Clinical trial NCT02770716
Conditions: Hepatorenal Syndrome
Keywords: Type 1
Sponsor: Mallinckrodt
Start date: 2016-07-13; Completion date: 2019-07-24
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to treat adult patients with hepatorenal syndrome (HRS) Type 1.

Out of every three participants, two will receive terlipressin and one will receive placebo.

Assignments will be made randomly.

Detailed description:
The primary objective of this trial is to confirm the efficacy and safety of intravenous terlipressin versus placebo in the treatment of adult subjects with hepatorenal syndrome (HRS) Type 1.

Arms: arm 1: Participants receive terlipressin intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol. arm 2: Participants receive matching placebo intravenously as a bolus injection, followed by a saline flush. Dose, duration, retreatment and/or discontinuation may be modified by the investigator, per protocol.
Interventions: intervention 1: Terlipressin intervention 2: Placebo
Intervention descriptions: intervention 1: Terlipressin solution for injection intervention 2: Matching placebo solution for injection

Protocol documents:
Prot_SAP_001.pdf: 
Official Title: 
A Multi-Center, Randomized, Placebo Controlled, Double-Blind Study 
to Confirm Efficacy and Safety of Terlipressin in Subjects With 
Hepatorenal Syndrome Type 1 (The CONFIRM Study) 
NCT Number: 
NCT02770716 
Document Date: 
Protocol Version 3: 2 October 2018 


 
CLINICAL STUDY PROTOCOL
A Multi-Center, Randomized,
Placebo-Controlled, Double-Blind Study
To Confirm Efficacy And Safety Of Terlipressin
In Subjects With Hepatorenal Syndrome Type 1
(The CONFIRM Study – Incorporating Amendments 1, 2 and 3)
Protocol Number:
MNK19013058
Study Drug:
Terlipressin (Terlivaz®)
Development Phase:
Phase 3
IND Number:
68,582
Original Protocol Date:
01 March 2016
Amendment #1 Date:
09 May 2016
Amendment #2 Date:
16 December 2016
Amendment #3 Date:
26 September 2018
Sponsor:
Mallinckrodt Pharmaceuticals
Clinical Research and Development
1425 US Route 206
Bedminster, NJ, 07921
United States of America
This confidential document is the property of Mallinckrodt Pharmaceuticals. No unpublished information 
contained herein may be disclosed without prior written approval from Mallinckrodt Pharmaceuticals. Access to 
this document must be restricted to relevant parties.


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SUMMARY OF CHANGES FROM AMENDMENT 2 TO AMENDMENT 3
DATED 26 SEPTEMBER 2018
This protocol amendment was required in order to address FDA comments and 
recommendations from a meeting on 13 September 2018.
A sentence was added as follows: SCr values obtained after midodrine administration will be 
included if midodrine was started on Day 1, was administered for no more than 24 hours, and 
the subject was enrolled on or after 17 August 2018. SCr values will also be included if 
obtained after the administration of a single dose of dobutamine.
This sentence was added to the following sections:
1. Protocol Synopsis, Criteria for Evaluation, Primary Efficacy Endpoint (pg 25).
2. Protocol Synopsis, Criteria for Evaluation, Secondary Efficacy Endpoints, Fourth 
Bullet Point (pp 25-26).
3. Protocol Synopsis, Statistical Methods, Primary Efficacy Analysis (pg 26).
4. Primary Efficacy Variables, Section 6.1.1.
5. Secondary Efficacy Variables, Fourth Bullet Point, Section 6.1.2.
6. Primary Efficacy Variable, First Paragraph, Section 13.6.1.
7. Secondary Efficacy Variable, Last Paragraph, Section 13.6.2.
8. Primary Efficacy Analysis, First Paragraph, Section 15.3.6.1.
9. Secondary Efficacy Analyses, Last Paragraph, Section 15.3.6.2.
The sponsor’s address was updated on the title page, pg 20 and pg 22. The Mallinckrodt 
clinical study manager name was updated on pg 20. ICH name was updated.


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SUMMARY OF CHANGES FROM AMENDMENT 1 TO AMENDMENT 2
DATED 16 DECEMBER 2016
This protocol amendment was required in order to address FDA comments and 
recommendations from a letter dated 14 October 2016.
1.  Physical Examinations: Physical examinations have been changed
(Table 13–1, Schedule of Assessments and Section 13.3.1) to add abbreviated physical 
examinations every day during the 14-day active study period in addition to the general 
physical assessment examinations conducted at baseline and the 30-day post-treatment 
follow-up.
2.  Qualifying Serum Creatinine For Subjects Taking Vasopressors at Baseline: The protocol 
text (Section 8.3, Section 13.2.2, Section 13.6, and Appendix A) was modified to clarify that 
the qualifying serum creatinine for subjects on vasopressors will be taken after vasopressor 
washout.
3.  Definition of HRS Recurrence: The endpoint definition of HRS recurrence was revised
(Section 10.5) to state all parameters explicitly.
4.  Sensitivity Analyses: The text (Section 15.3.6.3) regarding sensitivity analyses was revised 
to specify sensitivity analyses related to the assumption that if the investigator cannot exclude 
a recurrence of HRS Type 1, the subject will be considered to have a recurrence.
5. Withdrawal By Subject: The text (Section 8.5) was revised to specify that a reason will 
be recorded.
6.  Death of Subject: The text (Section 14.3.1) was revised to specify the collection and 
recording of the investigator-reported immediate cause of death on the appropriate 
eCRF page.
7.  Ischemic Abdominal, Cardiac and Respiratory Adverse Events: The text (Section 14.2) 
was revised to specify that all necessary data are collected and recorded to determine whether 
an ischemic abdominal event, ischemic cardiac event, or a bronchospasm-related respiratory 
event has occurred. 


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8. Title Page and Headers: The text of every page was revised to indicate “Incorporating 
Amendments 1 and 2” and an Amendment 2 revision date was added to the title page.
9. Any additional format, spelling, or grammatical changes were made as needed.


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SUMMARY OF CHANGES FROM THE ORIGINAL PROTOCOL
TO AMENDMENT 1
DATED 09 MAY 2016
This protocol amendment was required in order to address FDA recommendations from the 
Special Protocol Assessment (SPA) agreement letter dated 21 April 2016. The amendment 
incorporates FDA comments as outlined in the SPA agreement letter and agreements 
as outlined in an IND communication of 15 April 2016.
For the changes noted below, deletions are indicated by strikethrough font and additions 
by italics.
1.  Protocol Synopsis, Primary Efficacy Endpoint:
The primary efficacy analysis timing after 
the final dose of study drug was changed from 72 hours to 24 hours as follows:
Incidence of verified HRS reversal, defined as the percentage of subjects with 
2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on 
treatment by Day 14 or discharge (on treatment defined as up to 24 hours after the final 
dose of study drug). 
2.  Protocol Synopsis, Secondary Efficacy Endpoint: The definitions of HRS reversal 
and RRT were clarified and provided in the protocol synopsis as follows:

Durability of HRS reversal, defined as the percentage of subjects with HRS reversal 
without RRT to Day 30. HRS reversal is defined as the percentage of subjects with a 
SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). RRT is defined as any procedure to replace non-endocrine kidney function 
and includes intermittent hemodialysis, ultrafiltration, continuous hemofiltration and 
hemodialysis, peritoneal dialysis and other dialysis and filtration techniques.

Incidence of HRS reversal in the systemic inflammatory response syndrome (SIRS) 
subgroup, defined as the percentage of SIRS subjects with HRS reversal. HRS reversal 
is defined as the percentage of subjects with a SCr value no more than 1.5 mg/dL while 


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on treatment by Day 14 or discharge (SCr values after RRT, TIPS, liver transplant, or 
open-label vasopressor use will be excluded).

