Conditions: Hepatorenal Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
Hepatorenal syndrome-acute kidney injury (HRS-AKI), a potentially reversible renal failure, is a serious, rapidly progressing, often fatal, complication of decompensated cirrhosis. Terlipressin is a synthetic vasopressin analogue that acts as a systemic vasoconstrictor via the vascular vasopressin V1 receptors. In HRS-AKI patients the strong V1 receptor-mediated vasoconstrictor activity of terlipressin, particularly in the splanchnic area, increases effective intravascular volume and mean arterial pressure (MAP), ameliorates renin-angiotensin-aldosterone system and sympathetic nervous system hyperactivity, and improves renal blood flow. The INFUSE trial will evaluate the use of continuous terlipressin infusion in patients on the liver transplant waiting list with HRS-AKI.

Detailed description:

Arms:
arm 1: All prospective patients receive open-label Terlipressin.

Interventions: intervention 1: Terlipressin
Intervention descriptions: intervention 1: For the first dose of terlipressin, each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution and administered intravenously as a bolus injection and given over 1 minute at a dose of 0.5 mg.

For continuous infusion, the dose of terlipressin is to be dissolved in 0.9% sodium chloride solution and infused with a pump

Protocol document:
Prot_SAP_000.pdf: 
University of Pennsylvania 
 
 
CLINICAL STUDY PROTOCOL 
 
A Multi-Center, Open Label, Collaborative Research Study to 
Treat HRS-AKI Patients with Continuous Terlipressin Infusion  
 
Protocol Number: 
TER001 
Study Drug: 
Terlipressin 
Development Phase: 
Phase 3 
IND Number: 
146962 
Protocol Release Version 1 Date: 
Protocol Release Version 2 Date: 
Protocol Release Version 3 Date: 
January 13, 2020 
September 15, 2020 
March 30, 2021 
Protocol Release Version 4 Date: 
June 29, 2021 
Sponsor: 
K. Rajender Reddy, M.D. 
University of Pennsylvania 
2 Dulles, Liver Transplant Office 
3400 Spruce Street, Philadelphia, PA 
19104 
 
 
 
 
 
 
This confidential document is the property of The University of Pennsylvania (UPenn) and International HealthCare 
(IHC). No unpublished information contained herein may be disclosed without prior written approval from UPenn 
or IHC. Access to this document must be restricted to relevant parties. 
 
 


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EMERGENCY CONTACT INFORMATION 
 
Role in Study 
Name 
Address and Telephone Number 
Trial Director UPENN 
K. Rajender Reddy M.D 
Sponsor 
University of Pennsylvania 
2 Dulles, Liver Transplant Office 
3400 Spruce Street, Philadelphia, PA 
19104 
Tel No: 267-357-3803 
Fax No: 215-615-3756 
 
Trial Director - IHC 
William Tobin 
Project Director 
International HealthCare 
98 East Avenue 
Norwalk, CT 06850 
Tel No: 203-852-8900 
Fax No: 203-286-1927 
 
 
 


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INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol entitled “A Multi-Center, Open Label, Collaborative Research- 
Study to treat HRS-AKI patients with Continuous Terlipressin Infusion”and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Conference on Harmonization (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), the ethical principles stated in the latest version of 
the Declaration of Helsinki, and the applicable local and international regulations, whichever 
provide the greater protection of the individual. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the sponsor, University of Pennsylvania. 
 
 
 
Investigator’s Signature 
 
Date  
 
     Institution Conducting Research 
 
 
 
 
 
 
 




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INFUSE: Summary of VERSION 4 Dated: June 29, 2021 Changes 
Section: SYNOPSIS 
• Expansion of inclusion criteria to include patients that are not liver transplant eligible 
or listed for liver transplantation 
• Modification of inclusion criteria 
• Modification of exclusion criteria to exclude patients 1) MELD ≥ 35 2) Advanced 
HCC with expected survival of < 6 months 
 
Section: SAFETY AND EFFICACY ASSESSMENTS 
• Clarification of secondary efficacy endpoint for Serum creatinine and incidence of 
dialysis at Day 30, Day 90, Day 180, and Day 365 after liver transplantation and those 
alive without transplantation (transplant eligible and ineligible patients) 
Section: STUDY POPULATION 
• Clarification that patients who are not liver transplant eligible or listed for liver 
transplantation will also be eligible for the study 
• Modification of inclusion and exclusion criteria 
 
Section: SECONDARY ANALYSES 
• Clarification of the timepoint for those patients who were transplant ineligible or did 
not undergo a transplant. 
General formatting and administrative clarifications were made throughout the protocol. 
 
INFUSE: Summary of VERSION 3 Dated: March 30, 2021 Changes 
Section: SYNOPSIS 
• Clarification that patients who are liver transplant eligible with anticipation of being 
placed on the liver transplant wait list are eligible for the study 
• Clarification of inclusion criterion to remove the restriction that eligible subjects are 
anticipated to be placed in the liver transplant wait list within 7 days of screening 
• Clarification of total volume of 0.9% sodium chloride used for drug infusion 


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• Clarification that some lab assessments and procedures will only be collected if they 
are performed as per site’s standard of care 
 
Section: STUDY POPULATION 
• Clarification that patients who are liver transplant eligible with anticipation of being 
placed on the liver transplant wait list are eligible for the study 
 
Section: TERLIPRESSIN 
• Update of stability and microbiology testing, including stability at refrigerated 
temperatures of 48 hours and room temperature for 24 hours 
• Clarification of total volume of 0.9% sodium chloride used for drug infusion 
 
Section: ASSESSMENTS AND PROCEDURES 
• Clarification that assessments are completed per sites’ Standard of Care. 
• Clarification of the timepoints for echocardiogram 
• Clarification of the timepoints for optional cystatin c and biomarker samples 
• Clarification that optional biomarker samples may be drawn +/- 1 day of the target day 
• Clarification that some lab assessments and procedures will only be collected if they 
are performed as per site’s standard of care 
• Clarification of acceptable window for follow up assessments 
 
Section: STUDY ASSESSMENTS 
• Clarification that some lab assessments and procedures will only be collected if they 
are performed as per site’s standard of care 
 
Section: DETAIL OF LABORATORY ASSESSMENTS AND PROCEDURES 
• Clarification of the timepoints for optional cystatin c and biomarker samples 
• Clarification that some lab assessments and procedures will only be collected if they 
are performed as per site’s standard of care 
 
Section: REFERENCES 
• Addition of reference Bui 2020 
 
Section: APPENDIX C 
• Addition of Appendix C: Terlipressin Microbiology 


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General formatting and administrative clarifications were made throughout the protocol. 
 
 
INFUSE: Summary of VERSION 2 Dated: September 15, 2020 Changes 
 
Section: SYNOPSIS 
• Added clarification for retrospective case collection time-period parameters. 
• Exclusion criteria addition to exclude ACLF grade 3 subjects. 
• Exclusion criteria addition to exclude subjects with SCr greater than 5.0 mg/dL unless 
approved by Sponsor Medical Monitor. 
• Exclusion criteria clarification on participation in other clinical trials. 
• Exclusion criteria clarification on prior use of vasopressors for prospective subjects. 
• Dosing clarification that only 0.9% sodium chloride solution should be used. 
• Lab clarification on collection of BUN and eGFR. 
 
Section: INVESTIGATIONAL PLAN 
• Added clarification for retrospective case collection time-period parameters. 
• Exclusion criteria addition to exclude ACLF grade 3 subjects. 
• Exclusion criteria addition to exclude subjects with SCr greater than 5.0 mg/dL unless 
approved by Sponsor Medical Monitor. 
• Exclusion criteria clarification on participation in other clinical trials. 
• Exclusion criteria clarification on prior use of vasopressors for prospective subjects. 
 
Section: STUDY DRUG STORAGE AND PREP 
• Corrected stability of study drug once reconstituted is 48 hours for this study. 
 
Section: ADMINISTRATION 
• Clarification on dosing procedures. 
 
Section: SCHEDULE OF ASSESSMENTS 
• Clarifications on assessments to be collected 


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Section: PHYSICAL EXAMINATION 
• Added collection of Estimated Dry Body Weight. 
 
Section: ECHOCARDIOGRAM 
• Clarification on collection requirements. 
 
Section: VITAL SIGNS 
• Clarification of vital sign collection parameters. 
 
Section: ADVERSE EVENTS 
• Clarification that SAEs are collected through 30 days post treatment.  Deaths are 
reported until study completion but will not be SAEs if occurred after SAE reporting 
timeframe. 
 
Section: SERUM ELECTROLYTES & BIOCHEMISTRY 
• Clarification of assessments to be collected. 
 
Section: HEMATOLOGY 
• Clarification of assessments to be collected. 
 
Section: SERIOUS ADVERSE EVENTS 
• Clarification on reporting requirements 
• Deletion of Adverse Event information due to not applicable for protocol. 
• Clarification on SUSAR reporting. 
 
Section: COLLECTION OF ADVERSE EVENTS/SERIOUS OR UNEXPECTED 
• Clarification of reporting procedures. 
 
Section: SITE REPORTING TO SPONSOR 


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• Correction to reporting contact information. 
 
Section: SAFETY VARABLES 
• Clarification of death collection. 
 
Section: STUDY AND STUDY SITE DISCONTINUATION CRITERIA 
• Removal of incorrect Sponsor reference. 
 
Section: REFERENCES 
• Added a protocol reference for Electrocardiogram/Echocardiogram assessments. 
 
General formatting and administrative clarifications were made to overall Protocol 
 
 


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1 SYNOPSIS 
(synopsis to follow)


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SYNOPSIS 
Name of Sponsor/Company: University of Pennsylvania 
Name of Investigational Product: Terlipressin 
Name of Active Ingredient: Terlipressin 
Title of Study: A Multi-Center, Open Label, Collaborative Research Study to Treat 
HRS-AKI Patients with Continuous Terlipressin Infusion 
Study Centers: Approximately 5-10 sites in the United States of America  
Phase of Development: Phase 3 
Objectives:  
Primary: To assess safety/efficacy for continuous terlipressin infusion in adult subjects  
with Hepatorenal syndrome- Acute Kidney Injury (HRS-AKI)  who are in one of two 
groups: 
1. On the liver transplant wait list or liver transplant eligible with anticipation of 
being placed on the liver transplant wait list  
2. Not eligible for liver transplant (limited to 25 patients) 
 
Methodology:  
Prospective Terlipressin Group - Patients to be treated with open label terlipressin by 
infusion following an initial bolus dose of 0.5mg. 
Retrospective Control Group – Historical patients who would have met 
inclusion/exclusion criteria detailed below and received at least 48 hours of treatment for 
HRS-AKI according to center’s standard-of-care (Midodrine/Octreotide (M&O), 
albumin, or other vasopressor) 
Number of Subjects (Planned):   
Prospective Terlipressin Group - approximately 50 terlipressin treated subjects 
Retrospective Control Group - approximately 15-25 subjects per clinical site that were 
treated for HRS-AKI, that would have met the inclusion/exclusion criteria below as well 
as having critical clinical data points to enable a comparison of the Prospective and 
Retrospective groups. Retrospective cases collected from each site should include 
eligible patients starting from prior to site IRB approval for this protocol and going back 


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to January 2015.  Subjects enrolled in a blinded clinical trial in this time period are 
excluded. 
Diagnosis and Main Inclusion/Exclusion Criteria: 
Adult subjects that are listed for liver transplant or liver transplant eligible with 
anticipation of being placed on the liver transplant wait list and have a diagnosis of 
HRS-AKI based on 2015 revised International Ascites Club (IAC) diagnostic criteria. 
 
