. 
APPENDIX 4 – CHILD-PUGH SCORE ................................................................... 73 
17. 
APPENDIX 5 – MELD SCORE ................................................................................. 74 
18. 
APPENDIX 6 - FRACTIONAL SODIUM EXCRETION RATE ........................... 75 
19. 
APPENDIX 7 – HEPATIC ENCEPHALOPATHY SCORE ................................... 76 
20. 
APPENDIX 8 – COMPUTATION OF GLOMERULAR FILTRATION RATE . 77 
21. 
APPENDIX 9 – SHORT FORM 36 AND CLDQ ..................................................... 78 


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1. LIST OF ABBREVIATIONS 
 
 
 
Abbreviation or specialist term 
Explanation 
8-LVP 
8-lysine-vasopressin 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine amino transferase, also known as SGPT 
ANCOVA 
analysis of covariance 
AST 
aspartate amino transferase, also known as  SGOT 
AUC 
area under the curve 
BP 
blood pressure 
BUN 
blood urine nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CO2 
carbon dioxide 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
d 
day 
DCF 
data clarification form 
dL 
deciliter 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
electrocardiogram 
Emax 
maximum effect 
EVH 
esophageal variceal hemorrhage 
FENa 
fractional excretion of sodium 
FDA 
Food and Drug Administration 
FU 
follow-up 
GCP 
Good Clinical Practice 


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Abbreviation or specialist term 
Explanation 
GCRC 
General Clinical Research Center 
GFR 
glomerular filtration rate 
hr 
hour 
HR 
heart rate 
HRS 
hepatorenal syndrome 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
MAP 
mean arterial pressure 
MedRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
MDRD 
modification of diet in renal disease 
NSAIDs 
nonsteroidal  anti-inflammatory drugs 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PD 
pharmacodynamic 
pp 
per protocol 
PPCD 
post paracentesis circulatory dysfunction 
q6h 
once every six hours 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RRT 
renal replacement therapy 
SAE 
serious adverse event 
SAER 
serious adverse event report 
SBP 
systolic blood pressure 
SCr 
serum creatinine 
SGOT 
serum glutamic-oxaloacetic transaminase, also known as 


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Abbreviation or specialist term 
Explanation 
SGPT 
serum glutamic-pyruvic transaminase, also known as 
SmPC 
summary of product characteristics 
SNPs 
single nucleotide polymorphisms 
TBD 
to be determined 
TIPS 
transjugular intrahepatic portosystemic shunt 
US 
United States 
UTI 
urinary tract infection 


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2. SYNOPSIS 
 
 
 
Title of 
Study: 
Safety and pharmacodynamic activity of low-dose terlipressin delivered by 
continuous intravenous infusion in patients with cirrhosis and refractory 
ascites requiring recurrent large volume paracentesis 
Objectives 
Primary Objectives 
• To assess the safety and tolerability of continuous infusion of terlipressin for 28 days 
in cirrhotic patients with refractory ascites. 
• To determine the steady state pharmacokinetics of terlipressin and 8-LVP in cirrhotic 
patients with refractory ascites. 


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Study Design: 
The study is an open label trial of continuous infusion terlipressin. 
The study will enroll 6 patients with cirrhosis and refractory ascites. Two sentinel patients 
with serum creatinine <1.5 mg/dL will be enrolled first in a safety lead-in Phase. Thereafter 4 
additional patients will be enrolled, with no less than 2 patients with serum creatinine ≥ 1.5 
and < 2.0 mg/dL 
After being enrolled in the trial patients will be monitored for up to 28 days until they 
require a therapeutic paracentesis. Starting within 3 days of the paracentesis, patients will be 
treated with a continuous infusion of terlipressin over 7 days in-house and, if tolerated, 
continue treatment in the ambulatory setting for another 21 days. The initial Terlipressin 
infusion dose will be 2 mg/day, which may be escalated to 3 mg and to 4 mg based on effect 
of treatment on morning MAP and observed safety and therapeutic response. Upon 
completion of treatment, patients will be monitored for safety for 28 days in the ambulatory 
setting. The study design is outlined below: 


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Main Inclusion/Exclusion Criteria: 
Criteria for Inclusion: 
• Patients with cirrhosis 
• Patient has diuretic-resistant or intractable ascites and required 3 or more large volume 
paracenteses in the previous 60 days 
• Patient male and female age between 18-70 years 
• Women of child bearing potential (e.g. not post-menopausal for at least one year or 
surgically sterile) must be neither pregnant or lactating and must agree to use adequate 
birth control or be abstinent for the duration of the study 
• If patient is treated with an ACE inhibitors or beta blockers, has been on a stable dose 
for at least 2 months prior to enrollment and may be maintained on that dose for the trial 
duration. 


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Main Inclusion/Exclusion Criteria: 
Criteria for Exclusion 
• 
Ascites with causes other than cirrhosis such as cardiac, nephrogenic ascites or 
malignant ascites due to peritoneal carcinomatosis 
• 
Total bilirubin > 5 mg/dL 
• 
Blood clotting International normalized ratio (INR) > 2.5 
• 
For two sentinel patients  Serum creatinine < 1.5 mg/dL 
• 
For other patients: Serum creatinine < 2.0 mg/dL 
• 
Current or recent (within 3 months of consent) renal dialysis 
• 
Hepatic encephalopathy grade 3 or 4 
• 
Superimposed acute liver failure/injury due to factors including alcoholic hepatitis, 
acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins (e.g., 
mushroom [Amanita] poisoning) 
• 
Current or recent treatment (within 7 days) with octreotide, midodrine, vasopressin, 
dopamine or other vasopressors 
• 
Respiratory failure requiring PAP devices or intubation 
• 
SIRS/sepsis episode in the previous 28 days from consent 
• 
Episode of spontaneous bacterial peritonitis or gastrointestinal hemorrhage within 28 
days of consent 
• 
Ongoing documented or suspected infection 
• 
Severe cardiovascular disease that are contraindication to terlipressin therapy such as 
advanced arteriosclerosis, arrhythmia, coronary insufficiency or uncontrolled 
hypertension 
• 
Findings suggestive of severe organic renal disease (proteinuria, hematuria, or 
abnormal renal ultrasound suggestive of obstructive or other renal pathology) 
• 
Severe comorbidity that in the opinion of the Investigator would affect short-term 
prognosis (such as for example, advanced progressive neoplasia such as 
hepatocellular carcinoma [confirmed with serum AFP testing], severe COPD or 
asthma) 
• 
Alcoholics who have not been abstinent for the past 12 weeks 
• 
Transjugular intrahepatic portosystemic shunt or other surgical shunt 
• 
Known allergy or hypersensitivity to terlipressin 
• 
For female patients: Confirmed pregnancy 
• 
Participation in other clinical research studies involving treatment with other 
investigational drug or evaluation of implantable device within 30 days of 
t
Study Evaluations: Refer to the Table in Section 6.1 


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3. INTRODUCTION 
Cirrhotic patients that require paracentesis for mobilization of ascites, despite treatment with 
diuretics and sodium restriction, have a very poor prognosis and expedited referral for liver 
transplantation is recommended (Runyon, 2013). Since these patients are not hospitalized, 
outpatient therapies are desperately needed to manage ascites and decrease rate of complication 
and the need for hospitalization, in addition to improving quality of life. Such a therapy can act 
as a bridge to liver transplantation in those eligible for transplant and as palliative care in those 
ineligible for transplant. 
A reduction of the splanchnic vasodilation associated with portal hypertension and sodium and 
water retention can lead to a decrease in ascites formation by means of an increase in effective 
blood volume and a decrease in activation of the renin-angiotensin system with resulting 
increase in renal sodium excretion (Kalambokis, 2005). Terlipressin (triglycyl lysine 
vasopressin; a long-acting synthetic analogue of vasopressin), binds to vasopressin 1 receptors 
and acts as a vasoconstrictor on the splanchnic circulation. A number of studies support the use 
of terlipressin to correct hemodynamic dysfunction and manage ascites in cirrhotic patients. 
Terlipressin has been shown to: 1) reduce portal hypertension in cirrhotic patients (Ding, 2013, 
Escorsell, 1997, Narahara, 2009, Baik, 2005); 2) improve renal function and induce natriuresis 
in cirrhotic patients with ascites without hepatorenal syndrome (HRS) (Krag, 2007); 3) increase 
GFR, urine volume and urine sodium while decreasing renin and aldosterone levels in HRS 
patients in combination with albumin (Ortega, 2002); 4) decrease the need for large volume 
paracentesis, increasing urinary sodium excretion when used in combination with albumin and 
diuretics in refractory ascites patients with normal renal function (Fimiani, 2011) and 5) reduce 
the volume of ascites and number of paracentesis procedures in refractory ascites patients 
treated for 28 days with terlipressin administered as a continuous infusion on an outpatient 
basis (Gow, 2016). 
Currently, terlipressin is approved in Europe for the treatment of bleeding esophageal varices 
and HRS type 1. In two US clinical trials in patients with type 1 HRS terlipressin was 
administered as an IV bolus starting at 1 mg every 6 h and increased to 2 mg every 6 h 
(maximum 8 mg/day depending on response). 


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Recent studies support the increased safety and efficacy of low-dose terlipressin delivered by 
continuous infusion. While bolus dosing of terlipressin (1 or 2 mg) leads to a significant 
reduction of HVPG for 3-4 h, continuous infusion of terlipressin (4 mg/day) for 24 h results in 
a sustained reduction in portal venous pressure with no side effects (Ding, 2013). Continuous 
infusion allows for a significant reduction in the daily effective dose required for HRS reversal 
(2.23 mg/day versus 3.51 mg/day, p < 0.0001) with a concomitant reduction in AEs (35.29% 
continuous infusion vs 62.16% bolus regimen, p < 0.025) and SAEs (20.59% continuous 
infusion vs 44.4% bolus regimen, p < 0.05) (Cavallin, 2016). It thus appears that the improved 
safety of terlipressin delivered as a low-dose continuous infusion could enable its use in the 
outpatient setting in the prolonged treatment of patients with refractory ascites. In a pilot study, 
continuous outpatient infusion of terlipressin has been used successfully on an outpatient basis 
to reduce ascites and decrease the number of paracentesis procedures in 5/5 cirrhotic patients 
with refractory ascites (Gow, 2016). 
There is limited PK data for terlipressin in humans despite being available since the early 
1980s. Following IV bolus administration terlipressin plasma concentrations decline in a bi- 
exponential fashion. Terlipressin, which itself has vasopressive activity (Ryckwaert, 2009; 
Colson, 2016), reaches Cmax of > 50 ng/ml after a single IV dose of 0.7 mg after approximately 
5 minutes (Nilsson, 1990). Terlipressin is metabolized via enzymatic cleavage of its three 
glycine residues by endothelial peptidases into 8-lysine-vasopressin (8-LVP), its more 
biologically active component, with measurable levels of 8-LVP appearing approximately 30 
minutes after bolus administration, peaking at between 1 and 2 h (Forsling, 1980, Nilsson, 
1990). In 29 HRS patients, a dose of terlipressin of 1 mg every 6 h resulted in a mean Cmax of 
terlipressin and 8-LVP of 62 ng/mL and 0.75 ng/mL, respectively (Lucassin AusPAR 130827- 
cer). 
The pharmacokinetics and pharmacodynamics activity support the current bolus dosing 
regimen of every 4-6 h though significant reduction of portal hypertension lasts only half of a 6 
hour dosing interval with a bolus dose of 1 mg (Escorsell, 1997) and effects on hemodynamic 
parameters, including portal hypertension, are intermittent with this regimen (Ding, 2013). To 
date PK data is not available for continuous infusion of low-dose terlipressin but this regimen 
would presumably result in sustained therapeutic levels of both peptides. PK projections for 


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plasma concentrations at steady state (Css) of both terlipressin and 8-LVP during continuous 
infusion of a dose of 2 mg/day/subject estimate steady state levels to be 2-3 ng/ml and 0.1 to 
0.3 ng/ml, respectively. The projected Css of terlipressin is far less than the Cmax obtained with 
bolus dosing (2-3 ng/ml vs 62 ng/ml) and might result in a reduction of the rate and severity of 
AEs related to the immediate severe hemodynamic effects of terlipressin as a bolus dose. 
In our planned pilot study, low-dose continuous infusion of terlipressin will be administered via 
ambulatory pump to a cohort of cirrhotic patients with refractory ascites, initially for 7 days in 
a GCRC to establish safety and tolerability followed by transition to an outpatient setting for a 
further 21 days of treatment. Initially, 2 sentinel patients with SCr < 1.5 mg/dL will be enrolled 
followed by 4 additional patients with SCr < 2.0 mg/dL. An extensive PK analysis will be 
performed. The Css of both terlipressin and 8-LVP during continuous infusion of terlipressin 
will be determined. Successful management of ascites, as evidenced by a reduction in the need 
for paracentesis procedures and decreased ascites fluid volume, further supported by 
improvement in renal function, is anticipated to have a significant impact on the quality of life 
of these patients, including a decrease in the need for hospitalization. 
 