Incidence of verified HRS reversal without HRS recurrence by Day 30. HRS Type 1 
recurrence is defined in Section 10.5. Incidence of verified HRS reversal is defined as 
the percentage of subjects with 2 consecutive SCr values no more than 1.5 mg/dL at 
least 2 hours apart, while on treatment up to 24 hours after the final dose of study drug, 
by Day 14 or discharge. Subjects must be alive without RRT for at least 10 days after 
achieving verified HRS reversal. SCr values after RRT, transjugular intrahepatic 
portosystemic shunt (TIPS), liver transplant, or open-label vasopressor use will be 
excluded from primary end point analysis.
3.  Protocol Synopsis, 
4. Protocol Synopsis, Treatment Discontinuation, first sentence, was modified as follows:
Treatment should be continued until 24 hours after a second consecutive SCr value no more 
than 1.5 mg/dL has been obtained, OR up to a maximum of 14 days (maximum of 15 days if 
SCr first reaches 1.5 mg/dL on Day 14). 
5.  Protocol Synopsis, Statistical Methods:
A. The first sentence in the ‘Primary Efficacy Analyses’ subsection was modified 
as follows:
The primary efficacy variable of verified HRS reversal is defined as the percentage of subjects 
with 2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on 
treatment by Day 14 or discharge (on treatment defined as up to 24 hours after the final dose 
of study drug).
B. The ‘Secondary Efficacy Analyses’ subsection was modified as follows:
A Hochberg procedure for multiple testing and the alpha level corresponding to the Z 
score of the primary efficacy analysis will be used for testing the secondary efficacy 
analyses at either the interim analysis or the final analysis.
C. The ‘Sample Size’ subsection was modified as follows:


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PROC SEQDESIGN in SAS (SAS® software version 9.2 or higher) was used for the 
sample size calculation. With a 2:1 randomization of terlipressin to placebo and an 
interim analysis after 50% of the subjects have completed Day 14 or Discharge, 
300 subjects will provide 9089.76% power to detect a statistically significant 
difference between the groups.
6.  Section 6.1.1 was modified as follows:
Incidence of verified HRS reversal, defined as the percentage of subjects with 
2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on 
treatment by Day 14 or discharge (on treatment defined as up to 24 hours after the 
final dose of study drug).
7.  Section 8.1 was modified as follows:
Subjects with a baseline SCr level greater than 7.0 mg/dL will be excluded from the study.
In this study, the threshold for the upper cut of SCr will be set to exclude subjects with 
SCr > 6 mg/dL. The threshold for upper cut-off of SCr in entry criteria is derived from the 
results of previous NDA studies. In OT-0401, none of the subjects with a baseline SCr level 
greater than 7.0 mg/dL achieved HRS reversal. Subjects will be stratified by qualifying 
SCr (less than 3.4 mg/dL or at least 3.4 mg/dL).
where, across individual studies as well as in the pooled analysis, subjects with SCr of 
≤6 mg/dL have shown a much greater likelihood of achieving HRS reversal than subjects 
with SCr > 6 mg/dL. Pooling the OT 0401 and REVERSE studies resulted in 11.1% (1/9) 
of subjects with SCr > 6 mg/dL achieving HRS reversal and 37.4% (49/131) of subjects 
with SCr ≤ 6 mg/dL achieving HRS reversal. The aim of lowering the upper cut off is to 
minimize exposure to terlipressin in subjects with high SCr who may not receive as much 
benefit to therapy but still be exposed to the risks of the therapy. Subjects will be stratified 
by qualifying SCr (less than 3.4 mg/dL or at least 3.4 mg/dL).
Qualifying SCr is a prognostic factor for survival and HRS reversal. Excluding subjects 
with a baseline SCr of greater than 6 7 mg/dL and LVP at least 4 L within 2 days prior to 


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randomization (both are exclusion criteria for this study), 3.4 mg/dL (N = 253) was the 
median baseline SCr of subjects enrolled in the OT-0401 and REVERSE studies combined.
8.  Section 8.4, Exclusion Criteria, was modified (and in Synopsis) as follows:
#9.
The footnote to this criterion was moved under exclusion #11.
Note: Urine sediment examination is required to exclude presence of heme granular 
casts and other clinically significant casts.
#11.
A footnote was added :
Note: Urine sediment examination is required to exclude presence of heme granular 
casts and other clinically significant casts.
#13. Severe cardiovascular disease, including, but not limited to, unstable angina, 
pulmonary edema, congestive heart failure requiring increasing doses of drug 
therapy, 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.
#17. Ongoing useUse of vasopressors (eg, midodrinenorepinephrine, epinephrine or 
vasopressin, dopamine or other vasopressors) or octreotide of at least 3 consecutive 
days within prior 14 day screening period. Patients receiving a vasopressor other than 
midodrine within 24 hours of qualifying SCr are excluded, ie, 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 randomization.*doses will require a 
washout of 8 hours before randomization.
9. Section 10.3.1 was modified as follows:
Blinded terlipressin or placebo will be administered intravenously as a bolus injection 
over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (± 30 minutes). After study drug 
administration the line should be flushed with saline.


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10. Section 10.4 was modified as follows:

Treatment should be continued until 24 hours after a 2 consecutive SCr values no more 
than 1.5 mg/dL haves been obtained, OR up to a maximum of 14 days (maximum of 
15 days if SCr first reaches 1.5 mg/dL on Day 14). 
11. Section 10.5 was modified as follows:
Any subject with a SCr value of at least 2.25 mg/dL after achieving verified HRS reversal, 
but prior to transplant/discharge/Day 14, will be assessed for HRS Type 1 recurrence. HRS 
Type 1 recurrence is another episode of HRS Type 1 as per the protocol 
inclusion/exclusion criteria.  HRS recurrence by Day 30 is defined as another episode 
of HRS Type 1, by Day 30, after achieving verified HRS reversal, characterized by rapidly 
progressive worsening in renal function to a SCr at least 2.25 mg/dL, without sustained 
improvement in renal function (less than 20% decrease in SCr and SCr at least 2.25 
mg/dL) at least 48 hours after diuretic withdrawal and the beginning of plasma volume 
expansion with albumin, and meeting all other inclusion and exclusion criteria defining 
the initial diagnosis of HRS Type 1. The investigator will determine whether the subject 
has had a recurrence of HRS Type 1. If the investigator cannot exclude a recurrence of 
HRS Type 1, then the subject will be considered to have HRS Type 1 recurrence.
HRS Type 1 recurrence will be monitored as follows: Recurrence of HRS Type 1 
during the follow-up period (after discharge or Day 14) will be assessed based upon the 
investigator’s opinion and serious AE data collected up to 30 days after end of treatment. 
Following the initial hospital discharge, all re-hospitalizations within 30 days after end 
of treatment (except for planned hospital admissions or procedures as described in the 
protocol) are to be recorded as an SAE. Re-hospitalizations will require an investigator 
assessment and opinion regarding possible recurrence of HRS Type 1. All available 
relevant medical records, MedWatch forms, discharge summaries or other relevant source 
documents should be requested and reviewed for all SAEs, including all hospitalizations, 
until 30 days after discontinuation of study drug.
12. 
Section 11.3 was modified as follows:
Study drug should be stored in a secure location at 2ºC to 8ºC until reconstitution and can 
be stored up to 24 48 hours at refrigerated storage conditions (2ºC to 8ºC) once 
reconstituted with sterile 0.9% NaCl solutionprovided.