Inclusion Criteria: 
1. 
Written informed consent by subject or legally authorized representative. 
2. 
At least 18 years of age. 
3. 
Cirrhosis and ascites. 
4. 
No sustained improvement in renal function (less than 20% decrease in SCr) 
at least 48 hours after diuretic withdrawal and after plasma volume expansion with 
albumin (given daily for two days - 48 hours minimum from 1st dose).If SCr 
improves by ≥ 20 % but plateaus ( ≤ 10 % fluctuation in sCr) and remains above 
1.5 mg/dl for ≥another 48 hrs and there are no features of acute tubular necrosis.  
5. 
Increase in SCr by at least ≥ 0.3 mg/dl OR 1.5-2 fold above baseline (AKI stage 1 
and above), to a SCr of ≥ 1.5 mg/dl at the time of initiating treatment. Baseline 
SCr is defined as the most recent, lowest SCr within last 6 months before date of 
current admission. 
6.     A.) On liver transplant wait list or liver transplant eligible with anticipation of   
    being placed on the liver transplant wait list.  B.) Patients not on the transplant   
    waitlist or transplant eligible are also eligible for the trial (maximum 25 subjects)  
Exclusion Criteria: 
 
1. Serum creatinine level greater than 5.0 mg/dL.  Subjects with value greater than 
5.0 mg/dL may be enrolled with Sponsor prior approval. 
2. MELD score of ≥ 35 
3. Acute on Chronic Liver Failure (ACLF) grade 3 (according to the CLIF 
Consortium grading system) 
4. Uncontrolled sepsis and/or uncontrolled bacterial infection (e.g., persisting 
bacteremia, persisting ascitic fluid leukocytosis, fever, increasing leukocytosis 
with vasomotor instability). 
5. Shock. 
6. Current or recent (within 4 weeks) treatment with or exposure to nephrotoxic 
agents: e.g., aminoglycosides, amphotericin, cyclosporine A, cisplatin, 
nonsteroidal anti-inflammatory drugs (NSAIDs: e.g., ibuprofen, naproxen, 
diclofenac), significant exposure to radiographic contrast agents (large doses or 
multiple injections of iodinated contrast media; e.g., during coronary or 
abdominal angiogram). 


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7. Estimated life expectancy of less than 7 days. 
8. Advanced hepatocellular Carcinoma with expected life expectancy of < 6 months 
9. Superimposed acute liver injury due to drugs (e.g., acetaminophen), dietary 
supplements, herbal preparations, viral hepatitis, or toxins (e.g., Amanita toxin 
with mushroom poisoning carbon tetrachloride), with the exception of acute 
alcoholic hepatitis. 
10. Evidence of obstructive uropathy or parenchymal renal disease.  Renal 
ultrasound or other imaging not required but should be taken if suspicious. 
11. Tubular epithelial casts, heme granular casts (range of 1-3 granular casts 
acceptable), hematuria or microhematuria on urinalysis that is indicative of acute 
tubular necrosis and/or intrinsic renal disease. 
12. Subjects known to be pregnant; all women of child-bearing age and potential 
must have a negative pregnancy test. 
13. Severe cardiovascular disease, including, but not limited to, unstable angina, 
pulmonary edema, congestive heart failure, or persisting symptomatic peripheral 
vascular disease, myocardial infarction or stable chronic angina within the past 
12 months, or any other cardiovascular disease judged by the investigator to be 
severe and creates a risk to subject with concurrent terlipressin use. 
14. Current or recent (within 4 weeks) renal replacement therapy (RRT) or 
anticipation of RRT within 3 days on enrollment. 
15. Participation in other clinical research involving investigational medicinal 
products within 30 days of starting study drug that would adversely affect 
participation in this or the current trial. 
16. Transjugular intrahepatic portosystemic shunt (TIPS) within 30 days of starting 
study drug. 
17. For the Prospective Group: All vasopressors must be stopped prior to treatment 
with terlipressin.  Use of vasopressors (e.g., norepinephrine, epinephrine or 
vasopressin dopamine or other vasopressors) of ≥ 3 consecutive days within the 
prior 14-day screening period are excluded. Patients receiving a vasopressor 
other than midodrine within 24 hours of qualifying SCr are excluded, i.e, a 24-h 
washout is required prior to enrollment. 
Note: Patients receiving midodrine and octreotide may be enrolled. Midodrine 
and octreotide treatment must be stopped prior to enrollment. 
18. Known allergy or sensitivity to terlipressin. 
Investigational Product, Dosage and Mode of Administration: 
 
Prospective Terlipressin Group: 


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Terlipressin will be administered intravenously as a bolus injection for the first dose, 
then by continuous IV infusion.   
 
Retrospective Control Group: 
Dose and method of administration for M&O, albumin, or other vasopressor 
 
Dosage and Mode of Administration: 
 
For Retrospective Control Group: 
Dosing for M&O , albumin, or other vasopressor will be reported as it was recorded 
on the subject’s chart. 
 
For Prospective Terlipressin Group: 
 
Terlipressin will be supplied in single-use, sterile 6-mL vials containing 1 mg of 
lyophilized Terlipressin acetate (equivalent to 0.85 mg Terlipressin free base) with 10 
mg mannitol as a bulking agent/stabilizer. 
 
Initial Dosing: 
2 
Terlipressin will be administered intravenously as a bolus injection (the vial will be 
reconstituted with 5 mL of sterile 0.9% sodium chloride solution and given over 
1 minute at a dose of 0.5 mg.   
• Continued dosing will be by 2 mg infusion per day.  For continuous infusion, the 
dose of terlipressin is to be dissolved in 0.9% sodium chloride solution and 
infused with a pump. 
 
Dose Modifications: 
- 
If on Day 3 the SCr is not 30% lower from the baseline value, increase infusion 
dose to 4 mg per day.  
 
- 
If on Day 5 the SCr is not 50% lower from the baseline value, increase infusion 
dose to 6-8 mg per day, per PI discretion. Dosing can be increased by more than 
1 mg increment at Day 5 or beyond, up to a maximum of 8 mg/day. 
 
• If the subject has infusion stopped for ≥ 4 hours, a 0.5 mg bolus should be given 
prior to restarting infusion.  
• The drug should not be used in subjects with severe coronary artery disease or in 
the setting of circulatory overload, pulmonary edema, or bronchospasm as 
determined by the Investigator. If drug therapy has been initiated, Investigator 
can also decide not to increase the dose, based on the patient’s status with regard 
to the above, based on individual subject condition. 


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• If dosing is interrupted due to an adverse event, terlipressin may be re-started, at 
the discretion of the investigator, at the same or lower dose as per protocol. 
Terlipressin will not be restarted if dosing was interrupted due to cardiac 
ischemia or mesenteric ischemia. 
 
Treatment Discontinuation: 
• Terlipressin may be continued until 24 hours after serum creatinine has reached 
the lowest value possible as determined by Principal Investigator, up to a 
maximum of 14 days.  
• After a minimum of 72 hours post final dose escalation and tolerability, if the SCr 
is at or above enrollment value, terlipressin should be discontinued.  
• If 72 hours after final dose escalation, there is no further improvement in SCr, 
continuation of terlipressin is at the discretion of the Principal Investigator at the 
clinical site. 
• If a subject is initiated on RRT, terlipressin can be continued for a maximum of 72 
hours after initiation of RRT. 
• Terlipressin must be discontinued when the subject is to undergo liver 
transplantation, TIPS, or any other vasopressor therapy (single administration of 
vasopressor for cardiac stress test is acceptable) 
• Dosing must be permanently discontinued if an event of cardiac ischemia or 
mesenteric ischemia occurs. 
 
Retreatment: 
If judged by the investigator to be potentially beneficial, subjects who demonstrate at 
least a partial response during the initial treatment course (at least 50% reduction in 
SCr) and develop recurrence of HRS-AKI may be retreated for a maximum of 
14 days. To qualify for retreatment the subject must again meet the study 
inclusion/exclusion criteria. Retreatment may occur within 90 days of the subject’s 
first dose of terlipressin. 
Duration of Treatment: 
For the Prospective Terlipressin Group, the active treatment period will be up to 14 days, 
allowing 1 retreatment cycle.  
For both Prospective and Retrospective Subjects: 
All subjects will be followed: 
Post treatment clinical data collection will be through phone call and chart review.  
Creatinine, BUN and eGFR will be recorded per standard of care, recording mortality 
and the date of last dialysis (CVVH or HD) session for the following time points:  


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Day 7 +/- 2 days;  
Day 14 +/- 3 days;  
Day 30 +/- 1 week and  
Day 90 +/- 1 week 
Day 180 +/- 2 weeks and  
Day 365 +/- 2 weeks. 
For subjects who have a liver transplant Post Treatment 
If the subject has a liver transplant recorded prior to the 90-Day visit (phone call or chart 
review), additional follow up will occur through one year after liver transplant. 
Creatinine, BUN and eGFR will be recorded per standard of care, recording mortality 
and the date of last dialysis (CVVH or HD) session for the following time points:  
Day 0 (date of transplant) – record allocation MELD and last calculated MELD prior to 
transplant; 
Day 7 +/- 2 days;  
Day 14 +/- 3 days;  
Day 30 +/- 1 week,  
Day 90 +/- 1 week,  
Day 180 +/- 2 weeks and  
Day 365 +/- 2 weeks. 
Key Efficacy and Safety Data Assessment: 
 
Primary Efficacy Assessment:  
Improvement of renal function (SCr) from Day 1 through end of treatment, repeated 
measure analysis.  SCr will be collected at baseline and daily from Day 1 through end of 
treatment.  
Secondary Efficacy Endpoints: 
• Improvement of renal function (SCr) from Day 1 through end of treatment, repeated 
measure analysis as compared to the Retrospective Control Group. 


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• For the Prospective Terlipressin Group alone and also in comparison to the 
Retrospective Control Group: 
o Incidence of dialysis by Day 30 and Day 90 of follow up. 
o Survival by Day 30 and Day 90 follow up. 
o Transplant by Day 30 and Day 90 follow up. 
o Serum creatinine at Day 30 and Day 90 follow up 
o Serum creatinine and incidence of dialysis at Day 30, Day 90, Day 180, and 
Day 365 after liver transplantation 
o Incidence of kidney transplant within one year after liver transplant 
o Descriptive analysis of number of simultaneous liver kidney transplants and 
episodes of graft rejection by Day 90 and Day 365 after liver transplant 
Safety: 
Safety review and assessments will be made only for the Prospective Terlipressin Group 
and will include the following: 
• Serious adverse events up to 30 days after end of treatment. 
 
Statistical Methods: 
 
A formal sample size calculation is not applicable for this study. It is expected that at 
least 50 subjects across more than 5-10 institutions may receive terlipressin treatment 
during the course of the research study.  
 
Additionally, up to 150 subjects across all clinical sites will have their Retrospective data 
collected.  Descriptive analysis will be planned for the efficacy and safety data collected. 
Sponsor may perform additional analysis not specified in study protocol.  


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Contents 
1 SYNOPSIS ................................................................................................................................... 10 
2 LIST OF ABBREVIATIONS ............................................................................................................. 22 
3 INTRODUCTION .......................................................................................................................... 24 
3.1 
HEPATORENAL SYNDROME ............................................................................................................ 24 
3.2 
TERLIPRESSIN ............................................................................................................................. 25 
3.3 
EFFICACY ................................................................................................................................... 25 
3.4 
SAFETY ..................................................................................................................................... 26 
3.5 
RETROSPECTIVE CONTROL GROUP:  M&O TREATED SUBJECTS ............................................................... 26 
3.5.1 MIDODRINE AND OCTREOTIDE .................................................................................................................. 26 
3.5.2 M&O OFF-LABEL USE ............................................................................................................................. 26 
4 STUDY RATIONALE ..................................................................................................................... 27 
5 SAFETY AND EFFICACY ASSESSMENTS ......................................................................................... 27 
5.1 
EFFICACY VARIABLES .................................................................................................................... 27 
6 INVESTIGATIONAL PLAN ............................................................................................................. 28 
6.1 
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION .............................................................................. 28 
7 STUDY POPULATION ................................................................................................................... 29 
7.1 
POPULATION RATIONALE .............................................................................................................. 29 
7.2 
NUMBER OF SUBJECTS TO BE STUDIED .............................................................................................. 29 
7.3 
INCLUSION/EXCLUSION CRITERIA .................................................................................................... 29 
7.4 
SUBJECT WITHDRAWAL CRITERIA .................................................................................................... 31 
7.5 
PROTOCOL DEVIATIONS ................................................................................................................ 31 
8 TERLIPRESSIN ............................................................................................................................. 32 