4. OBJECTIVES 
 
4.1. 
PRIMARY OBJECTIVES 
The primary objectives of this study are: 
 
• To assess the safety and tolerability of continuous infusion of terlipressin for 28 days in 
cirrhotic patients with refractory ascites. 
• To determine the steady state pharmacokinetic of terlipressin and 8-LVP in cirrhotic 
patients with refractory ascites. 
 
4.2. 
EXPLORATORY OBJECTIVES 
• To assess the reduction in requirement of frequency and volume of paracentesis with 
continuous infusion of terlipressin. 
• To assess the improvement in patient quality of life using the SF36 instrument with 
continuous infusion of terlipressin. 


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• To assess renal function based on the change in serum creatinine, glomerular filtration 
rate and sodium excretion with continuous infusion of terlipressin 
• To assess the plasma renin activity (PRA) and plasma aldosterone concentration with 
continuous infusion of terlipressin 
 
5. MATERIALS AND METHODS 
 
5.1. 
STUDY DESIGN 
The study is an open label single arm uncontrolled trial of continuous infusion terlipressin. The 
study will be completed in two sequential steps: 
• Two sentinel patients with cirrhosis and refractory ascites with serum creatinine < 1.5 
mg/dL will be enrolled and complete the 28 day infusion period. 
• Then, 4 additional patients with cirrhosis and refractory ascites with serum creatinine 
 
< 2.0 mg/dL). No less than 2 patients should have a serum creatinine ≥ 1.5 and < 2.0 
mg/dL. 
After being consented and enrolled in the trial patients will be monitored without intervention 
for up to 28 days until they require a therapeutic paracentesis. Starting within 3 days after the 
paracentesis, patients will be admitted to the GCRC and be treated with a continuous infusion 
of terlipressin over 7 days in-house with step-wise dose escalation, and, if tolerated, continue 
treatment in the ambulatory setting for an additional 21 days. The initial terlipressin infusion 
dose will be 2 mg/day, which may be escalated to 3 mg and to 4 mg based on effect of 
treatment on morning MAP, overall safety and pharmacodynamic response as detailed in 
Section 6.4.2.   Upon completion of treatment, patients will be monitored for safety for 28 
days in the ambulatory setting.  The study design is outlined below. 


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Patients will then enter a long-term observation only follow-up post-trial for an additional 3 
months to monitor morbidity (transplant free survival, requirement for dialysis and need for 
therapeutic paracentesis). 
 
5.2. 
STUDY SITES 
Patients will be enrolled at up to 3 sites in the US. 
 
5.3. 
STUDY POPULATION 
 
5.3.1. Patient Screening and Enrollment 
Informed consent will be obtained from each potential patient prior to screening for eligibility. 
A sufficient number of patients will be enrolled to ensure that a total of 6 patients complete the 
planned treatment periods. 
 
5.3.2. Criteria for Inclusion 
• Patients with cirrhosis. 
 
Note: The diagnosis of cirrhosis will based on liver biopsy (Ishak fibrosis stage 5–6) or, 
in the absence of a liver biopsy, on clinical diagnosis by the Investigator on the basis of 
the combination of unequivocal clinical data (splenomegaly, spider angiomata, palmar 
erythema, gynecomastia, and jaundice), and compatible laboratory (thrombocytopenia, 
leucopenia, hypoalbuminemia and hyper-bilirubinemia) or combination Indices with 


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better specificity such as a Bonacini cirrhosis discriminant score greater than 7 [Section 
22] (Udell 2012), ultrasonography and endoscopic findings. 
• Patient has diuretic-resistant or intractable ascites and required 3 or more large volume 
paracenteses in the previous 60 days [A written record of these paracentesis - date and 
volume - must be available in the patient medical file]. 
Note: Diuretic-resistant ascites: Ascites that is unresponsive to sodium-restricted diet 
and high dose diuretic treatment (increasing doses of spironolactone up to 400 mg/day 
and addition of furosemide up to 160 mg/day) for a least 1 week. 
Note: Diuretic-intractable ascites: Ascites that cannot be treated with diuretics due to 
the development of clinically significant complications of diuretics, as determined by 
Investigator, e.g., encephalopathy, acute kidney injury, significant decreases in serum 
sodium or increases in serum potassium. (AASLD Practice Guideline 2012, Arroyo, 
1996). 
Note: Large volume will be defined as a paracentesis ≥ 4 liters. 
 
• Patient male and female age between 18-70 years 
 
• Women of child bearing potential (e.g. not post-menopausal for at least one year or 
surgically sterile) must be neither pregnant or lactating and must agree to use adequate 
birth control or be abstinent for the duration of the study 
• If patient is treated with an ACE inhibitors or beta blockers, has been on a stable dose 
for at least 2 months prior to enrollment and may be maintained on that dose for the trial 
duration. 
 
5.3.3. Criteria for Exclusion 
• 
Ascites with causes other than cirrhosis such as cardiac or nephrogenic ascites or 
malignant ascites due to peritoneal carcinomatosis 
Note: Cardiac ascites based on high serum-ascites albumin gradient (SAAG) greater 
than 1.1 g/dL and a high ascitic fluid total protein greater than 2.5 g/dL and compatible 
echocardiogram with an EF < 50%. 


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• 
Total bilirubin > 5 mg/dL 
 
• 
Blood clotting International normalized ratio (INR) > 2.5 
 
• 
For two sentinel patients: Serum creatinine < 1.5 mg/dL. For other patients: Serum 
creatinine < 2.0 mg/dL 
• 
Current or recent (within 3 months of consent) renal dialysis 
 
• 
Hepatic encephalopathy grade 3 or 4 
 
• 
Superimposed acute liver failure/injury due to factors, including acute alcoholic 
hepatitis, acute viral hepatitis, drugs, medications (e.g., acetaminophen), or other toxins 
(e.g., mushroom [Amanita] poisoning) 
• 
Current or recent treatment (within 7 days) with octreotide, midodrine, vasopressin, 
dopamine or other vasopressors 
• 
Respiratory failure requiring PAP devices or intubation 
 
• 
SIRS/sepsis episode in the previous 28 days from consent 
 
Note: SIRS is defined as the presence of 2 or more of the following findings: 
temperature > 38°C or < 36°C; heart rate > 90/min; respiratory rate of > 20/min or a 
PaCO2 of < 32 mm Hg; white blood cell count of > 12,000 cells/μL or < 4,000/ μL 
Note: Sepsis: Documented infection and SIRS 
 
• 
Episode of spontaneous bacterial peritonitis or gastrointestinal hemorrhage within 28 
days of consent 
• 
Ongoing documented or suspected infection 
 
• 
Severe cardiovascular disease that are contraindication to terlipressin therapy such as 
advanced arteriosclerosis, arrhythmia, coronary insufficiency or uncontrolled 
hypertension 
• 
Findings suggestive of severe organic renal disease (severe proteinuria/hematuria, or 
abnormal renal ultrasound suggestive of obstructive or other renal pathology) 


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• 
Severe comorbidity that in the opinion of the Investigator would affect short-term 
prognosis and/or disallow safe participation in the trial (such as for example, severe 
anemia or pancytopenia, advanced progressive neoplasia such as hepatocellular 
carcinoma [confirmed with serum AFP testing], severe COPD or asthma) 
• 
Alcoholics who have not been abstinent for the past 12 weeks 
 
• 
Transjugular intrahepatic portosystemic shunt or other surgical shunt 
 
• 
Known allergy or hypersensitivity to terlipressin. 
 
• 
For female patients: Ongoing pregnancy. 
 
• 
Participation in other clinical research studies involving treatment with other 
investigational drug or evaluation of implantable device within 30 days of 
consent. 
 
5.4. 
METHOD OF ASSIGNING TREATMENT NUMBERS TO PATIENTS 
Subjects will receive a study number after they have signed an informed consent and their 
eligibility to enter the study has been confirmed. Patients will be assigned a three-digit study 
number in the order in which they are enrolled at a site, with the first digit to represent the site 
number.  For example, the first patient enrolled at site #1 will carry the number 101. 
 
5.5. 
REPLACEMENT OF PATIENTS 
Patient who withdraw or drop-out of the study for a reason unrelated to drug safety prior to 
completion of planned continuous infusion with terlipressin will be replaced. The replacement 
subject will be assigned a new study number. 
 
5.6. 
DESCRIPTION OF CLINICAL SUPPLIES 
In this protocol terlipressin refers to terlipressin acetate, with approximately 85% terlipressin 
peptide content, i.e. a 2 mg terlipressin infusion, would refer to 1.7 mg terlipressin peptide 
equivalent. 
Terlipressin acetate will be formulated as a sterile product in 0.9% sodium chloride and 
provided in a volume of 65 ml (65 mL volume in order to deliver 50 mL) in a 100 mL flexible 
IV bags at a concentration of 0.04 mg/ml, 0.06 mg/ml or 0.08 mg/ml) to be administered 


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intravenously by continuous infusion at a dose of 2, 3 or 4 mg/day respectively. 


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Terlipressin IV solution is received at the site pre-formulated and ready to administer. The 
solution is maintained at 2 – 8 C and should be warmed to RT prior to initiating administration. 
A Pharmacy Manual will be provided to the site research pharmacy to detail preparation and 
handling of the terlipressin IV solution. 
IV infusion must be initiated within 72 hours of solution preparation. 
 
The solution is to be administered over 24 hours (infusion rate 2.1 ml/hr) using a Curlin 6000 
CMS Continuous Therapy ambulatory pump manufactured by Moog (see Moog Curlin 6000 
series Clinicians Guide V2.01 and User Manual for use with the 6000 CMS™ and 6000 
CMS™ IOD™ Ambulatory Infusion System in references, a copy of which will be provided to 
clinical sites). The solution must be administered using a Moog Curlin® Infusion 
Administration set with 1.2 micron filter and anti-siphon valve which is a non-DEHP 
microbore tubing with a non-vented bag spike. The ambulatory infusion pumps and 
administration sets will be provided to the site pharmacy by Coram Clinical Trials. A detailed 
study drug handling and administration manual will be provided to the site pharmacy and other 
site personnel. Fresh bags of solution are to be administered with new administration sets. 
Inventory and destruction of supplies sent to the GCRC floor or to the hospital pharmacy will 
be handled locally per the hospital pharmacy procedures. Otherwise, infusion bags will be 
returned to Coram Pharmacy weekly as part of the Drug Inventory process and properly 
disposed of at Coram Pharmacy. Medical waste (needles, etc.) are placed in a Mailback Sharps 
container. 
 
5.7. 
LABELING OF CLINICAL SUPPLIES 
The label affixed to the Terlipressin bag will include the following information: 
 
- 
Patient name 
 
- 
Patient ID <number> 
 
- 
Rx number 
 
- 
Prescriber 
 
- 
Terlipressin Acetate dose and volume <  
mg/ 
mL> 


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- 
Discard after <date> 
 
- 
Storage: Refrigerated 
 
- 
Date prepared: <date> 
 
- 
Caution: New Drug--Limited by Federal law to investigational use - 
mg/mL 
terlipressin (as terlipressin acetate) in 0.9% sodium chloride solution - Bag contains 65 
mL to deliver 50 mL over 24 hours - discard unused material via incineration 


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6. 
STUDY PLAN AND PROCEDURES 
 
6.1. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES 
 
Study Assessment 
Screening 
Period 
Pre-Treatment Period 
Not over 28 days 
(Days prior terlipressin 
infusion) [1] 
Treatment  Period [2] 
Follow-up Period (days after 
terlipressin infusion) [3] 
StudyEntry 
Day -28 to -1 
At GCRC 
Ambulatory 
Site visits 
Day +14 
(± 2 days) 
Day +28 
(± 3 days) 
Baseline 
Day 0 [6] 
Day 1 to 7 
Day 8 to 28 
Day 14±1 
and 28±1 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Assign Study Number 
X 
Medical History 
X 
Disease History – Child-Pugh score – 
Encephalopathy score 
X 
Physical Exam 
X 
X 
X 
X 
Pregnancy test 
X 
Height 
X 
Concomitant Medications 
X 
Collect Treatment emergent AEs 
X 
Record AEs of Interest 
X 
X (Day 7) 
X 
X 
X 
Weight / Abdominal circumference/ 
Temperature 
X 
X 
X [14] [17] 
X [8] 
X 
X 
X 
12-lead ECG 
X 
X 
X [14] 
X [16] 
X 
X 
Vital Signs (MAP/BP, HR) 
X 
X [5] 
X 
X [15] 
X [8] 
X 
X 
X 
Serum Creatinine & BUN 
X 
X [5] 
X 
X [14] 
X 
X 
X 
Serum Electrolytes, glucose, Calcium 
X 
X 
X [13] 
X 
X 
X 