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13. Table 13–1 (Schedule of Assessments) was revised as follows:
A. The ‘Discharge’ column heading was changed to read:  Day 14b or Discharge, 
whichever occurs first.
B. A new table row was added requiring a venous blood lactate level to be taken at 
baseline.
C. A new table row was added requiring the recording of all post-treatment paracentesis 
events.
D. Footnote ‘h’ was revised as follows:
hMedical history will include assessment of multi-organ dysfunction at baseline 
(refer to Section 13.3.5 and the Site/Investigator Study Manual for additional details).
E. Footnote ‘l’ was revised as follows:
lTreatment should be continued until 24 hours after a 2 consecutive SCr values no more than
1.5 mg/dL haves been obtained, OR up to a maximum of 14 days (maximum of 15 days if SCr 
first reaches 1.5 mg/dL on Day 14, when the Day 14 assessments will be performed on Day 
15). Window is (± 30 minutes).
F. The former footnote ‘n’ was deleted and remaining footnotes were re-lettered.
The new footnote ‘n’ incorporates FDA comments.
G. The new footnote ‘n’ (former footnote ‘o’) was revised (additions in italics) as follows:
nA blood sample for measurement of SCr must be drawn before discharge. The second
verifying sample of SCr no more than 1.5 mg/dL must be taken at least 2 hours apart and must 
be consecutive.
H. The new footnote ‘s’ was revised as follows:
sAll subjects will be contacted by telephone required to come back for for follow up on
Day 30 (± 10) visit and will be contacted by phone for Day 60 (± 14), and Day 90 (± 14) 
follow up to assess survival, RRT, TIPS and liver transplant status. Study days will be counted 
from first day of study drug administration (or from randomization for those subjects who do 


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not receive study drug). All information regarding RRT, TIPS and liver transplant must 
be collected.
I. The new footnote ‘t’ was revised as follows:
tFor the Day 30 follow-up visit, all subjects are required to provide a blood sample for SCr 
and BUN. The site staff must also collect an updated medical history, vital signs, concomitant 
medications, SAE assessment, paracentesis events, RRT, and HRS recurrence.
14. Section 13.2.3.2, first paragraph, was revised as follows:
Treatment should be continued until 24 hours after a 2 consecutive SCr values no more than
1.5 mg/dL haves been obtained, OR up to a maximum of 14 days (maximum of 15 days if SCr 
first reaches 1.5 mg/dL on Day 14, when the Day 14 assessments will be performed on Day 
15).
15. Section 13.2.4, second paragraph, was revised as follows:
All subjects will have a follow up visit or be contacted by telephone for follow up on Day 
30 (± 10), while Day 60 (± 14), and Day 90 (± 14) follow up can be done via telephone 
to assess survival, RRT, TIPS, and liver transplant status. Study days will be counted from 
first day of study drug administration (or from randomization for those subjects who 
do not receive study drug). In addition, during the Day 30 follow-up, a blood sample 
will be obtained to assess serium creatineserum creatinine. A physical examination, will be 
performed, and updated data on medical history, vital signs, concomitant medications, 
and SAE assessments will also be collected. On Days 60 and 90 (±14 days), the follow up 
will be completed via telephone to assess survival, RRT, TIPS, and liver transplant status.
In the same section, the third paragraph is deleted:
All subjects will be contacted by telephone for follow up on Days 30 (± 10), 60 (± 14), 
and 90 (± 14) follow up can be done via telephone to assess survival, RRT, TIPS, and liver 
transplant status. Study days will be counted from first day of study drug administration 
(or from randomization for those subjects who do not receive study drug). In addition, 
during the Day 30 follow-up, a physical examination will be performed, and updated data 
on medical history, vital signs, concomitant medications, and SAE assessments will be 
collected.


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16. Section 13.2.4.1 was modified as follows:
All subjects will be required to provide a blood sample at Day 30 (± 10 days) for analysis 
of SCr and BUN. This blood sample can be drawn during the Day 30 visit or by a visiting 
nurse if the subject is unable to return to the study site during the Day 30 follow-up 
window. Every effort will be made to collect a blood sample at Day 30 for all possible
subjects. No imputation will be made for missing values.
17. Section 13.3.1, 3rd paragraph, was modified as follows:
The investigator may perform additional unscheduled examinations to manage or evaluate 
a suspected AE as clinically necessary. The timing and scope of additional unscheduled 
examinations should be determined by the nature and severity of the AE being evaluated. 
In the case of suspected cardiac, intestinal or other ischemia, examination of the subject 
by a physician should be completed on an emergency basis (generally within 
15-30 minutes). For suspected cardiac ischemia, examination should include assessment 
of vital signs, cardiac and pulmonary auscultation, and evaluation of jugular venous 
pressure by clinical examination and other components as determined by the physician's 
clinical judgment. For suspected cardiac ischemia, site must performed an ECG and 
cardiac enzymes (high sensitivity troponin) at the time of assessment and 3 hours later.
Subjects with suspected intestinal ischemia should undergo careful examination of 
the abdomen to evaluate for the presence of diffuse or focal tenderness, rebound, or acute 
abdomen with diffuse rigidity. For suspected intestinal ischemia, venous (blood) lactate 
levels must be drawn and compared to baseline levels. Further investigations should be 
carried out based on clinical practice. All subjects with suspected ischemia should have 
evaluation of the skin of the trunk and extremities for mottling, cyanosis, blanching or 
pallor.
18. Section 13.3.2 was modified as follows:
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 AE 
as clinically necessary. Clinically relevant abnormalities found upon subsequent ECGs 
will be reported and analyzed as AEs and on ECG CRF. The dates of all subsequent ECGs 
will be reported on the ECG eCRF.


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19. Section 13.5.1 was modified as follows:
The laboratory tests specified in this section will be performed in the laboratory at the 
investigational site. All local laboratories must use the isotope dilution mass spectroscopy
method for the serum creatinine assay. 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 personnel should not draw the blood sample from an existing 
peripheral venous access site or a line used for IV fluid administration. See Site/Investigator’s 
Study Manual for additional details regarding blood drawing technique. 
20. Section 13.5.1.1 (2nd bullet) was modified as follows:

Blood urea nitrogen (BUN) (not collected at 30-day follow-up).
21. Section 13.6.1 was modified as follows:
Incidence of verified HRS reversal, defined as the percentage of subjects with 2 consecutive 
SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or 
discharge (on treatment defined as up to 7224 hours after the final dose of study drug).
Subjects must be alive without RRT for at least 10 days after achieving verified HRS reversal. 
SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded 
from primary end point analysis. 
SCr data for the primary end point will be collected at least daily until discharge or Day 14. 
The analysis will be based on ITT population. Treatment should be continued until 24 hours 
after a second confirmatory SCr value no more than 1.5 mg/dL has been obtained, OR up to a 
maximum of 14 days (maximum of 15 days if SCr first reaches 1.5 mg/dL on Day 14). The 
date and time of the first observed SCr value of no more than 1.5 mg/dL (HRS reversal) will 
be used for calculating the time window for the verifying SCr value. The first next 
(consecutive) SCr value of no more than 1.5 mg/dL must occurring during the time window in 
order to have a verified HRS reversal for verification will be selected as the second and 
verifying value. The date RRT is instituted for the first time will be used to determine if a 
subject underwent RRT by Day 30.
22. Section 13.6.2, Secondary Efficacy Variables, was modified as follows:

Incidence of subjects with HRS reversal, defined as the percentage of subjects with a 
SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr 


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values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded).

Durability of HRS reversal: the percentage of subjects with HRS reversal without RRT 
to Day 30. HRS reversal is defined as the percentage of subjects with a SCr value no 
more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr values after 
RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded). RRT is 
defined as any procedure to replace non-endocrine kidney function and includes 
intermittent hemodialysis, ultrafiltration, continuous hemofiltration and hemodialysis, 
peritoneal dialysis and other dialysis and filtration techniques. The date RRT is 
instituted for the first time will be used to determine if a subject underwent RRT by 
Day 30.

Incidence of HRS reversal in the SIRS subgroup: the percentage of SIRS subjects with 
HRS reversal. SCr values after RRT, TIPS, liver transplant, or open label vasopressor 
use will be excluded. HRS reversal is defined as the percentage of subjects with a SCr 
value no more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr values 
after RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded). The 
SIRS subgroup is defined as any subject with at least 2 of the following criteria: WBC 
less than 4,000 or greater than 12,000 cells/μL; heart rate greater than 90 bpm; 
temperature greater than 38°C or less than 36°C; respiratory rate greater than 20/min; 
HCO3 less than 21 mmol/L; the latter criterion represents an approximation of the 
SIRS criterion PaCO2 of less than 32 mm Hg, derived from the observed HCO3 in 
subjects with HRS in whom a PaCO2 value was available (from the TAHRS study) and 
the calculated HCO3 in subjects with decompensated liver disease and PaCO2 of less 
than 32 mm Hg.