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8.1 
PACKAGING AND LABELING ............................................................................................................ 33 
8.2 
STUDY DRUG STORAGE AND PREPARATION ....................................................................................... 33 
8.3 
RECONSTITUTION ........................................................................................................................ 33 
8.4 
ADMINISTRATION ........................................................................................................................ 34 
8.5 
STUDY DRUG ACCOUNTABILITY ....................................................................................................... 35 
9 ASSESSMENTS AND PROCEDURES ............................................................................................... 36 
9.1 
SCHEDULE OF ASSESSMENTS AND PROCEDURES .................................................................................. 36 
10 STUDY ASSESSMENTS ............................................................................................................... 40 
10.1 SCREENING PERIOD ...................................................................................................................... 40 
10.2 PRE-TREATMENT PERIOD .............................................................................................................. 40 
10.3 ACTIVE STUDY PERIOD (14 DAYS) ................................................................................................... 40 
10.4 FOLLOW-UP PERIOD (UP TO 365 DAYS AFTER TRANSPLANTATION) .......................................................... 40 
10.5 PHYSICAL EXAMINATION ............................................................................................................... 41 
10.6 ELECTROCARDIOGRAM .................................................................................................................. 41 
10.7 ECHOCARDIOGRAM ...................................................................................................................... 41 
10.8 CHILD-PUGH SCORES .................................................................................................................... 41 
11 DETAIL OF SAFETY ASSESSMENTS AND PROCEDURES ................................................................. 41 
11.1 VITAL SIGNS ............................................................................................................................... 41 
11.2 ENCEPHALOPATHY SCORE .............................................................................................................. 42 
11.3 MODEL FOR END-STAGE LIVER DISEASE SCORE ................................................................................... 42 
11.4 ADVERSE EVENTS ........................................................................................................................ 42 
12 DETAIL OF LABORATORY ASSESSMENTS AND PROCEDURES ....................................................... 42 
12.1 LOCAL LABORATORY AT INVESTIGATIONAL SITE ................................................................................... 42 
12.2 SERUM ELECTROLYTES & BIOCHEMISTRY ........................................................................................... 43 
12.3 HEMATOLOGY ............................................................................................................................ 44 
12.4 TOTAL VOLUME OF BLOOD COLLECTED ............................................................................................. 44 
13 DETAIL OF EFFICACY ASSESSMENTS AND PROCEDURES .............................................................. 44 


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13.1 PRIMARY EFFICACY VARIABLE ......................................................................................................... 44 
13.2 SECONDARY EFFICACY VARIABLES .................................................................................................... 45 
14 SERIOUS ADVERSE EVENTS........................................................................................................ 45 
14.1 SAE DEFINITIONS ........................................................................................................................ 45 
14.2 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) ........................................................... 46 
14.3 SERIOUS ADVERSE EVENT DEFINITION .............................................................................................. 46 
14.4 SEVERITY OF AN ADVERSE EVENT..................................................................................................... 47 
14.5 STUDY DRUG CAUSALITY ............................................................................................................... 47 
14.6 OVERDOSE ................................................................................................................................. 48 
14.7 COLLECTION OF ADVERSE EVENTS/SERIOUS OR UNEXPECTED ................................................................. 48 
14.8 LABORATORY ABNORMALITIES ....................................................................................................... 49 
14.9 HOSPITALIZATIONS ...................................................................................................................... 49 
14.10 COMPLICATIONS OF THE DISEASE .................................................................................................... 49 
14.11 PREGNANCY ............................................................................................................................... 49 
14.12 REPORTING SERIOUS OR UNEXPECTED ADVERSE REACTIONS OR ADVERSE EVENTS ...................................... 49 
15 STATISTICAL PLAN .................................................................................................................... 51 
15.1 PRIMARY ANALYSIS...................................................................................................................... 51 
15.2 SECONDARY ANALYSES ................................................................................................................. 51 
15.3 SAMPLE SIZE CONSIDERATIONS ....................................................................................................... 52 
15.4 SAFETY VARIABLES ....................................................................................................................... 52 
15.5 SUBJECT ACCOUNTING AND BASELINE CHARACTERISTICS ....................................................................... 53 
15.6 SAFETY POPULATION .................................................................................................................... 53 
16 DIRECT ACCESS, DATA HANDLING, AND RECORD KEEPING ......................................................... 53 
16.1 INVESTIGATOR ............................................................................................................................ 53 
16.2 SPONSOR .................................................................................................................................. 54 
16.3 RECORDS RETENTION ................................................................................................................... 54 
17 QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................... 54 
17.1 STUDY MONITORING .................................................................................................................... 54 
17.2 AUDITING .................................................................................................................................. 55 


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18 ETHICS AND RESPONSIBILITY..................................................................................................... 55 
18.1 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ........................................................ 55 
18.2 PROTOCOL AMENDMENTS ............................................................................................................. 56 
18.3 INFORMED CONSENT .................................................................................................................... 56 
18.4 CONFIDENTIALITY ........................................................................................................................ 56 
18.5 SUBJECT INJURY .......................................................................................................................... 57 
SUBJECT INJURY PROVISIONS WILL BE SPECIFIED IN THE SITE’S CLINICAL TRIAL AGREEMENT. .................................... 57 
18.6 STUDY SUSPENSION, TERMINATION, AND COMPLETION ........................................................................ 57 
18.7 STUDY AND STUDY SITE DISCONTINUATION CRITERIA ........................................................................... 57 
19 REGISTRATION OF STUDY AND PUBLICATION OF DATA .............................................................. 58 
19.1 INVESTIGATOR’S ABILITY TO PUBLISH ............................................................................................... 58 
20 REFERENCES ............................................................................................................................. 59 
21 APPENDIX A: TERLIPRESSIN STABILITY DATA: ............................................................................ 63 
22 APPENDIX B: SODIUM CHLORIDE SOLUTION: ............................................................................. 67 
23 APPENDIX C: TERLIPRESSIN MICROBIOLOGY .............................................................................. 68 
 
 
 


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2 List of Abbreviations 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
ACLF 
acute on chronic liver failure  
AE 
adverse event 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine amino transferase, also known as SGPT 
ANCOVA 
analysis of covariance 
AR 
adverse reaction 
AST 
aspartate amino transferase, also known as SGOT 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CrCl 
creatinine clearance  
CRF  
Case report form  
EASL 
European Association for the Study of the Liver 
ECG 
Electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EVH 
esophageal variceal hemorrhage 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HRS 
hepatorenal syndrome 
IAC 
International Ascites Club 
IAC-AKI 
IAC-acute kidney injury 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IME 
important medical events 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LVP 
large volume paracentesis 
MAP 
mean arterial pressure 


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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
M&O 
Midodrine/Octreotide 
NDA 
New Drug Application 
NSAID 
nonsteroidal anti-inflammatory drug 
RBC 
red blood cell 
RRT 
renal replacement therapy  
SAE 
serious adverse event 
SUSAR 
suspected unexpected adverse reaction  
SCr 
serum creatinine 
SIRS 
systemic inflammatory response syndrome 
SOC 
standard of care 
SpO2 
pulse oximetric saturation 
SRO 
Safety Review Officer 
TIPS 
transjugular intrahepatic portosystemic shunt 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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3 Introduction 
3.1 Hepatorenal Syndrome 
Hepatorenal syndrome (HRS) Type 1, a potentially reversible renal failure, is a serious, rapidly 
progressing, fatal orphan disease complicating decompensated chronic liver disease associated 
with cirrhosis (Arroyo, 1996; Salerno, 2007; Angeli, 2015). The estimated United States (US) 
annual incidence for HRS Type 1 ranges between 9,000 and 20,000 patients (Marrero, 2003; 
Muir, 2002; Murkerjee, 2002; National Hospital Discharge Survey 2005), establishing it as an 
orphan disease. The death rate from chronic liver disease and cirrhosis has been rising, while the 
death rates for other major diseases such as stroke, cancer, heart disease, and diabetes have gone 
down in the past 15 years (Centers for Disease Control and Prevention 2013; Ma, 2015). 
As indicated in the American Association for the Study of Liver Diseases (AASLD) Guidelines, 
at present, there is no available pharmacological therapy (i.e., approved or proven) in the US or 
Canada for HRS Type 1 (Runyon, 2013) and there remains a significant unmet need.  
An increasing body of knowledge of the pathophysiology of HRS Type 1 has demonstrated that 
vasoconstrictive drug therapy may improve renal function in HRS Type 1 (Salerno, 2007; 
European Association for the Study of the Liver 2010). Terlipressin has been extensively studied 
as a splanchnic vasoconstrictor for the treatment of HRS Type 1 and is the standard of care for 
this condition wherever the drug is available (European Association for the Study of the Liver 
2010). Although there has been some off-label use of other vasoconstrictors, a recent study has 
shown that the most commonly used agents (i.e., combination of midodrine and octreotide) are 
not effective (Cavallin, 2015). 
There is a shift in HRS terminology to move away from HRS Type 1 and HRS Type 2 to the new 
designations of HRS-Acute Kidney Injury (HRS-AKI) and HRS-Chronic Kidney Disease (HRS-
CKD), respectively, in order to better harmonize with the existing nomenclature in nephrology, 
the clinical consequences of kidney injury, and initiation of treatment at earlier time points when 
it is more effective (Angeli, 2015). HRS-AKI removes the condition of creatinine doubling over 
two weeks, as often patients with ascites, a precipitating event, and HRS physiology may not 
have had a creatinine checked in the preceding two weeks but would still benefit from HRS 
treatment.  Additionally, HRS-AKI divides the kidney injury into stages (1-3) to mirror the AKI 
criteria set forth by the Acute Kidney Injury Network (AKIN) (Angeli, 2015). 
 
 


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3.2 Terlipressin  
Terlipressin is a synthetic vasopressin analogue that acts as a systemic vasoconstrictor via the 
vascular vasopressin V1 receptors. In HRS patients the strong V1 receptor-mediated 
vasoconstrictor activity of terlipressin, particularly in the splanchnic area, increases effective 
intravascular volume and mean arterial pressure (MAP), ameliorates renin-angiotensin-
aldosterone system and sympathetic nervous system hyperactivity, and improves renal blood 
flow. These corrective hemodynamic effects culminate in improved renal function, thereby 
providing the pharmacologic rationale for treatment of HRS with terlipressin (Arroyo, 2000; 
Ginès, 2003; Kiszka-Kanowitz, 2004). 
After intravenous (IV) administration of terlipressin, the glycyl residues of terlipressin are 
cleaved by endogenous tissue proteases. Thus, terlipressin levels in the blood decrease rather 
rapidly and the pharmacologically active metabolite lysine-vasopressin is released gradually 
from tissues into the circulation.  Intravenous terlipressin can be delivered quickly via bolus 
injection or slowly through continuous infusion.  There is evidence that continuous infusion 
leads to fewer adverse events and lower total terlipressin doses to achieve HRS reversal 
(Cavallin, 2016).  A bolus injection prior to continuous infusion will achieve therapeutic levels 
earlier than continuous infusion alone. 
Terlipressin is approved in many countries and regions outside the US where it has been a 
standard of care for decades in the treatment of subjects with liver cirrhosis and esophageal 
variceal hemorrhage (EVH) (de Franchis, 2005; Ioannou, 2003), and has more recently become a 
standard of care for the treatment of subjects with HRS Type 1 where it is available 
(EASL, 2010). Terlipressin has been approved for the treatment of HRS Type 1 in Australia, 
France, Ireland, South Korea, Mexico, Taiwan, Spain, India, Brazil, Turkey, and Portugal.  
3.3 Efficacy  
Improvement in renal function is the goal of therapy for HRS-AKI; improvement in renal 
function is associated with improvement in clinical outcomes and improved prognosis, with or 
without liver transplantation. HRS reversal is a widely accepted, clinically meaningful response 
to treatment for HRS Type 1, as apparent inexorable, rapid progression of renal failure is arrested 
and normal renal function in the setting of decompensated liver disease is restored. The primary 
endpoint of HRS reversal (1 serum creatinine [SCr] value of ≤ 1.5 mg/dL) is the standard 
endpoint utilized in the literature and HRS treatment guidelines (Arroyo, 1996; Salerno, 2007; 
Angeli, 2015).  Both terlipressin bolus and continuous infusion have been shown to be effective 


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in the treatment of HRS Type 1, with fewer adverse events occurring in the cohort receiving 
continuous infusion. (Cavallin, 2016). 
3.4 Safety  
The safety characteristics of terlipressin is captured in the literature and post-marketing data 
from the World Health Organization (WHO) database. In general, terlipressin has a well-
established safety profile in the treatment of patients with HRS Type 1. The safety risks are 
predictable and recognizable. The adverse drug reactions can be readily managed and reversed 
by terlipressin dose reduction or interruption in hospital-care settings.  Continuous infusion of 
terlipressin may be more tolerable than bolus injection (Cavallin, 2016). 
3.5 Retrospective Control Group:  M&O Treated Subjects 
3.5.1 Midodrine and Octreotide 
Midodrine is an oral alpha-receptor agonist that binds to peripheral alpha-receptors on both 
arterioles and veins, leading to an increase in blood pressure (Cruz, 2000).   Midodrine is a 
prodrug; it is transformed into the active metabolite de-glymidodrine, a compound similar in 
structure to norepinephrine (Cruz, 2000). Midodrine was approved for use in the United States 
for treatment of orthostatic hypotension in 1996. Octreotide is somatostain analogue that binds to 
somatostain receptors and mimics the physiologic effects of somatostatin including inhibition of 
various hormones, some of which lead to vasodilation, thus octreotide can cause arteriolar 
vasoconstriction leading to increases in blood pressure (Gold Standard).  Octreotide can be 
administered via intravenous or subcutaneous routes and was approved for use in the United 
States in 1988 for treatment of certain neuroendocrine tumors. 
3.5.2 M&O Off-Label Use 
The combination of midodrine/octreotide (M&O), in conjunction with albumin, has been used 
“off-label” in the United States for treatment of HRS Type 1 for years. Small studies, mostly 
single center, have demonstrated favorable outcomes for M&O in treatment of HRS Type 1 
(Angeli, 1999; Wong, 2004; Esrailian, 2007).  The use of M&O plus albumin is recommended in 
the 2012 AASLD guidelines for the treatment of HRS Type 1 (Runyon, 2013) , particularly in 
light of the fact that terlipressin was not available in the United States at the time of publication.  
However, the largest multi-centered study comparing terlipressin to M&O undertaken by the 
Italian Association for the Study of the Liver Study Group on Hepatorenal Syndrome, was 
stopped early due to the considerable differences in HRS reversal between terlipressin and M&O 
(55.5 vs 4.8%, p<0.001) (Cavallin, 2015).  