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Study Assessment 
Screening 
Period 
Pre-Treatment Period 
Not over 28 days 
(Days prior terlipressin 
infusion) [1] 
Treatment  Period [2] 
Follow-up Period (days after 
terlipressin infusion) [3] 
StudyEntry 
Day -28 to -1 
At GCRC 
Ambulatory 
Site visits 
Day +14 
(± 2 days) 
Day +28 
(± 3 days) 
Baseline 
Day 0 [6] 
Day 1 to 7 
Day 8 to 28 
Day 14±1 
and 28±1 
ALT, AST, ALP, Protein, Albumin, 
Bilirubin, PT/INR 
X 
X 
X [13] 
X [16] 
X 
CBC and differential 
X 
X 
X [18] 
X 
X 
Plasma renin activity and aldosterone 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
24 hr. sodium urine excretion 
X [5] 
X 
X 
X 
Spot urinary creatinine and sodium 
X 
X [13] 
X 
X 
X 
GFR (sponsor calculation) 
X 
X 
X [13] 
X 
X 
X 
Fractional excretion of Sodium 
(sponsor calculation) 
X 
X [13] 
X 
X 
X 
MELDScore (sponsor calculation) 
[12] 
X 
X [13] 
X 
X 
Terlipressin infusion 
X [7] [15] 
X [8] 
PK sampling 
X [9] [10] [19] 
Therapeutic paracentesis 
X [4] 
X [4] [19] 
Short Form 36 and CLDQ QOL [11] 
X 
X 
X 
X 
Sodium-intake daily tracker weekly 
monitoring 
X 
X 
X 


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1- Pre-treatment phase of up to 28 day duration, prior start of terlipressin infusion – Numbered Day -28 to -1 
2- Treatment period, terlipressin infusion starts Day 1 – Numbered Day 1 to 28 – Day1-7 are administered at GCRC (patient discharge after Bag #7 started), 
while Day 8-28 are administered in ambulatory setting under home supervision by a nurse. 
3- Post-treatment follow-up period, after completion of terlipressin infusion – Numbered +1 to +28 
4- As required during pre-treatment, treatment and post-treatment period – date of procedures and volume removed will be recorded. Ascites fluid will be 
inoculated into blood culture bottles at the bedside and examined by microscopy for a neutrophil count to rule out spontaneous bacterial peritonitis (SBP). 
Date/volume removed of paracentesis following Day 28 discharge will be collected from the patient file to compute intervals between paracentesis. 
Requirement for dialysis during that period will also be recorded. 
5- Pre-paracentesis baseline serum creatinine, 24hr sodium urine excretion and MAP will be established by collection two values at least a week apart, one 
should be at time of therapeutic paracentesis performed prior to terlipressin infusion 
6- Day 0 is day of admission to GCRC 
7- Terlipressin dosing will start on Day 1 at 2 mg/day administered as IV continuous infusion via an infusion pump. The Terlipressin infusion rate may be 
raised step-wise. The first dose escalation may no earlier than Hour 48 to 3 mg/day Terlipressin; the second dose escalation no earlier than Hour 96 to 
4mg/day Terlipressin. (Dose escalation based on observed MAP response, safety and pharmacodynamic response - Refer to Section 6.4.2) 
8- Ambulatory, managed by daily home visit by study nurse 
9- PK sampling times (Refer to Section 6.7): [Blood samples on Day 1 will be collected in the arm contralateral to the terlipressin infusion, if possible, or 
below the terlipression infusion site in the same arm.] 
• 
Prior to the start of the terlipressin infusion on day 1 and 0.5, 0.75, 1, 1.5, 2, 3, 6, and 24 h after the start of the continuous infusion. 
• 
Prior to the change in infusion rate and 1, 2 and 8 hours after the change to 3 mg, if it occurs. 
• 
Prior to the change in infusion rate and 1, 2 and 4 hours after the change to 4 mg, if it occurs 
• 
Morning on days 7, 14 and 28. 
10- If infusion is discontinued due to AE, an additional blood sample will be obtained prior to interruption of terlipressin infusion 
11-Short Form 36 and CLDQ QOL instruments - Refer to Section 21 
12- Refer to Section 17 
13- Done on Day 3, 5 (i.e. prior to potential dose adjustments at hour 48 and 96) and at discharge 
14-Done Daily 
15- Terlipressin dose changes are based on MAP computed from first BP measurement in the morning (average from 2 morning measurement of MAP in 
sitting position – Refer to Section 15), safety and pharmacodynamic response (See Section 6.4.2. BP and HR compiled before Terlipressin start of infusion 
or dose adjustment(s) and at 0.5, 1, 2, 3, and 6 hours thereafter, then twice a day. 
16- Once weekly during outpatient treatment 
17- Done first thing in the morning prior to breakfast 
18-Done upon discharge from GCRC (Day 7) 


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19-If a LVP occurs during terlipressin infusion, then blood samples, 4-ml, will be collected in the arm contralateral to the terlipressin infusion, if possible, or 
below the terlipressin infusion site in the same arm immediately before the paracentesis, 30 minutes after completion of the paracentesis and if feasible 6 
hours after completion of the paracentesis 


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6.2. 
ETHICS AND REGULATORY CONSIDERATIONS 
This study will be conducted according to Good Clinical Practice, the Declaration of Helsinki, 
and U.S. 21 CFR Part 50 – Protection of Human Subjects, and Part 56 – Institutional Review 
Boards. Written informed consent for the study must be obtained from all patients before 
protocol-specific procedures are carried out. Patients will be informed of their right to withdraw 
from the study at any time. 
The written consent document will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations.  Each patient will receive 
an oral and a written explanation of the purposes, procedures and potential hazards of this study 
and will be offer the opportunity to ask questions. Consent will be documented by the dated 
signature of the subject. The signature confirms that the consent is based on the information that 
has been understood. Each subject’s signed informed consent will be kept on file by the 
investigator for possible inspection by sponsor representatives and regulatory authorities. 
 
6.3. 
SCREENING AND PRE-TREATMENT PERIOD 
 
6.3.1. Screening Procedures 
To determine whether a patient meets the eligibility criteria the site investigator or 
representative will examine medical records of patients who consult at the clinic for resistant 
ascites or patients who require therapeutic paracentesis, including cirrhosis history, recent safety 
laboratory results and medication records and may contact patients who appear to meet 
eligibility criteria. 
 
6.3.2. Informed Consent 
Obtain the written informed consent from the patient prior to performing any trial mandated 
activities and tests. 
Collect appropriate contact information to conduct follow-up assessment (i.e. name, mailing 
address, Email and phone number of patient, contact for caregiver and physicians). This 
confidential information should NOT be transmitted to BioVie Inc. personnel and should be 
stored accordingly. 


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6.3.3. Study Entry Visit 
The following assessments will be performed: 
 
• Significant medical history over the past 5 years and current medical conditions 
 
• Cirrhosis disease history 
 
• Collate Child-Pugh and encephalopathy score 
 
• Physical exam, with vitals (MAP/BP, HR), body height/weight, temperature, abdominal 
circumference 
• Electrocardiogram 
 
• Collect blood samples for clinical laboratory assessments including: Hematology (CBC 
with differential), Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total protein, albumin, total and direct bilirubin, PT/INR), PRA and plasma aldosterone. 
• Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein. 
• List concomitant medications 
 
• Administer the Short Form 36 and CLDQ QOL 
 
6.3.4. Enrollment of Patients 
Patients who meet inclusion/exclusion criteria will be assigned a study number and are also to 
be identified by first, middle and last initials. If the patient has no middle initial, a dash is to be 
used. For patients screened but found non-eligible the reason will be recorded in a screening 
log. 
 
6.3.5. Pre-Treatment Observation Period 
Patients will be monitored for up to 28 days after enrollment into the study. They will continue 
their standard medical care, including dietary restriction and stable therapy with diuretics (i.e. 
spironolactone, furosemide). 


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A pre-paracentesis baseline serum creatinine, 24 hr Na+ urine excretion and MAP will be 
established by collection of two values at least a week apart, one should be close to time of 
therapeutic paracentesis performed prior to terlipressin infusion. 
Admission to GCRC and start of Terlipressin infusion will be dependent on when a therapeutic 
paracentesis is warranted, as terlipressin treatment should start within 3 days of a paracentesis. 
If the patient does not require a paracentesis within this 28 days observation period then the 
patient will be terminated from the trial and will be replaced. The volume of ascites drained at 
paracentesis will be recorded. The ascites fluid will be tested for evidence of spontaneous 
bacterial peritonitis (SBP) (PMN count, culture). A patient found to have SBP will be 
withdrawn from the trial and not receive terlipressin infusion. Such patients will be replaced. 
At the time of the paracentesis, female patients will have a serum pregnancy test to confirm they 
are not pregnant. The patient will be admitted to the GCRC so that terlipressin infusion may be 
initiated within 1 and 3 days of completion of the paracentesis. 
 
6.4. 
TREATMENT PERIOD 
 
6.4.1. Baseline - Admission 
Patient will be admitted to the GCRC the day prior to planned initiation of terlipressin infusion. 
A peripherally inserted central catheter (PICC) or a midline catheter per site usual practice will 
be positioned for administration of terlipressin. 
The following tests will be completed prior to start of terlipressin infusion: 
 
• 
Sign and symptoms directed physical exam, with vitals, body weight, temperature, 
abdominal circumference 
• 
Electrocardiogram 
 
• 
Collect blood samples for clinical laboratory assessments including: Hematology (CBC 
with differential), Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total protein, albumin, total and direct bilirubin, PT/INR). 


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• 
Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein. 
• 
24 hour urinary sodium excretion 
 
• 
List concomitant medications 
 
• 
Administer the Short Form 36 and CLDQ QOL 
 
• 
Evaluate AE of interest pre-treatment 
 
The patient should be hemodynamically stable prior to starting the terlipressin infusion. BP/HR 
and MAP should be determined at least twice and terlipressin infusion may be delayed within 
the 72-hour window according to the inclusion criteria if the patient is found hemodynamically 
unstable. 
 
6.4.2. In-House Treatment of Patients 
Terlipressin will be administered by continuous intravenous infusion. Start of infusion should be 
within 1-3 day from completion of the first therapeutic paracentesis that occurs during the Pre- 
Treatment Period. 
Initial terlipressin dosing will be 2 mg/day administered via an ambulatory infusion pump. 
Refer to Section 5.6 for detailed pharmacy and preparation instructions. The following 
assessments will be obtained prior to starting terlipressin infusion in the morning: 
• 
Estimated MAP (computed as 2/3[diastolic] + 1/3[systolic] taken from the earliest 
morning BP measurement repeated once 10 minutes apart in a sitting position - Refer to 
Section 15. 
• 
Spot urinary creatinine and sodium 
 
• 
Vitals, including MAP/BP and HR will be monitored for safety during the infusion of 
terlipressin and after each dose adjustments (See below) at 0.5, 1, 2, 3 and 6 hours. 
A first dose escalation may occur no earlier than Day 3 (Bag #3) to 3 mg/day terlipressin; A 
dose escalation will occur unless the following is observed: 


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• 
Estimated MAP (computed as 2/3[diastolic] + 1/3[systolic] taken from the earliest 
morning BP measurement is increased compared from pre-dose escalation or pre- 
treatment values by more than 5 mmHg. Note: Estimated MAP will be obtained from 
the average of 2 BP measurements taken 10 minutes apart in a sitting position - Refer to 
Section 15. 
• 
Based on investigator judgment a dose increase is not advisable (including for example: 
Treatment emergent elevation of systolic BP over 120 mmHg, clinically significant signs 
or symptoms of vasoconstriction, headache, and arrhythmia or other treatment emergent 
ECG anomalies, treatment emergent gastrointestinal symptom, treatment emergent 
hyponatremia / hypokalemia or fluid imbalance, other clinically significant AE deemed 
probably related to treatment by the investigator). The reason(s) for not escalating the 
infusion rate will be documented on the CRFs. 
A second dose escalation may occur to 4 mg no earlier than Day 5 (Bag #5) if based on 
Investigator judgement a dose increase is advisable: 
• Treatment has been well tolerated and no concerning treatment emergent anomalies have 
occurred, such as: Sustained of morning MAP by more than 5mmHg from pre-treatment 
values, treatment emergent elevation of systolic BP over 120 mmHg, clinically 
significant signs or symptoms of vasoconstriction, headache, and arrhythmia or other 
treatment emergent ECG anomalies, treatment emergent gastrointestinal symptom, 
treatment emergent hyponatremia / hypokalemia or fluid imbalance, signs of 
dehydration, signs of reduced renal function, and other clinically significant AE deemed 
probably related to treatment in the opinion of the investigator). 
• There has been no sign of a pharmacodynamic response to terlipressin therapy, such as 
no clinically significant increased sodium excretion, no reduction in weight or abdomen 
circumference, volume of paracentesis or ascites accumulation appears unchanged from 
baseline. 
Should the dose escalation to 4 mg be decided by the Investigator after discharge form the 
GCRC (Refer to Section 6.4.4) then the patient will be monitored in-house for safety for no less 


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than 6 hours. Vitals, including MAP/BP and HR will be monitored for safety after the dose 
adjustments to 4 mg/day at 0.5, 1, 2, 3 and 6 hours. 
Bag for Terlipressin continuous infusion will be changed daily. 
 