Incidence of verified HRS reversal without HRS recurrence by Day 30 HRS Type 1 
recurrence is another episode of HRS Type 1 as per the protocol inclusion/exclusion 
criteria is defined in Section 10.5. Incidence of verified HRS reversal, defined as 
the percentage of subjects with 2 consecutive SCr values no more than 1.5 mg/dL at 
least 2 hours apart, while on treatment up to 24 hours after the final dose of study 
drug, by Day 14 or discharge. Subjects must be alive without RRT for at least 10 days 
after achieving verified HRS reversal. SCr values after RRT, transjugular intrahepatic 
portosystemic shunt (TIPS), liver transplant, or open-label vasopressor use will be 
excluded from primary end point analysis.


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23. 
 
 
24. Section 15.3.1, Sample Size Calculation, was revised as follows:
 
 
 
 
 
 
 
Table 15-1:
Sample Size Estimates
 
Based on REVERSE, subjects without a known event of pre-enrollment LVP at least 4 L within 2 days of 
randomization and OT-0401 subjects with baseline SCr no more than 7 mg/dL. SCr values were included while 
the subjects were on treatment, up to 72 24 hours after the final dose of study drug. SCr values were excluded 
after RRT and transplant. If a subject died within 10 days after the reversal, then the subject did not have a 
reversal. If a subject has an RRT by the 30-day follow-up visit, then the subject did not have a reversal. Three 
REVERSE terlipressin subjects who achieved a reversal after the 24 hour window were counted as reversals 
because they would have continued on study drug based on the CONFIRM trial design through the reversal.
PROC SEQDESIGN in SAS (SAS® software version 9.2 or higher) was used for the 
sample size calculation. The SAS code and SAS output are in Section 23. With a 2:1 
randomization of terlipressin to placebo and an interim analysis after 50% of the subjects 
have completed Day 14 or Discharge, 300 subjects will provide 90 89.76% power to 
detect a statistically significant difference between the groups, 200 subjects in 
the terlipressin group and 100 subjects in the placebo group.


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25. Section 15.3.6.1, Primary Efficacy Analysis, 1st paragraph, was revised as follows:
Incidence of verified HRS reversal, defined as the percentage of subjects with 
2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on 
treatment by Day 14 or discharge (on treatment defined as up to 7224 hours after the final 
dose of study drug). Subject must be alive without RRT for at least 10 days after achieving 
verified HRS reversal. SCr values after RRT, TIPS, liver transplant, or open-label 
vasopressor use will be excluded from primary end point analysis.
26. Table 15–2 (Title only) was revised as follows:
Table 15-2:
Potential Scenarios for Success at the Interim Analysis with a Placebo Rate 
of Approximately 13 12.5%
27. Section 15.3.6.2, Secondary Efficacy Analysis was revised as follows:
A Hochberg procedure for multiple testing and the alpha level corresponding to the 
Z score of the primary efficacy analysis will be used for testing the secondary efficacy 
analyses at either the interim analysis or the final analysis.
If the interim analysis for the primary endpoint is successful then the secondary efficacy 
analyses will be tested against a corresponding p-value of 0.005166 for a Z score of 
2.79651.  The p-values from the 4 secondary efficacy analyses will be ordered from largest 
to smallest and will be compared as in the table below:
Table 15-3:
Multiple Testing for the Interim Analysis of the Secondary Efficacy 
Analyses
p-value 
Ordering
α Comparator
If p-value less than α 
then:
If p-value at least
α then:
Largest p-
value
0.005166
=0.005166/(4-4+1)
All 4 analyses are 
significant
Test the second 
largest p-value
Second largest 
p-value
0.002583
=0.005166/(4-3+1)
The remaining 3 
analyses are significant
Test the third 
largest p-value
Third largest 
p-value
0.001722
=0.005166/(4-2+1)
The remaining 2 
analyses are significant
Test the smallest 
p-value
Smallest p-
value
0.001292
=0.005166/(4-1+1)
This analysis is 
significant
No analyses are 
significant


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If the interim analysis for the primary endpoint is not successful then the study will 
continue onto the final analysis. If the primary efficacy analysis is successful, then 
the secondary efficacy analyses will be tested against a corresponding p-value 
of 0.047993 for a Z score of 1.97743, as shown in the table below:
Table 15-4:
Multiple Testing for the Final Analysis of the Secondary Efficacy 
Analyses
p-value 
Ordering
α Comparator
If p-value less than α 
then:
If p-value at least
α then:
Largest p-
value
0.047993
=0.047993/(4-4+1)
All 4 analyses are 
significant
Test the second 
largest p-value
Second largest 
p-value
0.023997
=0. 047993/(4-3+1)
The remaining 3 
analyses are significant
Test the third 
largest p-value
Third largest 
p-value
0.015998
=0. 047993/(4-2+1)
The remaining 2 
analyses are significant
Test the smallest 
p-value
Smallest p-
value
0.011998
=0. 047993/(4-1+1)
This analysis is 
significant
No analyses are 
significant
If the primary endpoint is found significant, the pre specified secondary efficacy 
endpoints will be analyzed in a sequential manner at the 0.05 level of significance. Testing 
will stop if a secondary endpoint is not significant. The following are the secondary 
endpoints:

Incidence of subjects with HRS reversal, defined as the percentage of subjects with 
a SCr value no more than 1.5 mg/dL, while on treatment up to 72 24 hours after the 
final dose of study drug, by Day 14 or discharge. SCr values after RRT, TIPS, liver 
transplant, or open-label vasopressor use will be excluded. HRS reversal will be 
summarized by treatment group and analyzed using the Cochran-Mantel-Haenszel 
(CMH) chi-square test stratified by qualifying SCr (less than 3.4 mg/dL or at least 3.4 
mg/dL) and pre-enrollment LVP (at least one single event of at least 4 L or less than 4 
L within 3 to 14 days prior to randomization). If the proportion of subjects with HRS 
reversal is small (expected cell counts less than 5), an unstratified Chi-square test will 
be used instead of the CMH test. If the number of events per cell is still less than 5, 
then a Fisher’s Exact test will be used.

Durability of HRS reversal, defined as the percentage of subjects with HRS reversal 
without RRT to Day 30. HRS reversal is defined as the percentage of subjects with 


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a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr 
values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). RRT is defined as any procedure to replace non-endocrine kidney function 
and includes intermittent hemodialysis, ultrafiltration, continuous hemofiltration and 
hemodialysis, peritoneal dialysis and other dialysis and filtration techniques. The date 
RRT is instituted for the first time will be used to determine if a subject underwent RRT 
by Day 30. This endpoint will be summarized by treatment group and analyzed 
similarly to HRS reversal.

Incidence of HRS reversal in the SIRS subgroup, defined as the percentage of SIRS 
subjects with HRS reversal. SCr values after RRT, TIPS, liver transplant, or open label 
vasopressor use will be excluded. HRS reversal is defined as the percentage of 
subjects with a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or 
discharge (SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use 
will be excluded). This endpoint will be summarized by treatment group and analyzed 
similarly to HRS reversal. The SIRS subgroup is defined as any subject with at least 2 
of the following criteria: WBC less than 4,000 or greater than 12,000 cells/μL; HR 
greater than 90 bpm; temperature greater than 38°C or less than 36°C; respiratory rate 
of greater than 20/min; HCO3 less than 21 mmol/L; the latter criterion represents an 
approximation of the SIRS criterion PaCO2 of less than 32 mm Hg, derived from the 
observed HCO3 in subjects with HRS in whom a PaCO2 value was available (from the 
TAHRS study) and the calculated HCO3 in subjects with decompensated liver disease 
and PaCO2 of less than 32 mm Hg.