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Midodrine/Octreotide use in patients on the liver transplant wait list with HRS Type 1 
Increasing the duration of time in which a patient with decompensated cirrhosis experiences 
renal dysfunction decreases the likelihood of renal recovery after liver transplant (Campbell, 
2005). Wong et al retrospectively evaluated patients that had experienced HRS Type 1 without 
reversal prior to liver transplant at University of Toronto between 2001 to 2010 (n=62); M&O 
was used as treatment of HRS Type 1 in the majority of these patients (Wong, 2015).  While 
none of the patients in the cohort had HRS reversal, 76% were free from dialysis 30 days after 
liver transplant and had a serum creatinine ≤ 1.5 mg/dL (Wong, 2015).  The duration of HRS 
type 1 and the number of dialysis days prior to liver transplant were highly predictive of post-
transplant renal function (Wong, 2015).  Additionally, those patients that were not dialysis-free 
30 days post-transplant with serum creatinine ≤ 1.5 mg/dL had higher mortality rates (Wong, 
2015).  This data suggests that even if HRS reversal is not possible, that limiting the dialysis 
days and length of HRS type 1 can lead improve renal outcomes post-transplant. 
4 Study Rationale 
The purpose of this open labeled study is to assess safety/efficacy for continuous terlipressin 
infusion in liver transplant-eligible adult subjects with Hepatorenal syndrome- Acute Kidney 
Injury (HRS-AKI). 
5 Safety and Efficacy Assessments 
5.1 Efficacy Variables 
The efficacy variables are summarized below, and further details are provided in Section 13. 
Primary Efficacy Assessment:  
Improvement of renal function (SCr) from Day 1 through end of treatment, repeated measure 
analysis.  SCr will be collected daily, from Day 1 through end of treatment. Baseline SCr will 
also be entered. 
Secondary Efficacy Endpoints: 
 
• Improvement of renal function (SCr) from Day 1 through end of treatment, repeated measure 
analysis as compared to the Retrospective Control Group. 
• For the Prospective Terlipressin Group alone and also in comparison to the Retrospective 
Control Group: 
o Incidence of dialysis by Day 30 and Day 90 of follow up. 


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o Survival by Day 30 and Day 90 follow up. 
o Transplant by Day 30 and Day 90 follow up. 
o Serum creatinine at Day 30 and Day 90 follow up 
o Serum creatinine and incidence of dialysis at Day 30, Day 90, Day 180, and Day 365 
after liver transplantation and those alive without transplantation (transplant eligible 
and ineligible patients) 
o Incidence of kidney transplant within one year after liver transplant. 
o Descriptive analysis of number simultaneous liver kidney transplants and episodes of 
graft rejection at Day 90 and Day 365 after liver transplant. 
Safety: 
 
Safety review and assessments will be made only for the Prospective Terlipressin Group and will 
include the following: 
 
• Serious adverse events up to 30 days after end of treatment. 
6 Investigational Plan 
6.1 Overall Study Design and Plan: Description 
Prospective Terlipressin Group 
This is a collaborative open-label, multicenter study of terlipressin infusion following an initial 
bolus dose of 0.5mg. Written informed consent will be obtained by the investigator, sub-
investigator, or qualified designee from the subject or legally authorized representative (LAR) 
prior to the subject enrollment into the study. Approximately 50 subjects are planned to be 
enrolled at 5-10 sites in the US. Subjects will receive up to 14 days of terlipressin treatment. 
Retrospective Control Group 
This study will also seek clinical data from a Retrospective Control Group of patients who would 
have met inclusion/exclusion criteria detailed below and received at least 48 hours of treatment 
with Midodrine and Octreotide (M&O), albumin, or other vasopressor used for the treatment of 
HRS-AKI.  Retrospective cases collected from each site should include eligible patients starting 
from prior to site IRB approval for this protocol and going back to January 2015.  Subjects 
enrolled in a blinded clinical trial in this time period are excluded. 
 
 


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7 Study Population 
7.1 Population Rationale 
The study population consists of adult subjects with cirrhosis, ascites, and a diagnosis of HRS 
AKI based on based on the 2015 revised International Ascites Club (IAC) diagnostic criteria. 
7.2 Number of Subjects to be Studied 
Prospective Terlipressin Group - approximately 50 Terlipressin treated subjects. Retrospective 
Control Group - approximately 15-25 subjects per clinical site that were treated for HRS-AKI 
according to center’s standard-of-care (Midodrine/Octreotide (M&O), albumin, or other 
vasopressor) that would have met the inclusion/exclusion criteria below as well as having critical 
clinical data points to enable a comparison of the Prospective and Retrospective groups.  
Retrospective cases collected from each site should include eligible patients starting from prior 
to site IRB approval for this protocol and going back to January 2015.  Subjects enrolled in a 
blinded clinical trial in this time period are excluded. 
7.3 Inclusion/Exclusion Criteria 
Adult subjects with a diagnosis of HRS-AKI based on 2015 revised International Ascites Club 
(IAC) diagnostic criteria will be considered for enrollment. There are two groups: 1. listed for 
liver transplant or liver transplant eligible with anticipation of being placed on the liver 
transplant wait list; 2. Ineligible for liver transplant 
Inclusion Criteria:  Subjects must meet all of the following inclusion criteria to be eligible for 
enrollment: 
1. Written informed consent by subject or legally authorized representative. 
2. At least 18 years of age. 
3. Cirrhosis and ascites. 
4. No sustained improvement in renal function (less than 20% decrease in SCr) at least 48 hours 
after diuretic withdrawal and after plasma volume expansion with albumin (given daily for 
two days - 48 hours minimum from 1st dose). If SCr improves by ≥ 20 % but plateaus ( ≤ 10 
% fluctuation in sCr) and remains  above 1.5 mg/dl for ≥another 48 hrs and there are no 
features of acute tubular necrosis. 
 


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5. Increase in SCr by at least ≥ 0.3 mg/dl OR 1.5-2 fold above baseline (AKI stage 1 and 
above), to a SCr of ≥ 1.5 mg/dl at the time of initiating treatment. Baseline SCr is defined as 
the most recent, lowest SCr within last 6 months before date of current admission.  
6. A.) On liver transplant wait list or liver transplant eligible with anticipation of being placed 
on the liver transplant wait list.  B.) Patients not on the transplant waitlist or transplant 
eligible are also eligible for the trial (maximum 25 subjects)  
Exclusion Criteria:  If any of the following exclusion criteria are met, the subject will not be 
enrolled: 
1. Serum creatinine level greater than 5.0 mg/dL.  Subjects with value greater than 5.0 mg/dL 
may be enrolled with Sponsor prior approval. 
2. MELD score ≥ 35 
3. Acute on Chronic Liver Failure (ACLF) grade 3 (according to the CLIF Consortium grading 
system). 
4. Uncontrolled sepsis and/or uncontrolled bacterial infection (e.g., persisting bacteremia, 
persisting ascitic fluid leukocytosis, fever, increasing leukocytosis with vasomotor 
instability). 
5. Shock. 
6. Current or recent (within 4 weeks) treatment with or exposure to nephrotoxic agents: e.g., 
aminoglycosides, amphotericin, cyclosporine A, cisplatin, nonsteroidal anti-inflammatory 
drugs (NSAIDs: e.g., ibuprofen, naproxen, diclofenac), significant exposure to radiographic 
contrast agents (large doses or multiple injections of iodinated contrast media; e.g., during 
coronary or abdominal angiogram). 
7. Estimated life expectancy of less than 7 days. 
8. Advanced Hepatocellular Carcinoma (HCC) with expected survival of < 6 months. 
9. Superimposed acute liver injury due to drugs (e.g., acetaminophen), dietary supplements, 
herbal preparations, viral hepatitis, or toxins (e.g., Amanita toxin with mushroom poisoning 
carbon tetrachloride), with the exception of acute alcoholic hepatitis. 
10. Evidence of obstructive uropathy or parenchymal renal disease.  Renal ultrasound or other 
imaging not required but should be taken if suspicious. 


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11. Tubular epithelial casts, heme granular casts (range of 1-3 granular casts acceptable), 
hematuria or microhematuria on urinalysis that is indicative of acute tubular necrosis and/or 
intrinsic renal disease. 
12. Subjects known to be pregnant; all women of child-bearing age and potential must have a 
negative pregnancy test. 
13. Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary 
edema, congestive heart failure, or persisting symptomatic peripheral vascular disease, 
myocardial infarction or stable chronic angina within the past 12 months, or any other 
cardiovascular disease judged by the investigator to be severe and creates a risk to subject 
with concurrent terlipressin use. 
14. Current or recent (within 4 weeks) renal replacement therapy (RRT) or anticipation of RRT 
within 3 days on enrollment. 
15. Participation in other clinical research involving investigational medicinal products within 30 
days of starting study drug that would adversely affect participation in this or the current 
trial. 
16. Transjugular intrahepatic portosystemic shunt (TIPS) within 30 days of starting study drug. 
17. For the Prospective Group: All vasopressors must be stopped prior to treatment with 
terlipressin.  Use of vasopressors (eg, norepinephrine, epinephrine or vasopressin dopamine 
or other vasopressors) of  ≥ 3 consecutive days within the prior 14-day screening period are 
excluded. Patients receiving a vasopressor other than midodrine within 24 hours of 
qualifying SCr are excluded, i.e, a 24-h washout is required prior to enrollment. 
Note: Patients receiving midodrine and octreotide may be enrolled. Midodrine and octreotide 
treatment must be stopped prior to enrollment. 
18. Known allergy or sensitivity to terlipressin. 
 
7.4 Subject Withdrawal Criteria  
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. 
7.5 Protocol Deviations 
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and wellbeing of the subject requires immediate intervention that 


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deviates from the protocol, based on the judgment of the investigator (or a responsible, 
appropriately trained professional designated by the investigator). In the event of a significant 
deviation from the protocol due to an emergency, accident, or error, the investigator or designee 
must contact the sponsor, or their agent, at the earliest possible time by telephone. This will 
allow an early joint decision regarding the subject’s continuation in the study. The investigator 
and the sponsor will document this decision. The Institutional Review Board (IRB) will be 
informed of all protocol deviations by the investigator in accordance with the IRB established 
procedure. No deviations from the protocol of any type will be made without complying with all 
the IRB established procedures. Significant deviations from the protocol may not allow that 
patient’s clinical data to be included in the Intent-To-Treat Analysis. 
8 Terlipressin  
Terlipressin will be supplied in single-use, sterile 6-mL vials containing 1 mg of lyophilized 
terlipressin acetate (equivalent to 0.85 mg terlipressin free base) with 10 mg mannitol as a 
bulking agent/stabilizer.  
The lot numbers will be documented in the trial master file. 
 