6.4.3. Day 1-7 in-house monitoring 
The following assessments will be performed daily: 
 
• 
Body weight, abdominal circumference, temperature - first thing in the morning prior to 
breakfast 
• 
Vitals, including MAP/BP and HR (twice daily – the morning measurements [in 
duplicate] serves to adjust terlipressin dose) 
• 
Electrocardiogram 
 
• 
Collect blood sample for serum creatinine and BUN (except when a full metabolic panel 
is done – see below) 
• 
Collect treatment emergent AEs and concomitant medications 
 
The following assessment will be repeated on Day 3 and 5 (i.e. prior to Terlipressin dose 
adjustments): 
• 
Collect blood for Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total protein, albumin, total and direct bilirubin, PT/INR) 
• 
Spot urinary creatinine and sodium 
 
6.4.4. Discharge from GCRC 
The patient will be discharge from the unit on Day 7 (after Bag #7 has been started). However, 
when the 3 mg dose of terlipressin infusion has been maintained for no less than 24 hours the 
patient may at the Investigator discretion, be discharged home for the night and return for day 
monitoring at the GCRC in the morning. 
The following assessments will be performed on Day 7: 
 
• 
24 hour urinary sodium excretion 


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• 
Electrocardiogram 
 
• 
Collect blood samples for clinical laboratory assessments including: Hematology (CBC 
with differential), Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total protein, albumin, total and direct bilirubin, PT/INR). 
• 
Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein, and spot urinary creatinine/sodium. 
• 
Collect treatment emergent AE and concomitant medications 
 
• 
Evaluate AE of interest 
 
6.4.5. Ambulatory Treatment and Monitoring of Patients – Day 8-28 
Patient will continue treatment with terlipressin in the ambulatory setting. A licensed healthcare 
worker (RN, NP or MD) will make home visits twice a day for the first 7 days after discharge 
and once a day thereafter. The nurse will review with the patient his/her compliance with diet 
recommendation and salt restriction and spot evidences of possible intestinal bleeding (black 
stools). 
The following assessments will be performed: 
 
• 
Change terlipressin bag (morning visit only) 
 
• 
Body weight, abdominal circumference, temperature (morning visit only) 
 
• 
Monitor access line and infusion rate per instructions 
 
• 
Vitals, including BP and HR 
 
• 
Collect 24 hour urine for 24 hour urinary sodium excretion test prior to Visits at Day 14 
and 28 
• 
Monitor patient for emergent clinical complaints and emergent symptoms or AEs 
 
An electrocardiogram will be performed at weekly interval (refer also to visits at Day 14 and 28 
below). 


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Liver function test (ALT/AST, alkaline phosphatase, total protein, albumin, total and direct 
bilirubin, PT/INR) will be performed at weekly interval (refer also to visits at Day 14 and 28 
below). 
 
6.4.6. Interim Visits at Day 14 and 28 
The following assessments will be performed: 
 
• 
Sign and symptoms directed physical exam, with vitals, body weight, temperature, 
abdominal circumference 
• 
Electrocardiogram 
 
• 
Collect blood samples for clinical laboratory assessments including: Hematology (CBC 
with differential), Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total protein, albumin, total and direct bilirubin, PT/INR), PRA and plasma aldosterone. 
• 
Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein, and spot urinary creatinine/sodium. 
• 
24 hour urinary sodium excretion 
 
• 
Collect treatment emergent AEs and concomitant medications 
 
• 
Evaluate AEs of interest 
 
• 
Administer the Short Form 36 and CLDQ QOL (Day 28 Visit only) 
 
The terlipressin infusion will be terminated at the Visit on Day 28 and the IV line removed. 
 
6.4.7. Follow-up Period 
Patients will continue monitoring for emergence of AEs for 28 days after discontinuation of 
Terlipressin infusion. Two post-treatment visits are scheduled, 14 and 28 days (±2 days) after 
therapy. 
The following assessments will be performed at the visit on Day 14: 
 
• 
Vitals, body weight, temperature, abdominal circumference 
 
• 
Electrocardiogram 


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November 17, 2018 
 
 
 
• 
Collect blood samples for metabolic Panel (creatinine, BUN, electrolytes [sodium, 
potassium, CO2, chloride], glucose, calcium) and PRA and aldosterone. 
• 
Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein, and spot urinary creatinine/sodium. 
• 
Collect treatment emergent AEs and concomitant medications 
 
• 
Evaluate AEs of interest 
 
The following assessments will be performed at the final follow-up visit on Day 28: 
 
• 
Sign and symptoms directed physical exam, with vitals, body weight, temperature, 
abdominal circumference 
• 
Electrocardiogram 
 
• 
Collect blood samples for clinical laboratory assessments including: Hematology (CBC 
with differential), Metabolic Panel (creatinine, BUN, electrolytes [sodium, potassium, 
CO2, chloride], glucose, calcium), Liver function test (ALT/AST, alkaline phosphatase, 
total6.5 protein, albumin, total and direct bilirubin, PT/INR) and PRA and aldosterone. 
• 
Collect urine sample for urinalysis including: pH, glucose, bilirubin/urobilirubin, 
RBC/blood, WBC, protein, and spot urinary creatinine/sodium. 
• 
Collect treatment emergent AEs and concomitant medications 
 
• 
Evaluate AEs of interest 
 
• 
Administer the Short Form 36 and CLDQ QOL 
 
6.5. 
RECOMMENDED CONCOMITANT MEDICATION 
Diuretics will be maintained at the dose established in the pre-treatment period unless patient 
develops an adverse event, regardless of relationship attribution, that requires diuretic 
discontinuation (hypotension, acute kidney injury, GI hemorrhage). Patients will be maintained 
on the same dose of other medications (e.g. lactulose, rifaximin). 
If patients are on ACE inhibitors or beta blockers they will be required to be on a stable dose for 
at least 2 months prior to enrollment and maintained on that dose for the trial duration. 


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Albumin is recommended for all subjects per current standard of care after paracentesis to 
prevent post-paracentesis circulatory dysfunction (PPCD) and as clinically indicated. It is 
recommended (if clinically appropriate) that the albumin dose administered to prevent PPCD 
(usually 6-8 g/L of ascites fluid removed) is kept constant for each LVP that might be required 
during the study period.  Albumin use will be recorded in the CRF as a concomitant medication. 
 
6.6. 
PROHIBITED CONCOMITANT MEDICATIONS 
The following medications are prohibited or strongly discouraged during terlipressin infusion. 
 
Prohibited Concomitant Medications 
Midodrine and other vasopressive drugs including vasopressin, 
dopamine, dobutamine,norepinephrine 
Octreotide 
Prostaglandin analogs (e.g., misoprostol) 
NSAIDs (e.g., ibuprofen, naproxen, diclofenac) 
 
 
6.7. 
PHARMACOKINETICS OF TERLIPRESSIN 
In order to characterize the pharmacokinetics and examine the influence of potential covariates, 
serial blood samples will be obtained from subjects.  The pharmacokinetics of terlipressin and 
its metabolite, 8-lysine vasopressin, will be assessed following the start of the of the 2 mg/kg 
infusion on Day 1, at changes in infusion dose during the 7-day in-house stay, at interim visits 
while the infusion continues and prior to the discontinuation of the infusion due to an adverse 
effect. Blood samples will be collected in the arm contralateral to the terlipressin infusion, if 
possible, or below the terlipressin infusion site in the same arm. 
• Prior to the start of the terlipressin infusion on Day 1 and 0.5, 0.75, 1, 1.5, 2, 3, 6, and 
24h after the start of the continuous infusion. 
• Prior to the change in infusion rate and 1, 2 and 8 hours after the dose change to 3 mg (if 
such dose change occurs). 
• Prior to the change in infusion rate and 1, 2 and 4 hour after the dose change to 4 mg (if 
such dose change occurs) 


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• Morning on days 7, 14 and 28. 
 
• Prior to discontinuation of terlipressin for an adverse effect 
 
Samples on Day 1 up to 6 hr will be drawn through an intravenous catheter. The catheter will be 
kept patent between blood draws with normal saline until 6 hr. A waste sample, approximately 
1-2 mL, will be collected through the catheter and discarded prior to each sample. The 24 hr, 
weekly and adverse effect prompted blood draws will be performed by needle stick. Refer to 
Section 14 for instruction for sample processing. 
 
6.8. 
INFLUENCE OF PARACENTESIS ON TERLIPRESSIN PHARMACOKINETICS. 
The influence of removal of ascitic fluid on the pharmacokinetics of terlipressin and its 
metabolite, 8-lysine vasopressin, will be assessed. If a LVP occurs during terlipressin infusion, 
then blood samples, 4-ml, will be collected in the arm contralateral to the terlipressin infusion (if 
possible or below the terlipressin infusion site in the same arm) immediately before the 
paracentesis, 30 minutes after completion of the paracentesis and if feasible 6 hours after 
completion of the paracentesis. The total volume of ascites fluid removed during paracentesis 
will be measured and a 10-ml ascites fluid aliquot saved for assay. 
 
6.9. 
DIET 
Patient will remain on their regular diet with usual sodium restriction during the duration of the 
study per AASLD Practice Guideline 2012. Patients will be requested to complete a daily- 
sodium tracker form during the duration of the trial (American Heart Association Sodium 
Tracker) to be reviewed at weekly interval by a nutritionist to monitor their adherence to their 
diet. 
 
6.10. 
PATIENT EDUCATION 
Patient consented into the trial will receive dieticians’ guidance and information leaflets to assist 
in re-educating patient and relatives regarding salt restriction to a target of 90 mmol/day and 
helping the adoption of a no-added salt diet and avoidance of pre-prepared foodstuffs (for 
example, pies). 
Patients will also be educated to spot any evidence of intestinal bleeding (blood in stool or black 
stool). 


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6.11. 
THERAPEUTIC PARACENTESIS DURING AND AFTER THE STUDY PERIOD 
Paracentesis should be done as indicated by the patient condition when the following conditions 
are met: 
• Presence of moderate to severe ascites upon medical exam with patient discomfort 
(shortness of breath or umbilical hernia or abdominal pain and/or distension, and/or 
limitation of activity) and patient’s request for a repeat LVP 
• Weight gain to 90-100% of LVP delta weight loss (reference weight taken prior to initial 
LVP). For example, if the patient loss is 10kg immediately after LVP the patient must 
regain 9-10 kg (90%) of 10kg at the time of repeat paracentesis 
• Increase in abdominal girth to 90-100% of LVP delta abdominal girth (prior to initial 
LVP). 
Reason for deviations from the standardized triggers detailed above will be noted in the CRF. 
 
For each paracentesis performed in the course of the trial, the date and volume collected will be 
recorded. Ascites fluid will be inoculated into blood culture bottles at the bedside and examined 
by microscopy for a neutrophil count to rule out spontaneous bacterial peritonitis (SBP). 
A 10mL sample will be collected, labelled (Patient Number, Date of collection) and stored 
frozen for later determination of albumin and terlipressin ascites concentration if such 
determination is warranted. 
Adverse events following paracentesis including for example infection, post-paracentesis 
circulatory dysfunction (PPCD) and infection will be recorded, together with preventative 
measures such as administration of albumin. 
 
6.12. 
DATA COLLECTION AFTER THE STUDY PERIOD 
To better estimate the durability of the terlipressin effect and explore the possibility of a rebound 
effect, the date/volume of paracenteses occurring within 3 months after discharge from the trial 
will be collected from the patient file.  The requirement for dialysis, hospitalization and death 
will also be recorded. 
 
6.13. 
CRITERIA FOR WITHDRAWAL FROM STUDY 
Subjects have the right to discontinue treatment and/or withdraw from the study at any time 
without prejudice. The investigator may discontinue any subject at any time for any reason. 


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If study treatment or protocol-specified assessments are discontinued, the reason will be 
recorded on the CRFs and the sponsor should be notified promptly. 
Reasons for terminating participation in the clinical study may include the following: 
 
• 
Patient did not require a LVP during the up to 28 day Pre-Treatment Period. 
 
• 
Patient with evidence of SBP based on baseline ascites fluid examination. 
 