Incidence of verified HRS reversal without HRS recurrence by Day 30. HRS Type 1
recurrence is is another episode of HRS Type 1 as per the protocol inclusion/exclusion 
criteria defined in Section 10.5. Incidence of verified HRS reversal, defined as the 
percentage of subjects with two consecutive SCr values no more than 1.5 mg/dL at 
least 2 hours apart, while on treatment up to 24 hours after the final dose of study 
drug, by Day 14 or discharge. Subjects must be alive without RRT for at least 10 days 
after achieving verified HRS reversal. SCr values after RRT, transjugular intrahepatic 
portosystemic shunt (TIPS), liver transplant, or open-label vasopressor use will be 
excluded from primary end point analysis. This endpoint will be summarized by 
treatment group and analyzed similarly to HRS reversal.


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28. 
 
 
29. Section 15.3.8, Missing Data, was revised as follows:
Unless otherwise stated, N no imputation will be made for missing data.
30. Section 20, References, was revised (additions in italics) to add the following citation:
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-802.
31. Section 23, Appendix C: SAS Code and SAS Output was deleted (deletion not shown).
32. Other minor clarifications and grammatical corrections were made, which are not detailed.




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INVESTIGATOR’S AGREEMENT
I have read the attached protocol entitled “A Multi-Center, Randomized, Placebo-Controlled, 
Double-Blind Study to Confirm Efficacy and Safety of Terlipressin in Subjects with 
Hepatorenal Type 1 Syndrome (The CONFIRM Study)” and agree to abide by all provisions 
set forth therein.
I agree to comply with the International Council for Harmonisation (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, Mallinckrodt Inc.
Investigator’s Signature
Date (Day/Month/Year)




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2
Synopsis
Name of Sponsor/Company: Mallinckrodt Pharmaceuticals.
Name of Investigational Product: Terlivaz®.
Name of Active Ingredient: Terlipressin.
Title of Study: A Multi-Center, Randomized, Placebo-Controlled Double-Blind Study to Confirm Efficacy 
and Safety of Terlipressin in Subjects With Hepatorenal Syndrome Type 1 (The CONFIRM Study)
Study Centers: Approximately 70 sites in the United States of America and Canada.
Phase of Development: Phase 3.
Objectives: 
To confirm the efficacy and safety of intravenous terlipressin vs placebo in the treatment of adult subjects 
with hepatorenal syndrome (HRS) Type 1 receiving standard of care albumin therapy.
Methodology: 
Randomized, placebo-controlled, double-blind, multi-center study.
2:1 randomization to terlipressin 1 mg intravenously (IV) every 6 hours vs placebo.
Number of Subjects (Planned): 300 subjects.
Diagnosis and Main Inclusion/Exclusion Criteria:
Adult subjects with cirrhosis, ascites, and a diagnosis of HRS Type 1 based on the 2007 and 2015 updated 
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.
Rapidly progressive worsening in renal function to a serum creatinine (SCr) at least 2.25 mg/dL and 
meeting a trajectory for SCr to double over 2 weeks.
5.
No sustained improvement in renal function (less than 20% decrease in SCr and SCr at least 2.25 mg/dL) 
at least 48 hours after diuretic withdrawal and the beginning of plasma volume expansion with albumin.
Exclusion Criteria:
1.
Serum creatinine level greater than 7.0 mg/dL.
2.
At least 1 event of large volume paracentesis (LVP) at least 4 L within 2 days of randomization.
3.
Sepsis and/or uncontrolled bacterial infection (eg, persisting bacteremia, persisting ascitic fluid 
leucocytosis, fever, increasing leucocytosis with vasomotor instability).
4.
Less than 2 days anti-infective therapy for documented or suspected infection.
5.
Shock.
6.
Current or recent (within 4 weeks) treatment with or exposure to nephrotoxic agents: eg, aminoglycosides, 
amphotericin, cyclosporine A, cisplatin, nonsteroidal anti-inflammatory drugs (NSAIDs: eg, ibuprofen, 
naproxen, diclofenac), significant exposure to radiographic contrast agents (large doses or multiple 
injections of iodinated contrast media; eg, during coronary or abdominal angiogram).
7.
Estimated life expectancy of less than 3 days.
8.
Superimposed acute liver injury due to drugs (eg, acetaminophen), dietary supplements, herbal 
preparations, viral hepatitis, or toxins (eg, Amanita toxin with mushroom poisoning carbon tetrachloride),
with the exception of acute alcoholic hepatitis.
9.
Proteinuria greater than 500 mg/day.
10. Evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other imaging.
11. Tubular epithelial casts, heme granular casts, hematuria or microhematuria (greater than 50 red blood cells 


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per high power field in the absence of recent catheterization) on urinalysis.
Note: Urine sediment examination is required to exclude presence of heme granular casts and other clinically 
significant casts.
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 requiring increasing doses of drug therapy, 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.
14. Current or recent (within 4 weeks) renal replacement therapy (RRT).
15. Participation in other clinical research involving investigational medicinal products within 30 days
of randomization.
16. Transjugular intrahepatic portosystemic shunt (TIPS) within 30 days of randomization.
17. Use of vasopressors (eg, norepinephrine, epinephrine or vasopressin dopamine or other vasopressors ) 
of at least 3 consecutive days within the prior 14-day screening period. Patients receiving a vasopressor 
other than midodrine within 24 hours of qualifying SCr are excluded, ie, 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 randomization.
18. Known allergy or sensitivity to terlipressin or another component of the study treatment.
Investigational Product, Dosage and Mode of Administration:
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. Each vial will be reconstituted 
with 5 mL of sterile 0.9% sodium chloride solution.
Reference Therapy, Dosage and Mode of Administration:
Matching placebo vials (containing 11 mg mannitol) that are identical in appearance to terlipressin for injection 
vials. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride solution.
The following dosing scheme will be utilized for both terlipressin and matching placebo:
Initial Dosing:
Blinded terlipressin or placebo will be administered intravenously as a bolus injection over 2 minutes at a dose 
of 1 mg (1 vial) every 6 hours (± 30 minutes).
Dose Modifications:

If SCr has decreased, but by less than 30% from the baseline value on Day 4 after a minimum of 10 doses 
of study drug, the dose of study drug will be increased to 2 mg every 6 hours (± 30 minutes) (8 mg/day). 

The dose should not be increased in subjects with coronary artery disease or in the setting of circulatory 
overload, pulmonary edema, or bronchospasm. 

If dosing is interrupted due to an adverse event, study drug may be re-started, at the discretion of the 
investigator, at the same or lower dose as per protocol. Study drug will not be restarted if dosing 
was interrupted due to cardiac ischemia or mesenteric ischemia.

If in the investigator’s judgment, a dose increase is not advisable or otherwise justified in the individual 
subject, the reason(s) for not increasing the dose of study drug will be documented on the electronic case 
report form (eCRF).
Treatment Discontinuation:
Treatment should be continued until 24 hours after a second consecutive SCr value no more than 1.5 mg/dL has 
been obtained, OR up to a maximum of 14 days (maximum of 15 days if SCr first reaches 1.5 mg/dL on 
Day 14). 
If on Day 4 (after a minimum of 10 doses) SCr is at or above baseline value, study drug should be discontinued.
Treatment must be discontinued when the subject is to undergo RRT, liver transplantation, TIPS or vasopressor 


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therapy.
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 30% reduction in SCr) who develop recurrence of HRS Type 1 
during the study or follow-up period may be retreated with initially assigned blinded study drug for a maximum 
of 14 days (from the beginning of the retreatment, treatment and study procedures will be identical to the initial 
therapy). To qualify for retreatment the subject must again meet the study inclusion/exclusion criteria and 
the sponsor must be contacted prior to initiation of retreatment. Retreatment may occur within 90 days of 
the subject’s first dose of study drug. Subjects will not be re-randomized or re-stratified for the retreatment 
cycle.
Duration of Treatment:
The active treatment period will be 14 days (exception: 15 days as described above), allowing 1 retreatment 
cycle. Subjects will have a scheduled follow-up visit for Day 30 (±10), and will be contacted by phone for 
Day 60 (±14), and Day 90 (±14).
Criteria for Evaluation:
Primary Efficacy Endpoint: 
Incidence of verified HRS reversal, defined as the percentage of subjects with 2 consecutive SCr values no 
more than 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or discharge (on treatment defined as 
up to 24 hours after the final dose of study drug). Subjects must be alive without RRT for at least 10 days after 
achieving verified HRS reversal. SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use 
will be excluded from primary end point analysis. SCr values obtained after midodrine administration will be 
included if midodrine was started on Day 1, was administered for no more than 24 hours, and the subject was 
enrolled on or after 17 August 2018. SCr values will also be included if obtained after the administration of a 
single dose of dobutamine.
Secondary Efficacy Endpoints:

Incidence of subjects with HRS reversal, defined as the percentage of subjects with a SCr value no more 
than 1.5 mg/dL by Day 14 or discharge (SCr values after RRT, TIPS, liver transplant, or open-label 
vasopressor use will be excluded).