Figure 1: 
Terlipressin for Injection 
Structure: 
 
 
Molecular Formula: C52 H74 N16 O15 S2 
Molecular Weight: 
1227.4 Daltons 
Appearance: 
Homogenous lyophilized white to off-white solid 
Solubility: 
Clear, colorless solution in saline 
H2N
 H 
Cys
Tyr
Phe
Gln
Asn
Cys
Gly
Pro
Lys
Gly
Gly
Gly


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Vials: 
Colorless glass vials containing 11 mg of a white to off-white 
solid, 1 mg active ingredient and 10 mg mannitol. 
The active ingredient, N-[N-(N-glycylglycyl) glycyl]-8-L-lysinevasopressin, is a synthetically 
manufactured hormonogen of 8-lysine vasopressin, composed of 12 amino acids and having the 
characteristic ring structure of a cyclic nonapeptide with a disulfide bridge between the 4th and 
the 9th amino acid. Three glycyl-amino acids are substituted at position 1 (cysteine) of 
8-lysine-vasopressin. By this N-terminal extension of 8-lysine-vasopressin the metabolic 
degradation rate of the active ingredient is significantly reduced, because the glycyl molecules 
inhibit rapid N-terminal enzymatic degradation. 
 
8.1 Packaging and Labeling 
Single-use, sterile 6-mL vials of a lyophilized solid containing 1 mg of terlipressin acetate 
(equivalent to 0.85 mg terlipressin free base) will be provided to the sites. Study drug labels will 
comply with local regulatory requirements, including sponsor name and address, protocol 
number, storage conditions and US Investigational New Drug (IND) caution statement. 
8.2 Study Drug Storage and Preparation 
Study drug should be stored in a secure location at 2ºC to 8ºC until reconstituted.  Reconstituted 
study drug bolus and study drug infusion bags may be stored up to 48 hours at refrigerated 
storage conditions (2ºC to 8ºC) and at room temperature (25 ºC) for 24 hours. (Appendices A and 
C). 
Terlipressin is stable at 2ºC to 8ºC up to 48 hours in 0.9% sodium chloride solution at a 
concentration of 1mg Terlipressin in 5mL solution (Appendix A). 
Microbiology studies at a concentration of 2 mg Terlipressin in 50 mL of 0.9% sodium chloride 
solution are included in Appendix C.  Stability at a concentration of 0.034 mg/mL has been 
previously demonstrated (Bui 2020). Study drug assignment, preparation, and dosing will be 
strictly limited to the investigators and their designees.  Study doses will be labelled to ensure 
drug is used only for authorized investigational use only.  The subject’s initials will be placed on 
the label by the Pharmacists at the time of dispensing. 
8.3 Reconstitution 


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For the first dose of terlipressin, each vial will be reconstituted with 5 mL of sterile 0.9% sodium 
chloride solution and administered intravenously as a bolus injection and given over 1 minute at 
a dose of 0.5 mg.   
For continuous infusion, the dose of terlipressin is to be dissolved in 0.9% sodium chloride 
solution and infused with a pump (Appendix B).  
8.4 Administration 
Subjects in the Prospective Terlipressin Group: 
Single-use, sterile 6-mL vials containing 1 mg of lyophilized terlipressin acetate (equivalent to 
0.85 mg terlipressin free base) with 10 mg mannitol as a bulking agent/stabilizer.  
• For initial bolus dose of 0.5mg, the vial will be reconstituted with 5 mL of sterile 0.9% 
sodium chloride solution and given over 1-minute push.  
• Continued dosing will be by 2mg infusion per day for Days 1, and 2.  For continuous 
infusion, the dose of terlipressin is to be dissolved in 0.9% sodium chloride solution and 
infused with a pump.   
• If on Day 3 the SCr is not 30% lower from the baseline value, increase infusion dose to 4 mg 
per day.  
• If on Day 5 the SCr is not 50% lower from the baseline value, increase infusion dose to 6-8 
mg per day, per PI discretion. Dosing can be increased by more than 1 mg increment at Day 5 
or beyond, up to a maximum of 8 mg/day. 
• If the subject has infusion stopped for ≥ 4 hours, a 0.5 mg bolus should be given prior to 
restarting infusion.  
• The drug should not be used in subjects with severe coronary artery disease or in the setting 
of circulatory overload, pulmonary edema, or bronchospasm as determined by the 
Investigator. If drug therapy has been initiated, Investigator can also decide not to increase 
the dose, based on the patient’s status with regard to the above, based on individual subject 
condition. 


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• If dosing is interrupted due to an adverse event, terlipressin may be re-started, at the 
discretion of the investigator, at the same or lower dose as per protocol. Terlipressin will not 
be restarted if dosing was interrupted due to cardiac ischemia or mesenteric ischemia. 
Subjects in the Retrospective Control Group: 
 
The dose and method of administration for Midodrine/Octreotide (M&O), albumin, or other 
vasopressor will be recorded as noted in the patient’s medical record.  To be included as a 
completed subject in this study, patients must have been treated for at least 48 hours with 
albumin infusions beyond volume resuscitation and diuretic withdrawal.  Vasopressors also need 
to be used for a minimum of 48 hours. 
8.5 Study Drug Accountability 
The investigator or designee must maintain an inventory record of study drug administered to 
assure the regulatory authorities and the sponsor that the investigational new drug will not be 
dispensed to any person who is not a subject under the terms and conditions set forth in this 
protocol. Neither the investigators nor any designees may provide study drug to any subject not 
formally enrolled in this protocol. 
The study drug supplied for use in this study is to be prescribed only by the investigator or 
properly assigned designee and may not be used for any purpose other than that outlined in this 
protocol. 
All unused investigational product will be handled per study drug supplier instructions at 
conclusion of the study. Periodic review of drug accountability records will be conducted by 
investigational site monitors. Final review and reconciliation of the accountability records will be 
performed by the sponsor or designee. 


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9 Assessments and Procedures 
9.1 Schedule of Assessments and Procedures  
Table 1 presents the schedule of assessments and procedures to be performed during the study.  Assessments are completed per sites’ 
Standard of Care. 
Table 1 
Schedule of Assessments 
Study Assessmentk 
Screening 
Period 
Pretreatment 
Period 
Active Study Period 
Follow-up Period 
(Days from Last Dose) 
Baseline 
Assessment 
Days 1 to 14a (as applicable) 
End of 
Treatment 
7 ±2 
days 
14 ±3 
days 
30 ±7 
days 
90 ±7 
days 
180 ±14 
days 
365 ±14 
days 
1 2 3 4 5 6 7 
8-14 
Diagnosis of HRS - AKI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, body weight, 
estimated dry weightͣp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogramn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Child-Pugh score 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dosing 
 
 
X X X X X X X 
X 
 
 
 
 
 
 
 


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Study Assessmentk 
Screening 
Period 
Pretreatment 
Period 
Active Study Period 
Follow-up Period 
(Days from Last Dose) 
Baseline 
Assessment 
Days 1 to 14a (as applicable) 
End of 
Treatment 
7 ±2 
days 
14 ±3 
days 
30 ±7 
days 
90 ±7 
days 
180 ±14 
days 
365 ±14 
days 
1 2 3 4 5 6 7 
8-14 
Biomarker Blood and 
Urine Samplel 
 
X 
 
 
 X  
 
 
 
X 
 
 
 
 
 
 
Cystatin cm  
 
X 
 
 
 X  
 
 
 
X 
 
 
 
 
 
 
Assessments 
albumin dose if 
administered 
X 
X 
X X X X X X X 
X 
X 
 
 
 
 
 
 
SCrc (BUN & eGFR if 
taken f) 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
24 hr Urine Volume 
X 
X 
X X X X X X X 
X 
 
X 
 
 
 
 
 
Vital signsh 
 
X 
X X X X X X X 
X 
X 
 
 
 
 
 
 
Encephalopathy score 
 
X 
X X X X X X X 
X 
 
 
 
 
 
 
 
Serum electrolytes  
 
X 
X X X X X X X 
X 
X 
 
 
 
 
 
 
ALT, AST, ALP, protein, 
albumin, bilirubino 
 
X 
X  X  
 
 X 
 
X 
X 
X 
X 
X 
X 
X 
Serum glucose, calcium, 
magnesiumo  
 
X 
X  X  
 
 X 
 
X 
 
 
 
 
 
 
INR 
 
X 
X  X  
 
 X 
 
X 
X 
X 
X 
X 
X 
X 
CBCo 
 
X 
X  X  
 
 X 
 
X 
 
 
 
 
 
 
Concomitant medicationsi 
 
 
X X X X X X X 
X 
 
 
 
 
 
 
 
Assessments Throughout Study 
Adverse eventsg 
 
 
Monitor and record Serious Adverse Events throughout active study period 
to 30 days post-treatment. 
 
Record RRT, TIPS, 
transplant, and mortalityj 
 
 
Monitor and record throughout active study period and follow-up. 
Record all paracentesis 
events 
 
 
Record all paracentesis performed until drug treatment discontinued  


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All assessments are completed per Standard of Care. 
aMaximum treatment of 14 Days. 
bFemale subjects of child-bearing potential must have a negative urine or serum pregnancy test within 14 days prior to the first dose of study treatment. 
cThe qualifying SCr value (SCr value at least 48 hours after both diuretic withdrawal and the beginning of albumin fluid challenge) is considered the Enrollment 
SCr and must be drawn prior to start of study drug. The qualifying SCr value must be ≥ 1.5 mg/dL AND Baseline SCr is defined as the most recent, lowest SCr 
within last 6 months before date of current admission. 
dA general standard of care physical assessment of the major body systems evaluating any new clinically significant abnormalities within the following: general 
appearance, skin, head/eyes/ears/nose/throat, neck, heart, lungs, abdomen, extremities, and neurological systems. The investigator may perform additional 
unscheduled examinations to manage or evaluate a suspected AE as clinically necessary. The physical examination will also include weight and height. 
eCollection of the data from the last electrocardiogram done prior to admission and the electrocardiogram performed during admission, if performed as per 
standard of care 
fMust be performed at least once daily during active treatment AND until Day 14 (regardless of treatment status) or discharge, whichever occurs first. BUN & 
eGFR are recorded if taken per site standard of care.  If assessments are performed more than once daily as part of the subject’s medical care, all values are to be 
recorded on the CRF.  If subject has SCr, BUN and/or eGFR, including Vital signs taken at any of the Follow-up Periods, they are to be recorded on the CRF. 
gSerious Adverse Events will be required to be collected only for the Prospective Terlipressin Group. 
hVital sign measurements include body temperature, respiratory rate, systolic and diastolic blood pressure, SpO2 (pulse oximetric saturation), and heart rate. 
Vitals will be taken at baseline (within 24 hours of start of study drug) and daily during study drug treatment days.  The measurements should be assessed and 
recorded at a consistent, specific time of day.  Preferable morning assessment/measurement. 
iConcomitant medications include IV solutions and blood products. 
jAll follow-up visits will include assessments of survival, RRT, TIPS and liver transplant status. Study days will be counted from the last day of study drug 
administration. If the subject is in the hospital during any of the Follow-up Time Periods, the study assessment data will be recorded from the subject’s medical 
record. 
kAll study assessments are to follow SOC 
l Optional - Collection of Blood and Urine for future biomarker evaluation is optional and may be collected ± 1 day of target collection day 
mOptional - Cystatin C – assessment of cystatin c levels is optional – but if measured we want it assessed 3 times (at Baseline/pretreatment, on day 4 of treatment 
and last day of treatment) 
nCollection of last echocardiogram done prior to admission and any echocardiogram performed during admission, if performed as per standard of care 
oNeutrophils, lymphocyctes, total protein, and magnesium if collected Standard of Care 
p Estimated Dry Body Weight is collected if calculated by site  
 


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Table 2 presents the schedule of assessments and procedures to be performed Post Transplantation. 
Table 2 
Schedule of Assessments Post Transplantation 
Study Assessmentc 
Day of  
Liver 
Transplant 
 
Follow-up Period  (Days from Day of Liver Transplant 
 
7 ±2 
daysa  
14 ±3 
daysa  
30 ±7 
daysa  
90 ±7 
daysa  
180 ±14 
daysa  
365 ±14 
daysa 
Last Known 
follow-up 
datea 
Record events of RRT, 
TIPS and mortality 
X 
X 
X 
X 
X 
X 
X 
X 
Record all paracentesis 
events 
X 
X 
X 
X 
X 
X 
X 
X 
SCr (BUN & eGFR if 
taken b) 
X 
X 
X 
X 
X 
X 
X 
X 
MELD Scored 
X 
 
 
 
 
 
 
 
Dialysis 
 
 
 
X 
X 
X 
X 
X 
Incidence of Kidney 
Transplante 
X 
X 
X 
X 
X 
X 
X 
X 
 
aAll subjects will be contacted for all follow-up periods to assess survival, RRT, TIPS and liver transplant status. Follow-up days will be counted from days after 
transplantation. If the subject is in the hospital during any of the Follow-up Time Periods, the study assessment data will be recorded from the subject’s medical 
record. 
bBUN & eGFR are recorded if taken per site standard of care.  If assessments are performed more than once daily as part of the subject’s medical care, all values 
are to be recorded on the CRF.  If subject has SCr, BUN and/or eGFR, including Vital signs taken at any of the Follow-up Periods, they are to be recorded on the 
CRF. 
cAll study assessments are to follow SOC. 
d In addition to the Allocation MELD score (MELD score that qualifies subject for transplant), also record the date and the last calculated MELD score prior to 
transplant.   
 