• 
Any clinical adverse event (AE), laboratory abnormality, requirement for a concomitant 
medication, concurrent illness, or other medical condition or situation occurs such that, 
in the opinion of the Investigator, continued participation in the study would not be in 
the best interest of the subject. 
• 
Serious protocol violation 
 
• 
Patient is non-compliant or lost to follow-up 
 
• 
Patient withdrawal of consent 
 
• 
Patient dies 
 
A patient may choose to discontinue participation in the study at any time. However, the Site 
Investigator or designee will encourage subjects who have initiated terlipressin treatment to 
continue with safety follow-up for 28 days after discontinuation of terlipressin infusion. 
If a patient permanently discontinues terlipressin infusion for safety reason the patient should 
continue safety follow-up as detailed by the protocol for 28 days and the adverse event causing 
withdrawal should be followed until the event resolves or stabilizes. 
 
6.14. 
PATIENT REPLACEMENT 
If a treated patient withdraws for a reason unrelated to drug toxicity, or is determined to be 
ineligible before dosing (based upon the requirements of this protocol), that patient will be 
replaced by the next eligible patient. 
Loss to follow-up should be prevented whenever possible and every attempt should be made to 
re-contact the patient. 


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Patients who permanently discontinue terlipressin infusion and who request to not continue 
safety monitoring per the study schedule should, whenever possible, complete an early study 
drug termination visit per protocol (Day 28 Visit). 
 
6.15. 
DISCONTINUATION OF TREATMENT FOR ADVERSE EVENTS 
Treatment with Terlipressin will be discontinued for the following adverse events. 
 
Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise specified a 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
Gastro-Intestinal 
Persistent diarrhea: Persistence of several (>5) loose, watery stools for 
more than 3 days after the start of the treatment associated with the 
need of rehydration therapy. 
Clinical evidence of intestinal ischemia with or without hematochezia 
or positive fecal occult blood test. 
Terlipressin 
infusion 
Discontinue 
terlipressin 
infusion, go 
to follow-up 
phase 
Underlying 
disease related 
events 
Treatment emergent spontaneous bacterial peritonitis (SBP) 
Gastrointestinal hemorrhage - variceal bleeding 
Treatment emergent moderate hepatic encephalopathy 
Cardiovascular 
Arterial hypertension: Arterial blood pressure >150/90 at least in three 
measurements during treatment (at any time in patients randomized to 
continuous i.v. infusion of terlipressin, within 2 hours after the bolus in 
those who were randomized to i.v. boluses of terlipressin) 
Circulatory overload: Shortness of breath associated with one among 
the following: a) tachypnea with rales, b) dilatation of the jugular veins, 
c) a central venous pressure, when available, higher than 18 cm H2O, 
or d) radiological signs of pulmonary edema 
Peripheral ischemia: Onset of pain associated with one among the 
following: a) pallor, b) coldness or  c) pulselessness 
Angina pectoris: A thoracic pain suggestive of ischemic origin 
(retrosternal or across the anterior chest sometimes radiating to the 
arms, neck, or shoulders) or any thoracic pain associated with the new 
onset ECG signs of myocardial ischemia 
Arrhythmia: Onset of one among the following: a) bradyarrhythmia (an 
heart rate that was less than 45 beats per minute), b) tachyarrhythmia 
(an heart rate higher than 120 beats per minute) or c) atrial 
fibrillation.Intestinal ischemia 
 
 
a        http:/tep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless otherwise specified a 
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE EVENT 
AGENT 
ACTION 
Myocardial infarction 
Prolonged QTc: At least Grade 2 with QTc prolongation as 471–500 ms 
or >60 ms change from baseline 
Acute liver injury 
Sustained (>1 week) doubling of AST or ALT levels to no less than 
4xULN 
Or sign of increasing functional liver impairment with >2x baseline 
increase in total bilirubin or an ≥INR 
Or increased AST or ALT levels above 8xULN 
Renal and urinary 
disorders 
Confirmed increase serum creatinine within 48 hr. consistent with acute 
kidney injury – such as > 50% baseline increase in serum creatinine. 
New onset hepatorenal syndrome (HRS) Type 1 
All other adverse 
events 
≥Grade 3 
 
 
Patient who discontinue treatment will be monitored as outlined in Section 6.4.7 in the Follow- 
up Period. 
 
6.16. 
AES OF INTEREST 
The emergence of the following AEs of interest will be specifically monitored on a regular basis 
during treatment: 
Intestinal ischemia: Persistent moderate to severe abdominal pain with or without hematochezia 
or positive fecal occult blood test. 
Arterial hypertension: Arterial blood pressure >140/90 at least in three measurements during 
terlipressin treatment. 
Circulatory overload: Shortness of breath associated with one among the following: a) 
tachypnea with rales, b) dilatation of the jugular veins, c) a central venous pressure, when 
available, higher than 18 cm H2O, or d) radiological signs of pulmonary edema 
Peripheral ischemia: Onset of pain in fingers or toes associated with one among the following: 
a) pallor, b) coldness or c) mottling. 


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Angina pectoris: A thoracic pain suggestive of ischemic origin (retrosternal or across the 
anterior chest sometimes radiating to the arms, neck, or shoulders) or any thoracic pain 
associated with the new onset ECG signs of myocardial ischemia. 
Arrhythmia: Onset of one among the following: a) bradyarrhythmia (heart rate that was less than 
45 beats per minute), b) tachyarrhythmia (heart rate higher than 120 beats per minute) or c) 
atrial fibrillation. 
 
6.17. 
MANAGEMENT OF AES AND TREATMENT DOSE MODIFICATION 
Initial management of treatment emergent AEs occurring during the in-house phase of the 
treatment and that do not meet the threshold for discontinuation of terlipressin infusion as 
detailed above, may be managed by a temporary interruption of terlipressin infusion based on 
clinical judgement and at the discretion of the Investigator. After dose interruption, if the AE 
has abated by 48 hr., terlipressin may be restarted at the starting dose of 2 mg terlipressin, at the 
discretion of the Investigator.  After restarting terlipressin, the dose may NOT be increased to 
the previously reached dose level. 
There may be only one dose interruption for intercurrent AE. If the dose interruption is longer 
than 48 hr, then treatment will be discontinued and patient will start monitoring as outlined in 
the Follow-up Period in Section 6.4.7. 
Terlipressin infusion will also be briefly interrupted during and following paracentesis if one is 
required (refer to Section 6.11). 
Suspected acute liver injury (drug or ischemic induced) with elevated aminotransferases to more 
than 3xULN should be followed with a repeat liver panel testing within 48 hr (ALT. AST, 
alkaline phosphatase, total bilirubin). If the repeat testing shows AST or ALT >3xULN for 
subjects with normal baseline measures or 2-fold increases above baseline values for subjects 
with elevated values before drug exposure then close observation will be initiated including 
repeat liver enzyme testing every 3 days for no less than a week, ruling out viral hepatitis or 
ischemic or alcoholic liver injury and review history of concomitant drug use or other agents. 
Rising blood pressure during terlipressin period in the hospitalization period should be 
monitored closely.  If the SBP increases above 130 mmHg (or a SBP increase of > 20 mmHg if 


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Continuous Infusion Terlipressin 
For cirrhotic patients with refractory ascites 
Page 45 of 91 
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November 17, 2018 
 
 
 
pre-terlipressin baseline was elevated) the BP should be closely monitored with taking BP/HR at 
regular interval, no less than hourly, until stable. 
Sign of dehydration or rapid increase in sodium excretion possibly related to terlipressin 
response should be monitored closely. 
 
6.18. 
SAFETY MONITORING RULES 
The rates of AE of interest, SAEs, therapy interruptions for safety, and grade 3 or 4 treatment- 
related clinically significant toxicities (NCI Common Terminology Criteria for Adverse Events 
version 3.0) will be monitored. The first two patients in the trial (sentinel patients with baseline 
SCr < 1.5 mg/dL) will be monitored for emergence of these AEs until completion of terlipressin 
infusion. These patients may be replaced if the study treatment is interrupted for reason other 
than safety. Once at least 2 patients have been observed for at least 4 weeks and safely complete 
terlipressin infusion, enrollment of subsequent patients may then resume at the discretion of the 
Principal Investigator. 
During the course of the trial, observance of 1 or more unexpected, clinically-significant AE as 
described above that is possibly, probably, or definitely related to protocol therapy should prompt 
consideration to amend or terminate the protocol. 
 
7. STATISTICS 
 
7.1. 
JUSTIFICATION OF SAMPLE SIZE 
This study is a proof-of-concept study and the study is not powered for inferential statistics. The 
sample size chosen of this study is based on observations feasibility, data from a recently 
published study (Gow, 2016) and historical first-in-man studies. However, the assumptions in 
this study include the following: 
• 
Patients are expected to have ascites requiring large volume paracentesis. It is 
assumed that the ascites volume pre-treatment is at least 5 L per paracentesis per 
patient (average volume of ascites 7 L) as per Gow 2016 study). 
• 
Patients are expected to require a minimum of 1.5 paracentesis procedures per month 
with an average of 2 per month. 


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• 
The pre-treatment period will include the pre-treatment LVP before the terlipressin 
infusion is initiated. This LVP will occur when the patient would have normally 
needed it. 
• 
The total volume of ascites fluid removed during the pre-treatment period may be 
calculated as the product of the average ascites volume per paracentesis (7 L) and the 
average number of paracentesis procedures during the course of the pre-treatment 
period, including the pre-treatment LVP. 
 
7.2. 
SAMPLE SIZE 
This is a Phase I safety and feasibility study and no formal power analysis has been performed. 
 
7.3. 
DESCRIPTION OF STATISTICAL METHODS 
All patients who received terlipressin will be included in the analysis of safety and tolerability. 
All patients who have a result for the baseline and a follow-up will be included for the analysis 
of pharmacodynamics end-points. 
 
7.3.1. Demographics, Baseline and Other Characteristics 
Subject characteristics (demographic information and pre-treatment measurements) will be 
summarized. All medical history and physical examination findings will be coded as appropriate 
and listed by subject. 
 
7.3.2. Safety and Tolerability 
 
7.3.2.1. 
Adverse Event Analysis 
All Investigator-reported verbatim terms for AEs will be coded using the most current version of 
MedDRA coding and will be presented by primary system organ class (SOC) and preferred term 
(PRT). An overall summary of AEs will be presented to include the overall incidence and 
frequency of the following events: AE, related AE, severe AE, SAE, AE leading to 
discontinuation of study medication, and AE leading to interruption of study medication. 
 
7.3.2.2. 
Safety Laboratory 
Adverse events will be coded for purposes of summary by body system and preferred term. The 
incidence of treatment emergent adverse events will be summarized and tabulated by severity 


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and attribution. Serious adverse events and those leading to study withdrawal will also be 
tabulated. 
The results of laboratory tests results at each study visit will be listed by patient. Values outside 
the normal range will be identified, with special attention given to those values the PI or 
Medical Monitor flags as clinically significant. Shift table or scatter plots of numeric laboratory 
parameters will be provided, depicting changes on values, as appropriate. Normal ranges will be 
incorporated. 
 
7.3.3. Pharmacokinetics 
Pharmacokinetic analysis of terlipressin will be performed by fitting the plasma concentration- 
time data for terlipressin and lysine vasopressin from patients to the following models (Gibaldi, 
1975 and Rowland, 1989): 


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The pharmacokinetic analysis will involve individual fitting of the data from the subjects. 
Individual pharmacokinetic analysis will be performed using the nonlinear mixed effects 
software program, NONMEM (vs 7.3, ICON Development Solutions, Hanover, Maryland). 
Pharmacokinetic parameters obtained from the model fitting include CL, K, and CLf. The 
model building and validation will follow previously described procedures (Fischer, 2014). 
Secondary (derived) parameters include: volume of distribution of terlipressin (V), area under 
the terlipressin plasma concentration-time curve from 0 to 24 hours (AUC Terlipressin 0-24), area 
under the lysine vasopressin plasma concentration-time curve from 0 to 24 hours (AUC lysine 
vasopressin 0-24), and average steady-state plasma concentrations (C ss-ave ) for terlipressin and 
lysine vasopressin. 
Pharmacokinetic parameters will be summarized using standard descriptive statistics, including 
mean, median, SD, min, max, and CV%. Qualitative comparison of parameters between subjects 
with and without renal impairment will be performed. 
The individual PK analysis will be reported as a separate study report to be produced 
independently of the clinical study report. 
 