Durability of HRS reversal, defined as the percentage of subjects with HRS reversal without RRT to 
Day 30. HRS reversal is defined as the percentage of subjects with a SCr value no more than 1.5 mg/dL 
while on treatment by Day 14 or discharge (SCr values after RRT, TIPS, liver transplant, or open-label 
vasopressor use will be excluded). RRT is defined as any procedure to replace non-endocrine kidney 
function and includes intermittent hemodialysis, ultrafiltration, continuous hemofiltration and 
hemodialysis, peritoneal dialysis and other dialysis and filtration techniques. 

Incidence of HRS reversal in the systemic inflammatory response syndrome (SIRS) subgroup, defined as 
the percentage of SIRS subjects with HRS reversal. HRS reversal is defined as the percentage of subjects 
with a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr values after 
RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded).

Incidence of verified HRS reversal without HRS recurrence by Day 30. HRS Type 1 recurrence is defined 
in Section 10.5. Incidence of verified HRS reversal is defined as the percentage of subjects with 
2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment up to 24 hours 
after the final dose of study drug, by Day 14 or discharge. Subjects must be alive without RRT for at least 
10 days after achieving verified HRS reversal. SCr values after RRT, transjugular intrahepatic 
portosystemic shunt (TIPS), liver transplant, or open-label vasopressor use will be excluded from primary 
end point analysis. SCr values obtained after midodrine administration will be included if midodrine was 
started on Day 1, was administered for no more than 24 hours, and the subject was enrolled on or after 17 
August 2018. SCr values will also be included if obtained after the administration of a single dose of 
dobutamine.






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3
Table of Contents, List of Tables, and List of Figures 
1
Title page......................................................................................................................... 1
2
Synopsis ........................................................................................................................ 23
3
Table of Contents, List of Tables, and List of Figures..................................................... 28
List of Tables ....................................................................................................................... 33
List of Figures...................................................................................................................... 33
4
List of Abbreviations...................................................................................................... 34
5
Introduction ................................................................................................................... 36
5.1
Hepatorenal Syndrome............................................................................................... 36
5.2
Terlipressin ................................................................................................................ 36
5.3
Clinical Studies of Terlipressin in Subjects With HRS Type 1 .................................... 37
5.3.1
Pharmacokinetics and Pharmacodynamics ............................................................. 37
5.3.2
Efficacy ................................................................................................................. 38
5.3.3
Safety..................................................................................................................... 39
5.4
Study Rationale.......................................................................................................... 40
5.4.1
Primary Endpoint Rationale ................................................................................... 40
5.4.2
Dosing Regimen and Recommended Concomitant Albumin Administration........... 41
6
Objective ....................................................................................................................... 41
6.1
Efficacy Variables ...................................................................................................... 41
6.1.1
Primary Efficacy Variables..................................................................................... 41
6.1.2
Secondary Efficacy Variables................................................................................. 42
6.1.5
Safety: ................................................................................................................... 44
7
Investigational Plan........................................................................................................ 44
7.1
Overall Study Design and Plan: Description............................................................... 44
8
Study Population............................................................................................................ 45
8.1
Population Rationale.................................................................................................. 45
8.2
Number of Subjects to be Studied .............................................................................. 46
8.3
Inclusion Criteria ....................................................................................................... 46


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8.4
Exclusion Criteria ...................................................................................................... 48
8.5
Subject Withdrawal Criteria ....................................................................................... 50
9
Protocol Deviations........................................................................................................ 51
10 Treatment of Subjects .................................................................................................... 52
10.1
Blinding..................................................................................................................... 52
10.2
Randomization........................................................................................................... 52
10.3
Dosing With Study Drug............................................................................................ 52
10.3.1
Initial Dosing ......................................................................................................... 52
10.3.2
Dose Modifications................................................................................................ 53
10.3.2.1
Management of Adverse Events.......................................................................... 53
10.4
Treatment Discontinuation......................................................................................... 54
10.5
Assessment of Recurrence ......................................................................................... 54
10.6
Retreatment ............................................................................................................... 56
10.7
Concomitant Medication............................................................................................ 57
10.7.1
Recommended Concomitant Medication................................................................ 57
10.7.1.1
Albumin ............................................................................................................. 57
10.7.1.2
Prohibited or Discouraged Concomitant Medications ......................................... 57
10.8
Treatment Compliance............................................................................................... 57
10.9
Medical Hotline ......................................................................................................... 58
11 Study Drug Material and Management........................................................................... 58
11.1
Study Drug and Reference Therapy............................................................................ 58
11.1.1
Terlipressin ............................................................................................................ 58
11.1.2
Placebo .................................................................................................................. 59
11.2
Packaging and Labeling ............................................................................................. 59
11.3
Study Drug Storage and Preparation........................................................................... 59
11.3.1
Reconstitution........................................................................................................ 59
11.3.2
Administration....................................................................................................... 60
11.4
Study Drug Accountability......................................................................................... 60
12 Randomization, Breaking of Blinded Codes................................................................... 60
12.1
Randomization and Blinding...................................................................................... 60
12.1.1
Randomization....................................................................................................... 60
12.1.2
Blinding of Study Drugs......................................................................................... 61


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12.1.3
Unblinding of Treatment Assignment..................................................................... 61
13 Assessments and Procedures.......................................................................................... 61
13.1
Schedule of Assessments and Procedures................................................................... 61
13.2
Study Assessment Periods.......................................................................................... 68
13.2.1
Screening Period.................................................................................................... 68
13.2.2
Pre-Treatment Period ............................................................................................. 68
13.2.3
Active Study Period (14 Days)............................................................................... 69
13.2.3.1
Dosing (Up to 14 Days)...................................................................................... 69
13.2.3.2
End of Treatment, Discharge or Day 14 .............................................................. 69
13.2.4
Follow-up Period ................................................................................................... 69
13.2.4.1
Day 30 Blood Sample Collection........................................................................ 70
13.3
Detail of Baseline Assessments and Procedures.......................................................... 70
13.3.1
Physical Examination............................................................................................. 70
13.3.2
Electrocardiogram.................................................................................................. 71
13.3.3
Child-Pugh Scores ................................................................................................. 71
13.3.4
Vital Signs ............................................................................................................. 71
13.3.5
Assessment of Multi-Organ Dysfunction................................................................ 71
13.4
Detail of Safety Assessments and Procedures............................................................. 72
13.4.1
Vital Signs ............................................................................................................. 72
13.4.2
Encephalopathy Score............................................................................................ 72
13.4.3
Model for End-Stage Liver Disease Score.............................................................. 73
13.4.4
Adverse Events ...................................................................................................... 73
13.4.4.1
Adverse Events of Special Interest...................................................................... 74
13.5
Detail of Laboratory Assessments and Procedures...................................................... 74
13.5.1
Local Laboratory at Investigational Site ................................................................. 74
13.5.1.1
Serum Electrolytes & Biochemistry.................................................................... 74
13.5.1.2
Hematology........................................................................................................ 75
13.5.2
Total Volume of Blood Collected............................................................................ 76
13.6
Detail of Efficacy Assessments and Procedures.......................................................... 76
13.6.1
Primary Efficacy Variable ...................................................................................... 76
13.6.2
Secondary Efficacy Variables................................................................................. 77
14 Adverse Events.............................................................................................................. 79