 
 


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10 Study Assessments 
10.1 Screening Period 
The screening period occurs prior to enrollment and consists of establishing the diagnosis of 
HRS-AKI as per guidelines and standard medical practice and confirming eligibility for study 
participation. The investigator or qualified designee will not be required to obtain sponsor 
approval to enroll subjects.  Enrollment of subjects determined not to qualify for the study during 
sponsor monitoring oversight may result in study site closure.  Written informed consent will be 
obtained by the investigator, sub-investigator, or qualified designee from the subject or legally 
authorized representative prior to the subject qualification form being completed. 
10.2 Pre-Treatment Period 
The pre-treatment period occurs prior to administration of study drug and includes performing 
baseline assessments and collection of prior medication information.  
The qualifying SCr value (SCr value at least 48 hours after both diuretic withdrawal and after the 
beginning of albumin fluid challenge) is considered the enrollment SCr and must be drawn prior 
to study drug administration. 
10.3 Active Study Period (14 Days) 
Dosing (Up to 14 Days) 
The active study period extends from the initiation of study treatment through Day 14 or 
discharge from the hospital for any reason, whichever occurs first. Study drug will be 
administered as described in Section 7.3.2.  Concomitant medications will be collected during 
this active study period.  See Table 8.1 for the schedule of assessments during the active study 
period. 
End of Treatment, Discharge or Day 14 
Terlipressin may be continued until 24 hours after serum creatinine as reached the lowest value 
possible as determined by Principal Investigator, up to a maximum of 14 days. 
10.4 Follow-up Period (Up to 365 Days after transplantation) 
The follow-up period begins after the end of the study treatment and concludes Day 365 after 
liver transplantation. 


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10.5 Physical Examination 
A physical examination, including weight, estimated dry weight (if calculated as per standard of 
care), and height, will be conducted at baseline and will follow the standard of care for these 
subjects. 
The investigator may perform additional unscheduled examinations to manage or evaluate a 
suspected SAE as clinically necessary. The timing and scope of additional unscheduled 
examinations should be determined by the nature and severity of the SAE being evaluated. 
10.6 Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at baseline.  Clinically relevant 
abnormalities found will be reported on the medical history page. The investigator may perform 
additional unscheduled examinations to manage or evaluate a suspected SAE as clinically 
necessary. The data of all subsequent ECGs will be reported on the ECG/Echocardiogram CRF. 
10.7 Echocardiogram 
The last echocardiogram done prior to admission will be collected as well as any echocardiogram 
performed during admission.  Clinically relevant abnormalities found will be reported on the 
medical history page.  The data of all subsequent Echocardiograms will be reported on the 
ECG/Echocardiogram CRF. 
10.8 Child-Pugh Scores 
Child-Pugh score will be calculated at baseline and entered in the CRF. 
11 Detail of Safety Assessments and Procedures 
11.1 Vital Signs 
Vital sign measurements will be recorded at baseline and daily during study drug administration.  
The measurements should be assessed and recorded at a consistent, specific time of day,   
preferable morning assessment/measurement. 
Systolic and diastolic blood pressure, heart rate, body temperature, respiratory rate, and pulse 
oximetric saturation (SpO2) will be recorded at baseline and during study drug administration. 
 


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11.2 Encephalopathy Score 
Clinically detectable encephalopathy is to be assessed prior to study drug administration and 
daily during study drug administration using the clinical criteria described in Table 3. 
Table 3 
West Haven Criteria for Semiquantitative Grading of Mental State  
Grade 1 
Trivial lack of awareness. 
Euphoria or anxiety. 
Shortened attention span. 
Impaired performance of addition. 
Grade 2 
Lethargy or apathy. 
Minimal disorientation for time or place. 
Subtle personality change. 
Inappropriate behavior. 
Impaired performance of subtraction. 
Grade 3 
Somnolence to semi-stupor, but responsive to verbal stimuli. 
Confusion. 
Gross disorientation. 
Grade 4 
Coma (unresponsive to verbal or noxious stimuli). 
Source: Ferenci et al, 2002. 
 
11.3 Model for End-Stage Liver Disease Score 
Model for end-stage liver disease (MELD) scores will be calculated by the sponsor based on 
SCr, bilirubin and INR values at baseline and treatment termination. 
11.4 Adverse Events  
Only Serious Adverse Events will be recorded until 30 days after discontinuation of study drug. 
Those events that are unanticipated serious adverse events possibly related to the study drug 
(SUSAR) must be reported to the sponsor or its designee for safety reporting in an expedited.  
See section 14.2 for SUSAR definition. 
12 Detail of Laboratory Assessments and Procedures 
12.1 Local Laboratory at Investigational Site 
The laboratory tests specified in this section will be performed in the laboratory at the 
investigational site. All efforts should be made to take the blood sample from a clean new venous 
site, or the second option could be a central venous line to collect the blood specimen. Site 


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personnel should not draw the blood sample from an existing peripheral venous access site, or a 
line used for IV fluid administration.  
12.2 Serum Electrolytes & Biochemistry 
The following assessments are required at baseline, then once daily during treatment or hospital 
discharge (whichever occurs first):  
• Creatinine level (SCr) 
• Blood urea nitrogen (BUN, if taken as per standard of care) 
• Estimated Glomerular Filtration Rate (eGFR, if taken as per standard of care) 
If SCr, BUN and/or eGFR assessments are performed more than once daily as part of the 
subject’s medical care, all values are to be recorded on the CRF. 
SCr (BUN & eGFR if also taken standard of care) are to be collected and recorded at all Follow-
up Visits including: Day 7, 14, 30, 90, 180 and 365 as per standard of care. 
The following assessments are required at baseline and daily during treatment with study drug: 
• Sodium 
• Potassium 
• Chloride 
• HCO3 
• 24 Hour Urine Output (if available) 
 
The following assessments are required at baseline and on treatment days 1, 3, 7, and, whenever 
possible, at treatment termination: 
• Total bilirubin* 
• Alkaline phosphatase (ALP)* 
• Alanine aminotransferase (ALT)* 
• Aspartate aminotransferase (AST)* 
• Total protein* 
• Albumin* 
• Glucose 
 
*Total Bilirubin, ALP, ALT, AST, Total Protein, and Albumin are to be collected and 
recorded at all Follow-up Visits including: Day 7, 14, 30, 90, 180 and 365 if taken as per 
standard of care. 


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The following assessments are optional: 
• Collection of blood & urine for future biomarker evaluation - optional at baseline 
(pretreatment), on treatment day 4, and at treatment termination 
• Cystatin C - optional at baseline (pretreatment), treatment day 4, and at treatment 
termination 
 
12.3 Hematology 
The following assessments are required at baseline and on treatment days 1, 3, 7, and, whenever 
possible, at treatment termination: 
• International normalized ratio (INR) 
• Complete blood count (CBC) (no differential required, but neutrophils and lymphocytes 
if available) 
INR is to be collected and recorded at all Follow-up Visits including: Day 7, 14, 30, 90, 180 and 
365 as per standard of care. 
12.4 Total Volume of Blood Collected 
The total volume of blood collected from each subject over the course of 14 days and end of 
study should not exceed approximately 310 mL, and is standard of care for the subject being 
treated.  All blood draws and assessments requested are to follow standard of care procedures. 
13 Detail of Efficacy Assessments and Procedures 
Serum creatinine must be collected at enrollment (prior to study dosing), and at least once daily 
during treatment until Day 14 or hospital discharge, whichever occurs first. If SCr assessments 
are performed more than once daily as part of the subject’s medical care, all values obtained each 
day will be recorded on the CRF.  
13.1 Primary Efficacy Variable 
Improvement of renal function (SCr) from Day 1 through end of treatment, repeated measure 
analysis.  SCr will be collected at baseline and daily from Day 1 through end of treatment.  
 
 


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13.2 Secondary Efficacy Variables 
• Improvement of renal function (SCr) from Day 1 through end of treatment, repeated measure 
analysis as compared to the Retrospective Control Group. 
• For the Prospective Terlipressin Group alone and also in comparison to the Retrospective 
Control Group: 
o Incidence of dialysis by Day 30 and Day 90 of follow up. 
o Survival by Day 30 and Day 90 follow up. 
o Transplant by Day 30 and Day 90 follow up. 
o Serum creatinine at Day 30 and Day 90 follow up 
o Serum creatinine and incidence of dialysis at Day 30, Day 90, Day 180, and Day 365 
after liver transplantation 
o Incidence of kidney transplant within one year after liver transplant 
o Descriptive analysis of number simultaneous liver kidney transplants and episodes of 
graft rejection at Day 90 and Day 365 after liver transplant 
 
14 Serious Adverse Events 
Only Serious Adverse Events will be collected for this study for the prospective group only.  
Safety review and assessments will be made only for the Prospective Terlipressin Group from 
time of first dose through 30 days after end of treatment. SAEs are collected from the start of 
study drug until 30 days after study drug was discontinued.  Non-serious Adverse Events are not 
required to be collected for this study.   
The investigator will record the nature, causality, severity, treatment, and outcome of the SAE, 
and will determine whether there is a “reasonable probability” that the study drug treatment 
caused the event. 
14.1 SAE Definitions 
The following definitions are based on: 
• International Conference on Harmonization (ICH) E2A: International Conference on 
Harmonisation Tripartite Guideline: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting (1994). 
• ICH E6: International Conference on Harmonisation Tripartite Guideline: Guideline for 
Good Clinical Practice (1996) and Integrated Addendum [E6] (R2) June 2015.  


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• Office of Human Subjects Protection, Division of Department of Health and Human 
Services Policy; “Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events" (2007).  
• Code of Federal Regulations Title 21, Part 312.32 (2011).  
Also included are events that are common to this subject population. 
14.2 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
This is an unexpected SAE or suspected unexpected adverse reaction (SUSAR) which is not 
listed in the Investigator’s Brochure (IB), nor listed at the specificity or severity observed. If an 
SUSAR is listed in the IB as occurring with a specific class of drugs, or occurring as part of a 
disease process, or from the pharmacological properties of the drug, but not specifically 
mentioned as occurring with the particular drug under investigation, it should be considered 
unexpected. 
14.3 Serious Adverse Event Definition 
Serious adverse events (SAE) are defined (in the view of the investigator or the sponsor) as any 
untoward medical occurrence that meets any of the following criteria: 
• Resulted in death. 
• Is life-threatening (if an AE or SUSAR places a subject 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).  
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in disability (persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect.  
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of an 
important medical event include allergic bronchospasm, blood dyscrasias, convulsions 
that do not result in inpatient hospitalization, or drug dependence/abuse. 


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14.4 Severity of an Adverse Event 
Intensity of an AE, assessed by the investigator and graded as mild, moderate, or severe, 
irrespective of the relationship to the drug or seriousness of the event, and evaluated according to 
the following scales: 
• Mild - awareness of the symptom but easily tolerated. 
• Moderate - discomfort enough to interfere with normal activities. 
• Severe - Incapacitating with the inability to perform normal activities. 
14.5 Study Drug Causality 
Study drug causality will be assessed as follows: 
Unrelated: An AE that is clearly and incontrovertibly due to extraneous causes (disease, 
environment, etc.) and does not meet the criteria for ‘possible’ or ‘probable.’ 
Possible: The connection between the AE and study treatment appears unlikely but cannot be 
ruled out with certainty. An AE may be considered ‘possibly related’ if it has at least 2 of the 
following: 
• It follows a reasonable temporal sequence from administration of study drug. 
• It may readily have been produced by the subject's clinical state or by environmental or 
toxic factors. 
• It follows a known response pattern to study drug. 
 
Probable: An AE that is considered to be related to study drug treatment with a high degree of 
certainty. An AE may be considered probably related if: 
• It follows a reasonable temporal sequence from administration of study drug.  
• It cannot be reasonably explained by the known characteristics of the subject's clinical 
state. 
• It follows a known pattern of response to study drug treatment. 
• It reappears upon rechallenge. 
 


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Table 4 lists adverse events that are common in this subject population (i.e., with HRS), even in 
the absence of exposure to the study drug (Rozov-Ung and Panesar, 2010; Arroyo et al, 
2008).The investigator may use this as a guidance while assessing the causality.  
 