Where: 
Cterlipressin = plasma concentration of terlipressin 
K0 = terlipressin infusion rate 
CL = terlipressin clearance 
K = terlipressin terminal elimination rate constant 
t = time 
Clysine vasopressin = plasma concentration of lysine vasopressin 
CLf = formation rate CL of lysine vasopressin from terlipressin 
CLlysine vasopressin = CL for lysine vasopressin 


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7.3.4. Evaluation of Pharmacokinetic Design 
Simulations were used to evaluate the ability of the study to provide precise estimates of the 
pharmacokinetic parameters. The simulations were performed in NONMEM (vs 7.3, ICON 
Development Solutions, Hanover, Maryland) utilizing the one-compartment model with first 
order elimination and zero order infusion shown in equation 1.  Estimates of the 
pharmacokinetic parameters, inter-individual variability and residual variability were obtained 
from the literature (Forsling ML, Aziz LA, Miller M, Davis R, Donovan B. Conversion of 
triglycylvasopressin to lysine-vasopressin in man. J Endocr. 1980; 85:237-244; Nilsson G, 
Lindbom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single IV. 
doses to healthy volunteers. Drugs Exptl Clin Res. 1990; 16:307-314; Population 
pharmacokinetics report study OT-401). Fixed and random effect parameter values were 537 
ml/min for CL, 0.011 min-1 for k, 0.168 for the inter-individual variance for CL, 0.267 for the 
inter-individual variance (IIV) for k and 0.123 for residual error. Simulations provided 300 
replicates of the pharmacokinetic dataset (number of subjects and sampling times) specified in 
Section 6.7  Each simulated dataset was fit to the model. 
The mean, median and 95% confidence intervals from the model fitting of the replicated 
simulated datasets are shown in the table below. The means and medians of the replications 
from the simulations closely agree with actual values, with relative differences of -2.8% and 
-4.8% for CL and 6.8% and 5.2 % for k. Similarly, the modest coefficients of variation and 
narrow 95% confidence show the precision of parameter estimates. 


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Pharmacokinetic Parameters from Simulations of Dataset 
Parameter 
Mean 
Median 
95% Confidence 
Interval 
Coefficient of 
Variation (%) 
CL (ml/min) 
522 
511 
367, 738 
17.5 
Interindividual 
Variance for CL 
0.125 
0.125 
0.0149, 0.353 
30.7 
k (min-1) 
0.012 
0.012 
0.00830, 0.0181 
18.3 
Interindividual 
Variance for k 
0.189 
0.182 
0.034, 0.57 
34.0 
 
Our analysis supports the ability of the study design to provide accurate and precise estimates of 
the pharmacokinetic parameters. 
 
7.3.5. Efficacy 
This is an open label no-controlled trial and all patients will receive terlipressin infusion. 
Efficacy parameters include: 
• 
Total volume of ascites fluid removed by paracentesis, the volume of ascites fluid 
removed at each paracentesis, and the total number of paracentesis procedures during the 
course of the study 
• 
Time to recurrence of ascites (defined as requirement of large volume paracentesis 
during the study period compared to pre-study period) 
• 
Changes from baseline for: 
 
– Weight and abdominal girth 
 
– Mean arterial blood pressure 
 
– Serum creatinine level 
 
– Serum/urinary sodium levels and 24 hour sodium clearance 
 
– Computed GFR 
 
– MELD score 


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– PRA and aldosterone level and ratio 
 
– PRO (patient reported outcome- quality of life) 
 
Efficacy parameters including total volume of ascites fluid removed by paracentesis, the volume 
of ascites fluid removed at each paracentesis, the total number of paracentesis procedures, and 
the number/duration of hospital visits, during the course of the study will be analyzed by 
descriptive statistics including number of patients (N), mean, standard error (SE), median, 
minimum and maximum, and 95% confidence intervals (95%CI). Comparative statistics 
between pre-study period and study period will be conducted by student’s t-test, wherein 
patients would serve as their own control.  No sensitivity analysis is planned for this study. 
 
8. SERIOUS ADVERSE EVENT REPORTING 
 
8.1. 
DESCRIPTION OF ADVERSE EVENTS 
The term “adverse event” could include any of the following events that develop or increase in 
severity during the course of the study: 
1. Any signs or symptoms, regardless of severity, and whether or not ascribed to 
the test article; 
2. Any clinically significant laboratory abnormality, and; 
 
3. Any abnormality detected during physical examination. 
 
The Clinical Investigator will follow all subjects withdrawn from the study due to any adverse 
event, until the outcome is determined and where appropriate, additional written reports will be 
provided. 
Adverse events are graded using the CTCAE. If the CTCAE grading does not exist for an 
adverse event, the severity of mild (1), moderate (2), severe (3), life-threatening (4), and death 
related to an adverse event (5) will be used. Adverse event monitoring should be continued until 
adverse event resolution/stabilization (whichever is later). 
Medical conditions/diseases present before consenting the patient are only considered adverse 
events if they worsen after receiving any study drug. All laboratory values are to be reviewed by 
the Investigator and abnormal values will be graded according to the CTCAE  as well. 


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A laboratory abnormality is considered an adverse event if it results in 
 
1. Discontinuation from study drug, 
 
2. Necessitates therapeutic medical intervention, 
 
3. If the Investigator assesses the abnormality as an adverse event, or 
 
4. Any laboratory test that is clinically significant or meets the definition of an 
SAE 
 
8.2. 
RELATIONSHIP TO STUDY DRUG OR STUDY INTERVENTION 
The relationship of each adverse event to study drug or study intervention will be defined as 
“not related” or “related”. The Investigator is responsible for determining the relationship for an 
adverse event that occurs during the study. 
Not related: The temporal relationship of the clinical event to study intervention makes a causal 
relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event. 
Related: The temporal relationship of the clinical event to study intervention makes a causal 
relationship possible, and other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
 
8.3. 
DESCRIPTION OF AND PROCEDURAL REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
A serious adverse event is defined in general as an untoward (unfavorable) adverse event which: 
 
1. Is fatal or life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe); 
2. Requires or prolongs hospitalization; 
 
3. Is significantly or permanently disabling or incapacitating; 
 
4. Constitutes a congenital anomaly or a birth defect; or 
 
5. May jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above (Examples of such events include, but are 


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not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization). 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs for data transmission purposes to BioVie Inc. 
The following hospitalizations are not considered SAEs in BioVie Inc. clinical studies: 
 
1. A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening) 
2. Elective surgery, planned prior to signing consent 
 
3. Admissions as per protocol for a planned medical/surgical procedure 
 
4. Routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
5. Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases 
6. Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
8.4. 
REPORTING RESPONSIBILITY FOR SERIOUS AE 
The study site team will monitor for and track serious adverse events whether related or not to 
the study procedures/interventions and/or to participation in the study. Such events will be 
reported to the Clinical Investigator and reported to IRB per their requirements and pre- 
established written procedures, as required by 45 CFR 46 
Any serious adverse event occurring in a subject after he/she has provided informed consent and 
HIPAA authorization, and while in the study must be reported. 


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Each serious adverse event must be reported by the Clinical Investigator to the BioVie Inc. 
Medical Monitor or designee, within 24 hours of learning of its occurrence, even if it is not felt 
to be related to study drug. 
The report must include the adverse event term, subject identifier, attribution, description, 
concomitant medication used to treat the adverse event, and any other relevant information per 
BioVie Inc. SAE form. Follow-up information about a previously reported serious adverse event 
must also be reported to BioVie Inc. within 24 hours of receiving the information. BioVie Inc., 
or its designee, may contact the Investigator to obtain further information about a reported 
serious adverse event. If warranted, an Investigator Alert may be issued to inform all 
Investigators involved in any study with the same study drug that a serious adverse event has 
been reported. 
 
8.5. 
REPORTING PROCEDURES 
The Investigator must complete the Serious Adverse Event Report Form in English, assess the 
causal relationship to study procedure/intervention, and send the completed form to BioVie Inc. 
by Facsimile or Email, to BioVie Inc. Medical Monitor or its designee. The study monitor will 
review the Serious Adverse Event Report Form and the supporting source documents during 
monitoring visits. Follow-up information should be sent as well, within 24 hours of the time the 
information is known. Either a new Serious Adverse Event Report Form is faxed (indicating that 
the information is a follow-up), or the original form may be re-faxed (with the new information 
highlighted and a new date provided). The follow-up report should describe whether the serious 
adverse event has resolved or is continuing, if and how it was treated, and whether the subject 
continued or permanently discontinued study participation. The form(s) and FAX confirmation 
sheet(s) must be retained in the investigational site study file. The Investigator is responsible for 
informing the Institutional Review Board/Independent Ethics Committee (IRB/IEC) of the 
serious adverse event and providing them with all relevant initial and follow-up information 
about the event. BioVie Inc. medical monitor or designee will communicate serious adverse 
events to the study sites as required by regulatory authorities. SAEs must be recorded on the 
BioVie Inc. SAE Report Form; pregnancies on a BioVie Inc. Pregnancy Surveillance Form. 
These original BioVie Inc. Forms are to remain on site. SAEs, whether related or not related to 


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study intervention/procedures, and pregnancies must be reported to BioVie Inc. within 24 hours 
via a scanned and reported via electronic mail to: 
SAE Email Address: yeramian@comcast.net 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow- 
up SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BioVie Inc. using 
the same procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization. 
 
9. ETHICAL ASPECTS 
 
9.1. 
ETHICS AND GOOD CLINICAL PRACTICE 
This trial will be conducted in compliance with the appropriate protocol, ICH GCP guidelines, 
the principles of the Declaration of Helsinki, and all other applicable regulatory requirements. 
Participating sites must obtain written approval of the study protocol, consent form, other 
supporting documents, and any advertising for participant recruitment from their local 
institutional review board (IRB) in order to participate in the study. Prior to study initiation, the 
protocol and the informed consent documents will be reviewed and approved by an appropriate 
Ethics Review Committee (ERC) or IRB. Any amendments to the protocol or consent materials 
must be approved before they are implemented. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical license, debarment). All potential serious breaches must be reported 
to BioVie Inc. immediately. A serious breach is a breach of the conditions and principles of 
GCP in connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of the subjects of the study or the scientific 
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The regulatory files at the site should contain all required regulatory documents, study-specific 
documents, and important communications. Regulatory files will be checked at each 
participating site for regulatory compliance prior to study initiation, throughout the study, as 
well as at the study closure. 
 
9.2. 
CONFIDENTIALITY REGARDING STUDY SUBJECTS 
Investigators must assure that the privacy of subjects, including their personal identity and all 
personal medical information, will be protected at all times, as required by law. Study sites may 
be required by their institutions to obtain authorization from participants for use of protected 
health information. Sites will be responsible for communicating with their IRBs or Privacy 
Boards and obtaining the appropriate approvals or waivers to be in regulatory compliance with 
HIPAA. In CRFs and other study documents submitted to BioVie Inc. or its designee, subjects 
will be identified by their initials, subject number, date of birth, and gender. Personal medical 
information may be reviewed and/or copied for research, quality assurance, and/or data analysis. 
This review may be conducted by the study monitor, properly authorized persons on behalf of 
BioVie Inc., an independent auditor, IRBs/IECs or regulatory authorities. Personal medical 
information will always be treated as confidential. 
 
9.3. 
FINANCIAL DISCLOSURE 
All investigators will comply with the requirements of 42 CFR Part 54, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 
interest. Everyone with decision-making responsibilities regarding the protocol will have an up- 
to date signed financial disclosure form on file with the sponsor. 
 
9.4. 
SAFETY MONITORING COMMITTEE 
An independent Safety Monitoring Committee (SMC) composed of two physicians, with 
expertise with hepatology, cardiology and/or intensive care will be assembled for the duration of 
the trial. The SMC receives the summary reports of the frequency of all clinical adverse events 
and safety laboratory tests for planned periodic meetings throughout the study (after each 2 
patients complete treatment). Meetings will be held via teleconference. In addition, an SMC 
member may call ad hoc meetings. 


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Summaries of safety monitoring, adverse events and enrollment will be provided to the SMC 
prior to each meeting by the BioVie Medical Director. In addition, clinically significant events 
(including AEs of interest and interruptions of infusion for safety reason) and any severe (Grade 
3 or above) or serious adverse events are considered events of interest and will be reported in 
real-time (within 1 business day of sponsor becoming informed) to the SMC. All adverse events 
and abnormal laboratory values results will be listed and will be completely identified (using 
MedDRA adverse reaction codes) by subject. 
The SMC will review safety data throughout the trial. Recommendations for modification or 
termination of the trial based on safety data will be made by the SMC to the Protocol Steering 
Committee (PSC) that will include the Principal Investigator and the BioVie Medical Director 
and Clinical Manager.  The PSC will be responsible for communication with the sites and IRBs. 
 
9.5. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before implementing this study, the protocol, the proposed ICF, and other information provided 
to subjects must be reviewed by an IRB/IEC. A signed and dated statement that the protocol, 
and ICF, subject recruitment materials/process (eg, advertisements), and any other written 
information to be provided to subjects have been approved by the IRB/IEC must be given to 
BioVie Inc. before study initiation. The name and occupation of the chairperson and the 
members of the IRB/IEC (preferred) or the IRB’s Health and Human Safety Assurance number 
must be supplied to BioVie Inc. or its designee. This committee, as required by local law or 
procedure, will approve any amendments to the protocol that need formal approval. The 
IRB/IEC will also be notified of all other administrative amendments (i.e., administrative 
changes). The investigator or sponsor should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling, information to be provided to subjects and any 
updates. The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures. 
Study sites will be responsible for maintaining signed consent forms as source documents for 
quality assurance review and regulatory compliance. 