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14.1
Definitions................................................................................................................. 80
14.1.1
Adverse Event Definition....................................................................................... 80
14.1.2
Adverse Reaction Definition .................................................................................. 80
14.1.3
Suspected Adverse Reaction Definition.................................................................. 81
14.1.3.1
Unexpected Adverse Drug Reaction Definition................................................... 81
14.1.4
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction Definition 81
14.1.5
Treatment Emergent Adverse Event Definition....................................................... 81
14.1.6
Serious Adverse Event Definition........................................................................... 82
14.1.7
Severity of an Adverse Event ................................................................................. 82
14.1.8
Study Drug Causality ............................................................................................. 83
14.1.9
Overdose................................................................................................................ 84
14.2
Collection of Adverse Events/Serious or Unexpected................................................. 84
14.2.1
Laboratory Abnormalities....................................................................................... 85
14.2.2
Hospitalizations ..................................................................................................... 85
14.2.3
Complications of the Disease ................................................................................. 85
14.2.4
Pregnancy .............................................................................................................. 85
14.3
Reporting of Adverse Events/Serious or Unexpected Adverse Reactions or Adverse 
Events........................................................................................................................ 85
14.3.1
Site Reporting to Sponsor....................................................................................... 85
14.3.1.1
Overdose ............................................................................................................ 86
14.3.1.2
Pregnancy........................................................................................................... 86
14.3.2
Site Reporting to Institutional Review Board/Independent Ethics Committee......... 87
14.3.3
Sponsor Reporting to Regulatory Authorities and Investigators.............................. 87
15 Statistical Plan ............................................................................................................... 87
15.1
Safety Variables ......................................................................................................... 88
15.2
Subject Accounting and Baseline Characteristics ....................................................... 88
15.3
Statistical Methodology ............................................................................................. 88
15.3.1
Sample Size Calculation......................................................................................... 88
15.3.2
Interim Analysis..................................................................................................... 89
15.3.3
Subject Populations................................................................................................ 89
15.3.3.1
Intention to Treat Population............................................................................... 89
15.3.3.2
Safety Population ............................................................................................... 90
15.3.4
Statistical Analyses ................................................................................................ 90
15.3.5
Demographic and Baseline Characteristics............................................................. 90
15.3.6
Efficacy Analyses................................................................................................... 90


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15.3.6.1
Primary Efficacy Analysis .................................................................................. 90
15.3.6.2
Secondary Efficacy Analyses.............................................................................. 91
15.3.6.4
Safety Analyses .................................................................................................. 96
15.3.7
Definition of Baseline ............................................................................................ 96
15.3.8
Missing Data.......................................................................................................... 96
15.3.9
Procedure for Amendments to the Statistical Plan................................................... 96
16 Direct Access, Data Handling, and Record Keeping....................................................... 97
16.1
Investigator................................................................................................................ 97
16.2
Sponsor...................................................................................................................... 97
16.3
Records Retention...................................................................................................... 98
17 Quality Control and Quality Assurance .......................................................................... 98
17.1
Study Monitoring....................................................................................................... 98
17.2
Auditing..................................................................................................................... 99
18 Ethics and Responsibility............................................................................................... 99
18.1
Institutional Review Board/Independent Ethics Committee........................................ 99
18.1.1
Protocol Amendments............................................................................................ 99
18.2
Informed Consent .....................................................................................................100
18.3
Confidentiality..........................................................................................................100
18.4
Biological Samples ...................................................................................................101
18.5
Subject Injury ...........................................................................................................101
18.6
Study Suspension, Termination, and Completion.......................................................101
18.6.1
Study and Study Site Discontinuation Criteria.......................................................101
19 Registration of Study and Publication of Data...............................................................102
19.1
Investigator’s Ability to Publish................................................................................102
20 References ....................................................................................................................103
21 Appendix A: Study IK-4001-HRS-301: Nomogram to Determine the Criterion for SCR 
Doubling Over a 2-Week Period....................................................................................106
22 Appendix B: CLIF-SOFA Score....................................................................................108


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List of Tables
Table 10–1
Prohibited/Discouraged Concomitant Medications........................................ 57
Table 13–1
Schedule of Assessments .............................................................................. 62
Table 13–2
CLIF-C Organ Failure Score......................................................................... 72
Table 13–3
West Haven Criteria for Semiquantitative Grading of Mental State ............... 73
Table 14–1:
Adverse Events Common to the Hepatorenal Syndrome (HRS) Population... 84
Table 15–1:
Sample Size Estimates .................................................................................. 89
Table 15–2:
Potential Scenarios for Success at the Interim Analysis with a Placebo Rate of 
Approximately 12.5%................................................................................... 91
Table 15–3:
Multiple Testing for the Interim Analysis of the Secondary Efficacy Analyses
..................................................................................................................... 91
Table 15–4:
Multiple Testing for the Final Analysis of the Secondary Efficacy Analyses.. 92
Table 21–1:
Elapsed Time in Days and Required Fold Increase in SCr............................107
Table 22-1
CLIF-SOFA Score .......................................................................................108
List of Figures
Figure 1:
Schematic Diagram of Study Design............................................................. 45
Figure 2:
Terlivaz® (Terlipressin for Injection)............................................................. 58
Figure 3:
Nomogram to Determine the Criterion for SCr Doubling Over a 2-Week Period
....................................................................................................................106


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4
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
CG
Cockcroft-Gault
CrCl
creatinine clearance
CLIF-C
Chronic Liver Failure Consortium (organ failure score)
CLIF-SOFA
Chronic Liver Failure-Sepsis Organ Failure Assessment (score)
CMH
Cochran-Mantel-Haenszel
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic case report form
EASL
European Association for the Study of the Liver
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 Council for Harmonisation
IND
Investigational New Drug
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous


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Abbreviation
Definition
IXRS
Interactive Voice and Web Response System
LVP
large volume paracentesis
MAP
mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
MODS
multiorgan dysfunction syndrome
NDA
New Drug Application
NGAL
neutrophil gelatinase-associated lipocalin
NSAID
nonsteroidal anti-inflammatory drug
PaCO2
partial pressure of arterial carbon dioxide
q4h
once every 4 hours
q6h
once every 6 hours
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
SpO2
pulse oximetric saturation
TIPS
transjugular intrahepatic portosystemic shunt
US
United States
WBC
white blood cell
WHO
World Health Organization


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5
Introduction
5.1
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 et al, 1996; Salerno et al, 2007; Angeli et al, 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 et al, 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 et al, 2015). 
As indicated in the American Association for the Study of Liver Diseases (AASLD) 
Guidelines, at present, there is no available pharmacological therapy (ie, 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 et al,
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 
(ie, combination of midodrine and octreotide) are not effective (Cavallin et al, 2015).
5.2
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 et al, 2000; Ginès et al, 2003; Kiszka-Kanowitz et al, 2004).


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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.
Terlipressin is approved in many countries and regions outside the US where it has been 
the standard of care for decades in the treatment of subjects with liver cirrhosis and 
esophageal variceal hemorrhage (EVH) (de Franchis, 2005; Ioannou et al, 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. 
Refer to the Investigator’s Brochure for a summary of the nonclinical studies with terlipressin.
5.3
Clinical Studies of Terlipressin in Subjects With HRS Type 1
Clinical data are available from 2 randomized, double-blind, placebo-controlled studies, 
(OT-0401 and REVERSE), a randomized, open-label, active-controlled study (TAHRS), and 
a large body of published literature studies in over 800 terlipressin-treated subjects with 
HRS Type 1 (Investigator’s Brochure).
5.3.1
Pharmacokinetics and Pharmacodynamics
Following a 1-mg IV dose of terlipressin every 6 hours (q6h) in subjects with HRS Type 1 
(OT-0401 and REVERSE studies), terlipressin has a median terminal half-life of 
approximately 0.9 hours. Although the half-life of lysine-vasopressin is short (1 to 6 minutes), 
as a result of the slow metabolic conversion of terlipressin to lysine-vasopressin the median 
apparent half-life of lysine-vasopressin is increased to approximately 3 hours. 
Small transient changes in blood pressure and heart rate occurred 5 minutes after treatment 
with terlipressin and were likely attributable to the effect of terlipressin; maintaining these 
effects for 6 hours after treatment was most likely primarily attributable to the formation 
of lysine-vasopressin.
Refer to the Investigator’s Brochure for further details.