 
Table 4: 
Adverse Events Common to the Hepatorenal Syndrome (HRS) Population 
MedDRA System Organ Class 
Preferred Term 
Blood and Lymphatic System Disorders 
Anemia  
Coagulopathy 
Cardiac Disorders 
Atrial fibrillation  
Bradycardia 
Gastrointestinal Disorders 
Abdominal pain 
Diarrhea  
Nausea 
Vomiting 
General Disorders and Administration Site Conditions 
Multi-organ failure 
Hepatobiliary Disorders 
Hepatic failure  
Infections and Infestations 
Pneumonia 
Urinary tract infection 
Metabolism and Nutrition Disorders 
Hyperglycemia  
Nervous System Disorders 
Headache  
Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea  
Epistaxis 
Pulmonary edema 
Respiratory failure 
Vascular Disorders 
Hypotension  
Source: Rozov-Ung and Panesar, 2010; Arroyo et al, 2008. 
 
14.6 Overdose 
Overdose is defined as an accidental or intentional/infusion or excessive dose of a product. 
14.7 Collection of Adverse Events/Serious or Unexpected 
Any adverse event occurring prior to signing the ICF and prior to 1st dose of study drug should 
be considered medical history or a pre-existing condition and will be collected on the Medical 
History CRF.  


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SAEs will be assessed and recorded beginning with study drug administration until 30 days after 
discontinuation of study drug.  
14.8 Laboratory Abnormalities 
The investigator will review clinical laboratory test results in a timely fashion. Laboratory 
abnormalities deemed clinically significant and serious should be reported to the sponsor as 
appropriate. 
14.9 Hospitalizations 
Planned hospital admissions and/or planned surgical operations for an illness or disease, which 
existed before the subject was randomized are not to be considered SAEs (e.g., re-hospitalization 
for liver transplantation). However, a baseline condition which deteriorates during the clinical 
study may be considered an SAE.  
Following the initial hospital discharge, all re-hospitalizations within 30 days post end of 
treatment (except for planned hospital admissions or procedures as described above) are to be 
recorded as a SAE.  
14.10 Complications of the Disease 
Complications frequently associated with HRS - AKI are expected to occur, but should be 
recorded as a SAE, as applicable, e.g., EVH, hepatic encephalopathy, sepsis, pneumonia, urinary 
tract infection.  
Since HRS - AKI is the indication under investigation, worsening or aggravation of HRS - AKI 
during the active treatment period (including non-response) will NOT be recorded as a SAE 
unless HRS – AKI is the cause of death or results in a subsequent re-hospitalization due to 
suspected recurrence. 
14.11 Pregnancy  
Pregnancy occurring in a subject is NOT considered an SAE. However, the investigator must 
collect pregnancy information for subject and/or subject’s partner if the fetus was exposed to the 
study drug. 
14.12 Reporting Serious or Unexpected Adverse Reactions or Adverse Events 
Site Reporting to Sponsor 


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Investigators must report all SAEs to the sponsor (and applicable IRB) whether or not the events 
are study drug-related or expected.  
All SAEs must be reported on a SAE form and faxed/scanned to International HealthCare (IHC) 
within 24 hours of an investigator becoming aware of the event:  
IHC Safety Review Officer 
Email: infusealerts@ihcresearch.com   
 
The initial SAE form does not need to be signed by the investigator; however, a signed SAE 
form is required for final SAE reporting. The initial scan by the investigator will include 
(whenever possible) a detailed description of the event including start and stop dates, causality 
assessment by the investigator, and supported as needed with written copies of medical records, 
autopsy reports, and other appropriate documents. Follow-up information (including information 
requested by the sponsor) should be reported by fax/scan within 24 hours of availability. The 
investigator is expected to make every effort to collect follow up information for each SAE in a 
timely fashion after the initial reporting of the SAE. 
If there are any specific questions regarding a SAE classification, the investigator should contact 
the lead sponsor Principal Investigator for this study.  
If there are any specific questions regarding the completion of the SAE form, please contact your 
site monitor. 
Site Reporting to Institutional Review Board/Independent Ethics Committee 
The investigator must notify the local IRB which approved the trial of the event in accordance 
with applicable guidelines. 
Sponsor Reporting to Regulatory Authorities and Investigators 
All reportable SAEs, including narrative safety reports of overall findings or data from aggregate 
analyses, will be reported to the applicable regulatory authorities by the sponsor or designee in 
accordance with the local regulations as described in the safety review plan for this study. 
The reporting of SAEs will be conducted in accordance with ICH E2A (Clinical Safety Data 
Management: Definitions and Standards for expedited reporting) and regulatory guidelines. 
In addition, study endpoints described in Section 5.1 of the protocol that are serious adverse 
events will only be reported in the final clinical study report unless the event was unusual, 


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unexpected, and there is evidence suggesting a causal relationship between the study drug and 
the event (e.g., death from anaphylaxis). 
The sponsor will notify all participating Investigators of safety reports, in a blinded fashion, of 
potential serious risks as described in the safety review plan for this study.  
15 Statistical Plan 
Baseline characteristics, such as patient demographics, disease etiology, disease severity and 
factors present at time of listing for liver transplantation, will be compared between the 
terlipressin treatment group and the retrospective control group.  Categorical variables will be 
presented as proportions and percentages and compared using chi-squared or Fisher’s exact 
testing.  Continuous variables will be presented as means and standard deviations or medians and 
interquartile ranges.  Depending on the distribution of the variable, the Student’s t-test or 
Wilcoxon rank sum will be used for comparison.   
15.1 Primary Analysis 
The primary analysis will utilize mixed effects regression modeling to estimate changes in serum 
creatinine (SCr) over the study period, accounting for baseline SCr and the correlation structure 
between the repeated measures.  All potential confounders will be added to the model and 
sequentially removed if they do not confound the association between receipt of terlipressin and 
improvement in Scr.  Those confounders resulting in a ≥ 10% change in the coefficient for the 
association between terlipressin and improvement in SCr will be retained in the final model. For 
all generated models, Aikaike Information Criteria (AIC) scores will be calculated and 
compared. The model with the smallest absolute AIC value will be accepted as the most 
parsimonious and will be used as the primary model for the explanation of study results. As has 
been undertaken in other terlipressin studies in HRS, a least-squares means analysis will be 
conducted using a repeated-measures analysis of variance.  The results from this approach to the 
statistical analysis can then be directly compared to prior study results.   
15.2 Secondary Analyses 
A number of secondary outcomes will be examined for the study cohort.  These outcomes 
include the incidence of dialysis, mortality, and liver transplantation at day 30 and 90.  The 


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incidence of kidney transplant within one year of liver transplant will also be determined.  
Additionally, descriptive comparisons of SCr will be undertaken at day 30 and 90 of follow up 
and at 4 time points after receipt of liver transplantation (day 30, 90, 180 and 365) and also at 
similar time points for those patients who were transplant ineligible or did not undergo a 
transplant.  Incidence will be calculated as the number of new events during the observation 
period divided by the total persons at risk.  All statistical analyses will be conducted using Stata 
version 15.1 statistical software (StataCorp, College Park, TX).  Statistical significance will be 
declared for a two-sided hypothesis test if the P value was <0.05.  
15.3 Sample Size Considerations 
A formal sample size calculation is not applicable for the proposed study. However, at least 50 
subjects across more than 5-10 institutions may receive terlipressin treatment during the course 
of the intervention portion of the study.  For the comparison of the terlipressin treatment group 
and retrospective controls, we expect to have 50 subjects in the intervention group and 150 
subjects, assembled from the study sites, in the control group.  Assuming a type 1 error of 0.05 
and power of 80%, we expect to be able to detect a range of differences in serum creatinine (SCr) 
depending on the standard deviation of the change (primary endpoint) expected for the groups 
(see below).  Based on results from the REVERSE trial, a change in SCr of as small as 0.05 mg/ 
dL would be able to be detected if the standard deviation for the change approximated 0.10 
mg/dL and a pre-specified sample size of 200 subjects, 50 of whom are in the intervention arm, 
is used for the calculation.  
 
∆ SCr 
mg/dL 
∆ SCr 
mg/dL 
∆ SCr 
mg/dL 
∆ SCr 
mg/dL 
∆ SCr 
mg/dL 
Detectable Difference 
0.46 
0.34 
0.23 
0.11 
0.05 
Standard Deviation 
1.00 
0.75 
0.50 
0.20 
0.10 
Given the relatively small number of subjects proposed for inclusion in this terlipressin study, we 
will likely by underpowered to detect a difference in the other secondary outcomes being 
explored.  
15.4 Safety Variables  


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Safety variables will include the following: 
• Serious adverse events and all deaths.  Safety details may include: 
o Vital signs (body temperature, blood pressure, heart rate, respiratory rate, and SpO2). 
o MELD score. 
o Encephalopathy score. 
o Laboratory parameters. 
Serious Adverse events will be not classified by Medical Dictionary for Drug Regulatory 
Activities (MedDRA) system organ class, preferred term, severity, and seriousness.  SAEs will 
be summarized using site reported terminology, as well as by the investigator's assessment of the 
relationship of the SAE to the study drug. 
15.5 Subject Accounting and Baseline Characteristics 
A summary of the study completion status and reasons for discontinuation will be provided for 
both the Prospective Terlipressin Group and the Retrospective Control Group. Baseline 
characteristics (age, gender, race, etc.) will be summarized. The number of subjects with medical 
conditions within each body system will be reported. Summaries of the extent of exposure and 
protocol deviations will also be provided. 
15.6 Safety Population 
The safety population is defined as all subjects who received at least 1 dose of study drug. 
16 Direct Access, Data Handling, and Record Keeping 
16.1 Investigator 
The investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspections by providing direct access to original source data and documents. 
All subject information will be recorded on source documents. The CRFs must be fully 
completed and include all required data for all subjects enrolled. All CRF data must be submitted 
to the sponsor throughout and at the end of the study. 


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If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 
Any significant changes in study personnel will require an updated Statement of Investigator 
(e.g., FDA Form 1572) to be filed with the sponsor. 
The investigator must notify their IRB of protocol violations in accordance with local regulatory 
and IRB requirements. 
16.2 Sponsor 
The CRF data are stored in a database and processed electronically. The data are reviewed for 
completeness, and logical consistency. Requests for data clarification are forwarded to the study 
site for resolution. 
16.3 Records Retention 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in 
the course of the study, specifically including but not limited to those defined by Good Clinical 
Practice (GCP) as essential. Essential documents should be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational medicinal product. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained. Prior to destruction of any study essential documents, the investigator must first obtain 
written approval from the sponsor. 
17 Quality Control and Quality Assurance 
17.1 Study Monitoring 
The sponsor has ethical, legal, and scientific obligations to carefully follow this study in a 
detailed and orderly manner in accordance with established research principles and applicable 
regulations. The investigator, as part of his responsibilities, is expected to cooperate with the 
sponsor, or their designee International HealthCare, in ensuring that the study adheres to the 
protocol and GCP requirements. 