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9.6. 
INFORMED CONSENT 
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. The Investigator, or designee, will explain to each subject (or legally 
authorized representative) the nature of the research study, its purpose, the procedures involved, 
the expected duration of subject participation, alternative treatment, potential risks and benefits 
involved, and any discomfort that may occur during the subject’s participation in the study. 
Each subject will be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. This informed consent 
should be given by means of a standard written statement, written in non-technical language. 
The subject should read and consider the statement before signing and dating it and should be 
given a copy of the signed document. No subject can enter the study and no study-related 
procedures can be done before his/her informed consent has been obtained. The Investigator 
must submit the ICF with the protocol for IRB/IEC approval. 
BioVie Inc. supplies a proposed ICF template that complies with regulatory requirements, 
includes all elements required by ICH, GCP and applicable regulatory requirements, and is 
considered appropriate for the study. The sample informed consent form will adhere to the 
ethical principles that have their origin in the Declaration of Helsinki. Any changes to the 
proposed ICF suggested by the Investigator must be agreed to by BioVie Inc. or its designee 
before submission to the IRB/IEC, and a copy of the approved version must be provided to the 
BioVie Inc. study monitor after IRB/IEC approval. 
Investigators must: 
 
1. Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study. 


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3. Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed 
consent discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating their informed consent during the study, then consent must additionally 
be obtained from the subject. 
6. Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented. 
The consent form must also include a statement that BioVie Inc. and regulatory authorities have 
direct access to subject records. Subjects unable to give their written consent (eg, stroke patients, 
or subjects with severe dementia) may only be enrolled in the study with the consent of a legally 
acceptable representative. The subject must also be informed about the nature of the study to the 
extent compatible with the subjects’ understanding, and should they become capable, personally 
sign and date the consent form as soon as possible. The explicit wish of a subject unable to give 
his or her written consent, who is capable of forming an opinion and assessing this information 
to refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator. The rights, safety, and well-being of the study subjects are the 
most important considerations and should prevail over interests of science and society. 


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10. ADMINISTRATIVE REQUIREMENTS 
 
10.1. 
PROTOCOL AMENDMENTS 
Any change or modification to this protocol requires a written protocol amendment that must be 
approved by BioVie Inc. medical monitor before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require additional approval by the IRB/IEC of all centers and, in some countries, by the 
regulatory authority. A copy of the written approval of the IRB/IEC must be given to the BioVie 
Inc. study monitor, or their designee. Examples of amendments requiring such approval are: 
1. Increase in drug dosage or duration of exposure of subjects, or any significant 
increase in the number of subjects under study; 
2. Significant change in the study design (e.g., addition or deletion of a control group); 
 
3. Increase in the number of procedures to which subjects are exposed; or 
 
4. Addition or deletion of a test procedure intended to improve safety monitoring. 
 
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator or by BioVie Inc. medical monitor in the interests of preserving the 
safety of all subjects included in the study. If an immediate change to the protocol is felt by the 
Investigator to be necessary and is implemented by him/her for safety reasons, BioVie Inc. 
medical monitor should be notified and the IRB/IEC for the center should be informed within 1 
working day. Any significant deviation must be documented in the CRF. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: 
o IRB/IEC for review and approval/favorable opinion 
o BioVie Inc. medical monitor 
o Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BioVie Inc. If an amendment substantially alters the study design or increases the 


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potential risk to the subject: (1) the consent form must be revised and submitted to the 
IRB(s)/IEC(s) for review and approval/favorable opinion; (2) the revised form must be used to 
obtain consent from subjects currently enrolled in the study if they are affected by the 
amendment; and (3) the new form must be used to obtain consent from new subjects prior to 
enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval; however, the IRB/IEC for each center must be kept informed 
of such administrative changes. Examples of administrative changes not requiring formal 
protocol amendments and IRB/IEC approval that can be treated as administrative amendments 
include, but are not limited to: 
1. Changes in the staff used to monitor studies (e.g., BioVie Inc. staff versus a contract 
research organization); and 
2. Minor changes (within regulatory guidelines) in the packaging or labeling of study drug. 
 
10.2. 
MONITORING PROCEDURES 
Before study initiation, at an initiation visit conducted on-site or by video conference or at an 
Investigator’s meeting, a BioVie Inc. representative will review the protocol, CRFs, and other 
study documents with the Investigators and their staff. During the study, the BioVie Inc. study 
monitor, or designee, will visit the site regularly to check the completeness of subject records, 
accuracy of entries on the CRFs, adherence to the protocol and to GCP, progress of enrollment, 
and also to ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The Investigator must give the study monitor access to relevant hospital or clinical records to 
confirm their consistency with the CRF entries. No information in these records about the 
identity of the subjects will leave the study center. BioVie Inc. monitoring standards require full 
verification for the presence of informed consent, HIPAA authorization, adherence to the 
inclusion/exclusion criteria, documentation of serious adverse events, and recording of efficacy 
and safety variables. Additional checks of the consistency of source data with the CRFs are 


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performed according to the study-specific monitoring plan. Representatives of BioVie Inc. must 
be allowed to visit all study site locations periodically to assess the data quality and study 
integrity. On site they will review study records and directly compare them with source 
documents, discuss the conduct of the study with the investigator, and verify that the facilities 
remain acceptable. 
In addition, the study may be evaluated by BioVie Inc. internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BioVie Inc. audit reports will be kept confidential. The investigator must notify 
BioVie Inc. promptly of any inspections scheduled by regulatory authorities, and promptly 
forward copies of inspection reports to BioVie Inc. 
 
10.3. 
PROTOCOL DEVIATION AND VIOLATION 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice (GCP). The noncompliance may be either on the part of the subject, the Site 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
All deviations from the protocol must be addressed in the subject’s source documents. Protocol 
deviations must be sent to the local IRB per their guidelines and entered in the Protocol 
Deviations Log CRF. 
 
10.4. 
INVESTIGATIONAL SITE TRAINING 
BioVie Inc. may provide quality investigational staff training prior to study initiation. Training 
topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, study documentation, informed consent, and enrollment of WOCBP as 
applicable. 
 
10.5. 
RECORDING OF DATA AND RETENTION OF DOCUMENTS 
All information required by the protocol should be provided; any omissions or corrections 
should be explained. All CRFs should be completed and available for collection within a timely 
manner, preferably no more than 10 days after the subject’s visit (except for the last visit of the 
last subject, which should be completed in a timely manner, preferably within 5 working days), 


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so that the study monitor may check the entries for completeness, accuracy and legibility, ensure 
the CRF is signed by the Investigator and transmit the data to BioVie Inc. or its designee. All 
entries to the CRF must be made clearly in black ball-point pen to ensure the legibility of self- 
copying or photocopied pages. Corrections will be made by placing a single horizontal line 
through the incorrect entry, so that the original entry can still be seen, and placing the revised 
entry beside it. The revised entry must be initialed and dated by a member of the Investigator’s 
research team authorized to make CRF entries. Correction fluid must not be used. If Electronic 
Data Capture (EDC) system is deployed, the CRF will be completed by the authorized study site 
personnel. Electronic queries will be used to communicate eligible discrepant data with the 
study sites. 
The Investigator must maintain source documents for each subject in the study. All information 
on CRFs will be traceable to these source documents, which are generally maintained in the 
subject’s file. The source documents will contain all demographic and medical information, 
including laboratory data, ECGs, etc., and also a copy of the signed informed consent/HIPAA 
authorization, which should indicate the study number and title of the study. Essential 
documents, as listed below, will be retained by the Investigator for the maximum period 
required to comply with national and international regulations, or institutional procedures, or for 
the period specified by the sponsor, whichever is longer. BioVie Inc. will notify the 
Investigator(s)/institution(s) when study-related records are no longer required to be retained. 
The Investigator agrees to adhere to the document retention procedures by signing the protocol. 
The investigator must contact BioVie Inc. prior to destroying any records associated with the 
study. 
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BioVie Inc. Essential documents include: 
1. Signed protocol and all amendments; 
 
2. IRB/IEC approvals for the study protocol and all amendments; 
 
3. All source documents and laboratory records; 


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4. CRF copies; 
 
5. Subjects’ ICF/HIPAA authorization; and 
 
6. Any other pertinent study documents. 
 
10.6. 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered as a control in the investigation. Data reported on the CRF that are 
derived from source documents must be consistent with the source documents or the 
discrepancies must be explained. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly reviewed, 
signed, and dated by a qualified physician who is an investigator or sub-Investigator. 
The investigator must retain a copy of the CRFs including records of the changes and 
corrections. 
 
10.7. 
AUDITING PROCEDURES 
In addition to the routine monitoring procedures, BioVie Inc. or its designees, may conduct 
audits of clinical research activities in accordance with internal SOPs to evaluate compliance 
with the principles of GCP. BioVie Inc., its designee, or a regulatory authority may wish to 
conduct an inspection (during the study or after its completion). If an inspection is requested by 
a regulatory authority, the Investigator will inform BioVie Inc. immediately that this request has 
been made. 
 
10.8. 
DISCLOSURE AND CONFIDENTIALITY 
By signing the protocol, the Investigator agrees to keep all information generated in connection 
with the study or provided by BioVie Inc. or its designee in strict confidence and to request 


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similar confidentiality from his/her staff and the IRB/IEC. Study documents provided by BioVie 
Inc. (protocols, Investigators’ Brochures, CRFs, and other material) will be stored appropriately 
to ensure their confidentiality. Such confidential information may not be disclosed to others 
without direct written authorization from BioVie Inc., except to the extent necessary to obtain 
informed consent/HIPAA authorization from subjects who wish to participate in the study. 
 
10.9. 
DISCONTINUATION OF STUDY 
BioVie Inc. reserves the right to discontinue the study for any reason at any time. 
 
This study may be also prematurely terminated if, in the opinion of the SMC or Principal 
Investigator, there is sufficient reasonable cause. Written notification, documenting the reason 
for study termination, will be provided to BioVie Inc. 
Circumstances that may warrant termination include, include but are not limited to: 
 
• 
Determination of unexpected, significant, or unacceptable risk to subjects. 
 
• 
Enrollment is unsatisfactory. 
 
• 
Insufficient adherence to protocol requirements. 
 
• 
Data that are not sufficiently complete and/or evaluable. 
 
• 
Plans to modify, suspend or discontinue the development of the study drug. 
 
If the study is prematurely terminated or suspended, the sponsor will promptly inform the 
Investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The IRB/IEC will also be informed promptly 
and provided the reason(s) for the termination or suspension by the sponsor or by the 
Investigator/institution, as specified by the applicable regulatory requirement(s). 
 
11. DATA MANAGEMENT 
 
11.1. 
DATA COLLECTION 
Investigators must enter the information required by the protocol onto the BioVie Inc. CRFs. 
BioVie Inc. study monitors or designees will review the CRFs for completeness and accuracy, 
and instruct site personnel to make any required corrections or additions. The CRFs will be 
forwarded to BioVie Inc., or its designee, with one copy retained at the study site. If Electronic 


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Data Capture (EDC) system is deployed, CRF will be completed by the authorized study site 
personnel. An electronic version of the final CRF book for each subject will be forwarded to the 
study sites for record keeping at the study site closure. 
 
11.2. 
DATA CLARIFICATION 
Data items from the CRFs may be entered into the study database using double data entry with 
verifications. Obvious CRF errors will be corrected by BioVie Inc. personnel, or its designee. 
Other errors, omissions, or requests for clarification will be queried; queries will be returned to 
the study site for resolution using a Data Clarification Form (DCF). The original completed and 
signed DCF will be returned to BioVie Inc. while a copy will be kept with the CRFs at the site. 
 
12. REFERENCES 
Arroyo V, Gines P, et al. Definition and diagnostic criteria of refractory ascites and hepato- 
renal syndrome in cirrhosis. Hepatology.  1996; 23(1): 164-176. 
Baik SK, Jeong PH, Ji SW, et al. Acute hemodynamic effects of octreotide and terlipressin in 
patients with cirrhosis: a randomized comparison. The American journal of gastroenterology. 
2005; 100(3): 631-5. 
Cavallin M, Piano S, Romano A, et al. Terlipressin given by continuous intravenous infusion 
versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled 
study. Hepatology (Baltimore, Md). 2016; 63(3): 983-92. 
Colson PH, Virsolvy CA, Gaudard, P et al. Terlipressin, a vasoactive prodrug recommended in 
hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its 
safety profile.Pharmacological Research, in press. 
Ding C, Wu X, Fan X, et al. Hemodynamic effects of continuous versus bolus infusion of 
terlipressin for portal hypertension: a randomized comparison. Journal of gastroenterology and 
hepatology. 2013; 28(7): 1242-6. 
Escorsell A, Bandi JC, Moitinho E, et al. Time profile of the haemodynamic effects of 
terlipressin in portal hypertension. Journal of hepatology. 1997; 26(3): 621-7. 
Fimiani B, Guardia DD, Puoti C, et al. The use of terlipressin in cirrhotic patients with 
refractory ascites and normal renal function: a multicentric study. European journal of internal 
medicine. 2011; 22(6): 587-90. 
Fischer JH, Sarto GE, Hardman J, Endres L, Jenkins TM, Kilpatrick SJ, Jeong H, Geller S, 
Deyo K, Fischer PA, Rodvold KA. Influence of gestational age and body weight on the 
pharmacokinetics of labetalol in pregnancy. Clin Pharmacokinet 2014; 53(4):373-83 
Forsling ML, Aziz LA, Miller M, et al. Conversion of triglycylvasopressin to lysine-vasopressin 
in man. The Journal of endocrinology. 1980; 85(2): 237-44. 