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As part of a concerted effort to fulfill these obligations (maintain current personal knowledge of 
the progress of the study), the sponsor's monitor will visit the center(s) during the study in 
accordance with the monitoring plan set forth for this study as well as maintain frequent 
telephone and written communication. The investigator will permit the sponsor to monitor the 
study as frequently as is deemed necessary and provide access to medical records to ensure that 
data are being recorded adequately, that data are verifiable, and that protocol adherence is 
satisfactory. 
17.2 Auditing 
The sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, 
drug supply, presence of required documents, the informed consent process, and comparison of 
case report forms with source documents. The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also audit the investigator during or after the study. The 
investigator should contact the sponsor immediately if this occurs and must fully cooperate with 
regulatory authority audits conducted at a reasonable time in a reasonable manner. 
18 Ethics and Responsibility 
This study will be conducted in compliance with the protocol, with the sponsor’s standard 
operating procedures and/or guidelines, with the FDA or local regulatory regulations, with the 
ICH GCP guidelines, and with the Declaration of Helsinki. 
18.1 Institutional Review Board/Independent Ethics Committee 
This protocol and the written informed consent form shall be submitted to the IRB identified 
with this responsibility at the research facility. Notification in writing of approval must come 
from the IRB chairman or secretary, to the investigator, either as a letter or as a copy of the 
appropriate section of the IRB meeting minutes where this protocol and associated informed 
consent form were discussed. The investigator will not participate in the decision. If the 
investigator is an IRB member, the written approval must indicate such non-participation. 
The investigator will submit status reports to the IRB at least annually (when applicable). 
The IRB must be notified by the investigator in writing of the interruption and/or completion of 
the study; the investigator must promptly report to the IRB all changes in research (protocol 
amendments) and will not make such changes without IRB approval except where necessary to 
eliminate apparent immediate hazards to human subjects. In these cases, the IRB must be 


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notified within 5 days of the change. The investigator will promptly report to the IRB all 
unanticipated problems involving risk to subjects or others. The investigator is required to 
maintain an accurate and complete record of all written correspondence to and received from the 
IRB and must agree to share all such documents and reports with the sponsor. 
18.2 Protocol Amendments 
Any change in the study plan requires a protocol amendment. An investigator must not make any 
changes to the study without IRB and sponsor approval except when necessary to eliminate 
apparent immediate hazards to the subjects. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, but the change must then be 
documented in an amendment, reported to the IRB within 5 working days, and submitted to the 
appropriate regulatory agency in the required time frame. 
18.3 Informed Consent 
All subjects will have a signed document allowing the use of their medical data.  For the 
Prospective Terlipressin Group, written informed consent will be obtained from all subjects (or 
their guardian or legal representative) before any study-related procedures (including any pre-
treatment study-specific procedures) are performed. The investigator(s) has both ethical and legal 
responsibility to ensure that each subject being considered for inclusion in this study is given a 
full explanation of the protocol. This shall be documented on a written informed consent form, 
which shall be approved by the same IRB responsible for approval of this protocol. Each 
informed consent form shall include the elements required by regulatory regulations in 21 Code 
of Federal Regulations (CFR) Part 50 and ICH Guidance E6, Section 4.8. The investigator agrees 
to obtain approval from the sponsor of any written informed consent form used in the study, 
preferably prior to submission to the IRB.  
Once the appropriate essential information has been provided to the subject and fully explained 
by the investigators (or a qualified designee) and it is felt that the subject understands the 
implications of participating, the subject and the investigator (or designee) shall sign the 
IRB-approved written informed consent form. The subject shall be given a copy of the signed 
informed consent form, and the original shall be kept in the site’s regulatory file. A second copy 
may be filed in the subject's medical record, if allowed by the institution. 
18.4 Confidentiality 
All information generated in this study will be considered confidential and will not be disclosed 
to any persons not directly concerned with the study without written prior permission from the 


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sponsor. However, authorized regulatory officials and sponsor personnel will be allowed full 
access to the records. All medications provided and subject bodily fluids and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to in 
writing by the sponsor. 
Only initials and/or unique subject numbers in case report forms will identify subjects. Their full 
names may, however, be made known to a product regulatory agency or other authorized official 
if necessary. 
18.5 Subject Injury 
Subject injury provisions will be specified in the site’s Clinical Trial Agreement. 
18.6 Study Suspension, Termination, and Completion 
The sponsor or designee may suspend or terminate the study or part of the study at any time for 
any reason.  
If the investigator suspends or terminates the study, the investigator will promptly inform the 
sponsor or designee and the IRB and provide them with a detailed written explanation. The 
investigator will destroy all unused (after final drug accountability has been performed) and 
partially used investigational product per site standard operating procedure. Upon study 
completion, the investigator will provide the sponsor or designee, IRB, and regulatory agency 
with final reports and summaries as required by regulations. For IND application studies, or 
when the data will be used in support of an IND, the investigator must submit a written report to 
the sponsor or designee and the IRB within 3 months after the completion or termination of the 
study. Study termination and follow-up will be performed in compliance with applicable 
standard operating procedures. 
18.7 Study and Study Site Discontinuation Criteria 
The sponsor, investigator, medical monitor, or regulatory officials may discover conditions 
during the study that indicate that the study or study site should be terminated. This action may 
be taken after appropriate consultation between the sponsor and investigator. Conditions that 
may warrant termination of the study/study site include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 


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• The decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug. 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory regulations. 
• Submission of knowingly false information from the study site to the sponsor, study 
monitor, or regulatory authority. 
• Insufficient adherence to protocol requirements 
• Study/study site termination and follow-up will be performed in compliance with the 
sponsors’ standard operating procedures. 
19 Registration of Study and Publication of Data 
This study will be registered at the publicly accessible Web site www.clinicaltrials.gov. 
Registration at other publicly accessible registries will be performed as required. 
The results of this study will be published and/or presented at scientific meetings in accordance 
with usual and customary academic, editorial, and ethical practices and requirements. 
19.1 Investigator’s Ability to Publish 
Terms and provisions of publication rights are governed by the Publication Section in the clinical 
study agreement. 


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21 Appendix A: Terlipressin Stability Data: 
Table 1:          In-Use Stability Study Design of Terlipressin for Injection 
Batch Tested 
Lot No. 300953F 
Manufacturing Date 
16 June 2013 
Study Start Date 
January 2016 
Storage Conditions 
2-8°C 
25°C – Light Exposed (light level held at 1000 – 1200 Lux) 
25°C – Dark (Control, foil wrapped in the light chamber) 
Study Intervals 
Initial, 12 hours, 24 hours, 48 hours, 72 hours 
Test Parameters 
Completeness 
and 
Clarity of Solution 
The constituted solution is not significantly less 
clear than an equal amount of the diluent 
Assay  
90.0 – 110.0% 
Related Substances 
Lypressin: NMT 0.5% 
Unknown A: NMT 1.0% 
Acetyl-terlipressin: NMT 0.7% 
Individual unspecified: NMT 0.5% 
Total Impurities: NMT 5.0% 
pH 
4.3 – 7.5 
Reconstitution Time 
Dissolves completely within 30 sec, leaving no 
visible residue 
 
 
 


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Table 2:          In-Use Chemical Stability Data after reconstitution with 0.9% sodium 
chloride at 25°C, Light Exposed 
Diluent 
0.9% Sodium Chloride 
Storage 
Conditions 
25°C, Light Exposed 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 Hours 
72 Hours 
Completeness 
and Clarity of 
Solution 
The 
constituted 
solution is 
not 
significantly 
less clear 
than an equal 
amount of 
the diluent 
Complies 
Complies 
Complies 
Complies 
Complies 
pH 
4.3 – 7.5 
4.9 
4.9 
4.9 
4.9 
4.9 
Assay 
90.0 – 
110.0% 
99.9% 
100.1% 
101.6% 
99.4% 
100.4% 
Related Substances 
Lypressin 
NMT 0.5% 
0.15% 
0.21% 
0.21% 
0.21% 
0.19% 
Unknown A1 
NMT 1.0% 
0.25% 
0.26% 
0.26% 
0.22% 
0.21% 
Acetyl-
Terlipressin 
NMT 0.7% 
0.33% 
0.46% 
0.39% 
0.51% 
0.42% 
Individual 
Unspecified 
(largest 
reported) 
NMT 0.5% 
0.28%  
(RRT 1.08) 
0.29%  
(RRT 1.08) 
0.32% 
(RRT 1.08) 
0.26% 
(RRT 1.08) 
0.24% 
(RRT 1.08) 
Total 
Impurities 
NMT 5.0% 
1.72% 
2.04% 
1.90% 
1.92% 
1.75% 
1   Unknown A impurity was later identified as Impurity A 
 
 


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Table 3:          In-Use Chemical Stability Data after reconstitution with 0.9% sodium 
chloride at 25°C, Dark Control (Wrapped in Foil) 
Diluent 
0.9% Sodium Chloride 
Storage 
Conditions 
25°C, Dark Control (Wrapped in Foil) 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 Hours 
72 Hours 
Completeness 
and Clarity of 
Solution 
The 
constituted 
solution is 
not 
significantly 
less clear 
than an equal 
amount of 
the diluent 
Complies 
Complies 
Complies 
Complies 
Complies 
pH 
4.3 – 7.5 
4.9 
4.9 
4.9 
4.9 
4.9 
Assay 
90.0 – 
110.0% 
99.9% 
100.8% 
102.5% 
98.9% 
98.8% 
Related Substances 
Lypressin 
NMT 0.5% 
0.15% 
0.23% 
0.23% 
0.22% 
0.21% 
Unknown A 
NMT 1.0% 
0.25% 
0.32% 
0.25% 
0.24% 
0.32% 
Acetyl-
Terlipressin 
NMT 0.7% 
0.33% 
0.44% 
0.43% 
0.34% 
0.47% 
Individual 
Unspecified 
(largest 
reported) 
NMT 0.5% 
0.28%  
(RRT 1.08) 
0.30%  
(RRT 1.08) 
0.30%  
(RRT 1.08) 
0.34%  
(RRT 1.08) 
0.28%  
(RRT 1.08) 
Total 
Impurities 
NMT 5.0% 
1.72% 
2.01% 
1.82% 
1.83% 
2.04% 
 
 


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Table 4:          In-Use Chemical Stability Data after reconstitution with 0.9% sodium 
chloride at 2-8°C, Dark  
Diluent 
0.9% Sodium Chloride 
Storage 
Conditions 
2-8°C, Dark  
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 Hours 
72 Hours 
Completeness 
and Clarity of 
Solution 
The 
constituted 
solution is 
not 
significantly 
less clear 
than an equal 
amount of 
the diluent 
Complies 
Complies 
Complies 
Complies 
Complies 
pH 
4.3 – 7.5 
4.9 
4.9 
4.9 
4.9 
4.8 
Assay 
90.0 – 
110.0% 
99.9% 
100.0% 
100.8% 
99.5% 
98.9% 
Related Substances 
Lypressin 
NMT 0.5% 
0.15% 
0.21% 
0.21% 
0.23% 
0.21% 
Unknown A 
NMT 1.0% 
0.25% 
0.30% 
0.30% 
0.32% 
0.30% 
Acetyl-
Terlipressin 
NMT 0.7% 
0.33% 
0.43% 
0.43% 
0.33% 
0.47% 
Individual 
Unspecified 
(largest 
reported) 
NMT 0.5% 
0.28%  
(RRT 1.08) 
0.28%  
(RRT 1.08) 
0.26%  
(RRT 1.08) 
0.30%  
(RRT 1.08) 
0.26%  
(RRT 1.08) 
Total 
Impurities 
NMT 5.0% 
1.72% 
1.96% 
1.94% 
1.98% 
1.93% 
 
 
 
 
 
 
 
 
 
 


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22 Appendix B: Sodium Chloride Solution: 
NDC 
00338-0049-31 
Full FDB Description SODIUM CHLORIDE 0.9% USP SOLUTION, SINGLE USE
Generic Name  
0.9 % sodium chloride 
Mfr/Supplier Part # 
2B1308 
FDA Application # 
NDA 016677 
Supplier  
BAXTER 
Strength 
0.9 % 
 
 
 


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23 Appendix C: Terlipressin Microbiology  
Table 1: Microbiological Stability Testing Protocol  
Batch Tested:  
Lot No. 870403F 
Study Start Date:  
December 2020 
Product:  
Terlipressin 2mg in 50mL NSS IV bag 
Storage Conditions: 
2-8 °C – DEHP containing IV bag 
2-8 °C – DEHP-free IV bag 
25 °C – DEHP containing IV bag 
25 °C – DEHP-free IV bag 
Study Intervals: 
Initial, 12 hours, 24 hours, 48 hours, 72 hours (for Aerobic and Anaerobic testing) 
Initial, 72 hours (for Pyrogen testing) 
Test Parameters:  
Aerobic bacteria 
Negative for growth 
Anaerobic bacteria 
Negative for growth 
Pyrogen  
Less than 0.500 EU/mL  
 
Table 2: Microbiological Stability Testing Results 
Storage Conditions 
2-8 °C – DEHP containing IV bag 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 hours 
72 hours 
Aerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Anaerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Pyrogen 
Less than 0.500 
EU/mL 
Pass 
n/a 
n/a 
n/a 
Pass 
Storage Conditions 
2-8 °C – DEHP-free IV bag 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 hours 
72 hours 
Aerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Anaerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Pyrogen 
Less than 0.500 
EU/mL 
Pass 
n/a 
n/a 
n/a 
Pass 
Storage Conditions 
25 °C – DEHP containing IV bag 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 hours 
72 hours 


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Aerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Anaerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Pyrogen 
Less than 0.500 
EU/mL 
Pass 
n/a 
n/a 
n/a 
Pass 
Storage Conditions 
25 °C – DEHP-free IV bag 
Test Parameter 
Acceptance 
Criteria 
 
Initial 
12 Hours 
24 Hours 
48 hours 
72 hours 
Aerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Anaerobic Bacteria 
Negative for 
growth 
Pass 
Pass 
Pass 
Pass 
Pass 
Pyrogen 
Less than 0.500 
EU/mL 
Pass 
n/a 
n/a 
n/a 
Pass