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For cirrhotic patients with refractory ascites 
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Gibaldi M, Perrier D. Pharmacokinetics, 1 ed. Marcel Dekker, New York, 1975, p.27-30. 
Gow PJ, Ardalan ZS, Vasudevan A, et al. Outpatient Terlipressin Infusion for the Treatment of 
Refractory Ascites. The American journal of gastroenterology. 2016; 111(7): 1041-2. 
Kalambokis G, Economou M, Paraskevi K, et al. Effects of somatostatin, terlipressin and 
somatostatin plus terlipressin on portal and systemic hemodynamics and renal sodium excretion 
in patients with cirrhosis. Journal of gastroenterology and hepatology. 2005; 20(7): 1075-81. 
Krag A, Moller S, Henriksen JH, et al. Terlipressin improves renal function in patients with 
cirrhosis and ascites without hepatorenal syndrome. Hepatology (Baltimore, Md). 2007; 46(6): 
1863-71. 
Lucassin. (AusPAR-cer 2011). AusPAR Attachment 2: Extract from the Clinical Evaluation 
Report for Terlipressin. https://www.tga.gov.au/sites/default/files/auspar-terlipressin-130827- 
cer.pdf 
Narahara Y, Kanazawa H, Taki Y, et al. Effects of terlipressin on systemic, hepatic and renal 
hemodynamics in patients with cirrhosis. Journal of gastroenterology and hepatology. 2009; 
24(11): 1791-7. 
Nilsson G, Lindblom P, Ohlin M, et al. Pharmacokinetics of terlipressin after single i.v. doses to 
healthy volunteers. Drugs under experimental and clinical research. 1990; 16(6): 307-14 
Moog Curlin 6000 series Clinicians Guide V2.01 
Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with and without albumin for patients with 
hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology (Baltimore, 
Md). 2002; 36(4 Pt 1): 941-8. 
Rowland M, Tozer TN. Clinical Pharmacokinetics: concepts and applications, 2nd ed. Lea & 
Febiger, Philadelphia, 1989, p. 359-62. 
Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases 
Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 
(Baltimore, Md). 2013; 57(4): 1651-3. 
Ryckwaert F, Virsolvy A, Fort A, et al. Terlipressin, a provasopressin drug exhibits direct 
vasoconstrictor properties: consequences on heart perfusion and performance. Critical care 
medicine. 2009; 37(3): 876-81. 
Udell J, Wang C et al. Does this patient with liver disease have cirrhosis? JAMA. 2012; 
307(8): 832-842. 
User Manual for use with the 6000 CMS™ and 6000 CMS™ IOD™ Ambulatory Infusion 
System. Moog Medical Devices Group. Revision H. 


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13. APPENDIX 1:  OVERDOSE INSTRUCTIONS 
 
 
If overdose or serious adverse reaction related to overdose or terlipressin accumulation is 
suspected: 
1. Admit patient to the hospital for observation 
 
2. Assure IV access present with adequate hydration status 
 
3. Monitor vital signs hourly or more frequently as clinically indicated 
 
4. PI will manage patient, including administration of corticosteroid, anaphylaxis 
medications, and seizure medications as needed 
5. Notify hospital of potential need for ICU admission. 
 
6. Admit patient to hospital ICU if clinically indicated. 


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14. APPENDIX 2 - INSTRUCTIONS FOR THE COLLECTION, HANDLING AND 
SHIPPING OF SAMPLES 
 
14.1. 
COLLECTION OF BLOOD SAMPLES 
Sample Collection and Processing Procedures 
 
Blood will be collected at the specified time points (refer to study protocol) using a 10 mL 
K2EDTA Vacutainer® blood collection tube. Collect samples within ± 2 minutes from the time 
stated on the protocol, or indicate reason for deviation from planned schedule. At successive 
time points, the same order of sampling shall be followed.  Collect 4 mL of blood at the 
specified time. After drawing the blood, gently invert the tube approximately 8 times 
immediately after collection and immediately place in an ice bath for transport to a centrifuge. 
 
14.2. 
PROCESSING AT SITE 
Blood samples must be kept on ice and processed into plasma within 1 hour after collection. 
Record any draw deviations and reason(s) for deviation(s) on the Sample Processing Log if the 
clinical site has. Place the blood samples in a refrigerated centrifuge within 1 hour of collection 
and spin at high speed (approximately 2700 - 3000 RPM or approximately 1000 g) for 
approximately 10 minutes at 4˚C. As soon as the centrifuge stops, return the samples to an ice 
bath. Withdraw about 2.5 mL of plasma into a appropriately labeled 5-mL polypropylene 
cryovial as aliquot 1; transfer the rest of the plasma (transfer as much as possible) to a second 
appropriately labeled 5-mL polypropylene cryovial as aliquot 2. NOTE: Fill out sample label 
and affix on the tube before placing plasma into the tube. Affix a piece of transparent lab tape 
over the affixed label before transferring the plasma. 
 
14.3. 
SHIPPING OF SAMPLES FOR CENTRAL ANALYSIS 
All specimens will be labeled with Protocol Number, Subject number, and time points (as 
indicated in the study protocol), aliquot # and stored in the same location until shipped. The 
tubes are to be labeled with freezer-safe labels and/or marked by permanent marker. Sort the 
samples by subject and place them in a box or small zipper bag and place the samples in the 
freezer (-70ºC). Plasma samples should be immediately frozen in an upright position to keep the 
plasma in the bottom of the tube and record the time placed in the freezer in the sample 
accountability record. 


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Both aliquots from each set of specimens will be sent to Frontage Laboratories, Inc. for 
concentration measurement. 
A copy of the Sample Processing Log should be included in the sample shipment. Specimens 
must be shipped in accordance with rules and laws governing the shipment of human diagnostic 
specimens. Shipments are to be sent only on Monday, Tuesday or Wednesday of any given 
week and must be shipped by overnight delivery. There should be adequate amount of dry ice 
included in the shipment to last for three days of shipping. 
These samples will be shipped to: 
 
Sample management 
Frontage Laboratories, Inc. 
700 Pennsylvania Drive 
Exton, PA 19341 USA 
Tel. 484-348-4799/484-348-4790 
Fax. 610-232-0101 
samplemanagement@frontagelab.com 
 
 
Notify Frontage Laboratories at least 1 day prior to the arrival of the sample, providing shipping 
details and tracking numbers for the shipment. The site will e-mail Mira Hong (Executive 
Director, Project Management) at mhong@frontagelab.com and Joseph Falcone and Maulika 
Patel at samplemanagement@frontagelab.com. The e-mail must specify the study number, the 
number of pharmacokinetic samples, the time of shipment pick-up and include an electronic 
sample inventory. 
Important Note: SHIPMENTS MUST BE SENT ON MONDAY – WEDNESDAY, AS 
THERE MAY NOT BE SOMEONE AVAILABLE TO RECEIVE SHIPMENTS ON THE 
WEEKEND. 
Prior to shipment, prepare a sample shipment list (or Inventory list) containing the details of 
each sample / label identification included in the shipment. All of the sample details on this list 
must correspond with the details included on the individual sample labels, as each sample label 
will be checked against the list by Frontage sample coordination personnel.  Any discrepancies 


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between information on the sample tubes and information on the e-rosters will be verified and 
noted in the e-rosters prior to shipping. All sample correspondence must contain the Study 
Number, Study Drug, and Site references (including emergency contact details and responsible 
shipment coordinator). 


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15. APPENDIX 3 – BLOOD PRESSURE MEASUREMENT 
 
 
- 
Ensure the patient has been sitting for at least 10 minutes and is relaxed. 
 
- 
Explain the procedure and obtain consent. 
 
- 
Ask the patient to remove any tight clothing from around their arm. 
 
- 
Ensure the arm is supported at the level of the heart - on a pillow, for example. 
 
- 
Select an appropriately sized cuff: its bladder should encircle at least 80% of the 
arm but no more than 100%. 
- 
Place the cuff snugly onto the patient’s arm with the center of the bladder over 
the brachial artery. Most cuffs have a ‘brachial artery indicator’, an arrow that 
can be aligned with the artery. 
- 
Ask the patient to refrain from talking or eating during the procedure as this can 
result in an inaccurate higher blood pressure measurement being recorded. 
- 
Switch on the automated device and press start. 
 
- 
Document the systolic and diastolic blood pressures on the patient’s observation 
chart. 
- 
Compute the MAP. 
 
- 
Let the patient sit for 5 minutes. 
 
- 
Proceed to determine the repeat MAP measure. 
 
- 
Enter the average of the two MAPS in the CRF. 


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16. APPENDIX 4 – CHILD-PUGH SCORE 
 
 
 
 
The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 
indicating most severe derangement. 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time, prolongation (s) 
<4.0 
4.0-6.0 
> 6.0 
Ascites 
None 
Mild (or 
suppressed with 
medication) 
Moderate to Severe 
(or refractory) 
Hepatic encephalopathy 
None 
Grade I-II 
Grade III-IV 
 
 
Chronic liver disease is classified into Child-Pugh class A to C, employing the added score from 
above. 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 


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17. APPENDIX 5 – MELD SCORE 
 
 
MELD(i) uses the patient's values for serum bilirubin, serum creatinine, and the international 
normalized ratio for prothrombin time (INR) to predict survival. It is calculated according to the 
following formula: 
MELD(i) = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 
9.57×ln[serum creatinine (mg/dL)] + 6.43 
MELD scores are reported as whole numbers, so the result of the equation above is rounded. 
UNOS has made the following modifications to the score:[5] 
• 
If the patient has been dialyzed twice within the last 7 days, then the factor for serum 
creatinine used should be 4.0 
• 
Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8 a value of 1.0 is used) 
to prevent the occurrence of scores below 0 
In January 2016, OPTN Policy 9.1 (MELD Score) was updated to include serum sodium as a 
factor in the calculation of the MELD score. 
MELD Score (2016) = MELD(i) + 1.32*(137-Na) – [0.033*MELD(i)*(137-Na)] 
 
Note: Sodium has a range of 125-137 mEq/L 


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18. APPENDIX 6 - FRACTIONAL SODIUM EXCRETION RATE 
 
 
The fractional excretion of sodium (FENa) is the percentage of the sodium filtered by the 
kidney which is excreted in the urine. 
FENa = 100 x (Naurinary x Creatinineplasma) / (Sodiumplasma x Creatinineurinary) 


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19. APPENDIX 7 – HEPATIC ENCEPHALOPATHY SCORE 
 
 
The severity of hepatic encephalopathy is graded with the West Haven Criteria; this is based on 
the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, 
and the dependence on therapy. 
• 
Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; 
impaired performance of addition or subtraction 
• 
Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality 
change; inappropriate behaviour 
• 
Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross 
disorientation 
• 
Grade 4 - Coma 


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20. APPENDIX 8 – COMPUTATION OF GLOMERULAR FILTRATION RATE 
 
 
CKD-EPI Creatinine Equation (2009) b 
 
Expressed as a single equation: 
 
eGFR =141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 
0.993Age x 1.018 [if female] x 1.159 [if Black] 
 
 
Abbreviations / Units 
 
• eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
 
• SCr (standardized serum creatinine) = mg/dL 
 
• κ = 0.7 (females) or 0.9 (males) 
 
• α = -0.329 (females) or -0.411 (males) 
 
• min = indicates the minimum of SCr/κ or 1 
 
• max = indicates the maximum of SCr/κ or 1 
 
• age = years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b https://www.kidney.org/professionals/kdoqi/gfr_calculator 


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21. APPENDIX 9 – SHORT FORM 36 AND CLDQ 
 
 
 


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Appendix 10 – Bonacini cirrhosis discriminant score 
 
 
Score 
Platelets (x 103 /µL) 
ALT:AST ratio 
INR 
0 
>340 
>1.7 
<1.1 
1 
280-340 
1.2-1.7 
1.1-1.4 
2 
220-279 
0.6-1.19 
>1.4 
3 
160-219 
<0.6 
4 
100-159 
5 
40-99 
6 
<40 
 
 
The modified Bonacini CDA has a range of possible values from 0 to 11; higher scores identify 
patients with higher likelihood of cirrhosis.