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5.3.2
Efficacy
Improvement in renal function is the goal of therapy for HRS Type 1; 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 no more 
than 1.5 mg/dL) is the standard endpoint utilized in the literature and HRS treatment 
guidelines (Arroyo et al, 1996; Salerno et al, 2007; Angeli et al, 2015).
The OT-0401 study (112 subjects with HRS Type 1 randomized 1:1 to receive terlipressin 
or placebo, with concomitant albumin administration recommended in both treatment arms) 
demonstrated a significantly higher rate of HRS reversal (34% vs 13%, p = 0.008) in the 
terlipressin treatment group compared to the placebo group. The primary endpoint of 
Treatment Success at Day 14 (an initial reduction of SCr to no more than 1.5 mg/dL followed 
by a confirmatory SCr measurement of no more than 1.5 mg/dL 48 hours after the initial HRS 
reversal and an additional SCr value less than 2.5 mg/dL at Day 14, without intervening liver 
transplant or dialysis) was also met following the incorporation of additional SCr values post 
initial database closure (29% vs 13%, p = 0.037). Furthermore, the prespecified endpoint of 
change in SCr from baseline to Day 14 demonstrated a greater reduction in SCr with 
terlipressin vs placebo (-0.9 mg/dL; p = 0.0008).
In the REVERSE study (196 subjects with HRS Type 1 randomized 1:1 to receive terlipressin 
or placebo, with concomitant albumin administration recommended in both treatment arms), 
there was a trend for greater HRS reversals with terlipressin treatment vs placebo 
(24% vs 15%, p = 0.129). For a number of reasons (for example, discharge from hospital 
before confirmatory laboratory values), statistical significance (20% vs 13%, not significant)
was not achieved for confirmed HRS reversal (an initial reduction of SCr to no more than
1.5 mg/dL followed by a confirmatory SCr measurement of no more than 1.5 mg/dL 48 hours 
after the initial HRS reversal [in the case of hospital discharge or transplantation before 
48 hours, the 2 confirmatory SCr values had to be at least 22 hours apart]). Although the 
REVERSE study did not meet the prespecified endpoint of HRS reversal, the prespecified 
endpoint of change in SCr from baseline to end of treatment demonstrated a greater reduction 
in SCr with terlipressin vs placebo (-0.6 mg/dL; p = 0.0002). This current study has been 
designed to address the methodological obstacles encountered in the REVERSE trial.


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The open-label, active-controlled study (TAHRS) and a large body of published literature 
studies (including 44 published clinical investigations in over 800 terlipressin-treated subjects 
with HRS Type 1) have consistently demonstrated that terlipressin significantly improves 
renal function in subjects with HRS Type 1. In TAHRS, the incidence of HRS reversal
was significantly higher in terlipressin + albumin-treated subjects compared with 
albumin-treated subjects (39.1% vs 8.7%; p = 0.018) and the change in SCr from baseline 
to the end of treatment was -0.7 mg/dL (p = 0.031). Data from the literature studies 
consistently showed clinically relevant improvements in renal function, as measured 
by reduction of SCr (eg, reversal of HRS or overall change in SCr), in 20% to 83% of subjects 
studied. Furthermore, the literature has been analyzed in a systematic fashion by external 
authors in 11 meta-analyses (7 of these meta-analyses included published data from the 
OT-0401 and TAHRS studies), which also confirm the efficacy of terlipressin for the 
treatment of HRS.
Refer to the Investigator’s Brochure for further details.
5.3.3
Safety
Most subjects in both treatment groups in the OT-0401 and REVERSE studies experienced 
at least 1 adverse event (AE), which is expected given the high incidence of disease-related 
events in this severely ill patient population. The most commonly observed adverse reactions 
in terlipressin-treated subjects were abdominal pain and diarrhea (refer to Table of Adverse 
Drug Reactions in the Investigator’s Brochure). Less common adverse reactions with clinical 
significance that were reported in terlipressin-treated subjects include: wheezing, respiratory 
failure, peripheral ischemia manifested as skin necrosis, peripheral coldness, livedo reticularis 
and Raynaud’s phenomenon; intestinal ischemia including ischemic colitis; myocardial 
ischemia including myocardial infarction. The safety characteristics of terlipressin in the 
2 studies were consistent with its vasoconstrictor mechanism of action. None of the events 
leading to discontinuation of terlipressin in either study were fatal and all resolved afterwards. 
Refer to the Investigator’s Brochure for further details.
The safety characteristics of terlipressin observed in the 3 randomized, controlled trials 
is consistent with the established safety profile of terlipressin from 30 years of clinical 
experience, as captured in the literature and post-marketing data from the World Health 
Organization (WHO) database. There were no new, unusual or unexpected AEs observed 
in the clinical studies compared to the published data.


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For detailed terlipressin safety risk profiling, please refer to the Investigator’s Brochure.
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.
5.4
Study Rationale
The purpose of this randomized, placebo-controlled study is to confirm the efficacy and safety 
of terlipressin in the treatment of subjects with HRS Type 1 to provide data to support 
regulatory approval of the New Drug Application (NDA). Efficacy will be assessed through 
the primary endpoint of verified HRS reversal; other important efficacy parameters will be 
assessed including short-term durability of verified HRS reversal, magnitude of SCr lowering 
effect and effects in important subgroups (eg, systemic inflammatory response syndrome 
[SIRS] subgroup). Safety data will be collected and incorporated into the overall safety 
assessment of terlipressin. Methodological obstacles encountered in the REVERSE trial that 
reduced its ability to show statistical significance on the primary endpoint have been 
addressed in this trial design.
5.4.1
Primary Endpoint Rationale
HRS reversal, defined as at least 1 SCr measurement of no more than 1.5 mg/dL, has been 
used for decades to determine treatment response in published HRS clinical studies and is 
the standard endpoint utilized in the literature and in HRS treatment guidelines (Arroyo et al,
1996; Salerno et al, 2007; Angeli et al, 2015). The reversal of HRS Type 1 represents 
a dramatic clinical response to treatment: for the endpoint to be achieved, the rapid 
progression of renal failure must be arrested and normal renal function restored. The purpose 
of the primary end point of “verified” HRS reversal is to verify that the first SCr value of no 
more than 1.5 mg/dL is not a spurious laboratory value. An additional element of the primary 
endpoint requirement, ie, alive without RRT, has been added to demonstrate the short term 
durability of the primary end point on clinical outcomes. RRT is defined as any procedure to 
replace non-endocrine kidney function and includes intermittent hemodialysis, ultrafiltration, 
continuous hemofiltration and hemodialysis, peritoneal dialysis and other dialysis and 
filtration techniques.


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5.4.2
Dosing Regimen and Recommended Concomitant Albumin
Administration
The dosing regimen for the current study (see Section 10.3) will be the same as that used in 
OT-0401 and REVERSE. In OT-0401 and REVERSE, over 70% of subjects had no dose 
increase from the starting dose of 1 mg q6h and the majority of subjects who achieved HRS 
reversal responded at the 1 mg dose of terlipressin. Similarly, in the TAHRS study, 
the majority of subjects who achieved HRS reversal responded at the 1 mg every 4 hours 
(q4h) dose of terlipressin and all subjects who received a starting dose of 0.5 mg (q4h)
(3 mg/day) had a dose increase to at least 1 mg q4h (6 mg/day). No clear dose response 
was evident from an examination of the literature, with doses of terlipressin in 44 published 
studies in HRS Type 1 ranging from 1 to 12 mg/day. Most studies allowed for dose increases 
after several days if no significant SCr decrease from baseline was observed. 
As per standard medical practice, concomitant use of albumin in both treatment arms 
is strongly recommended, if clinically appropriate (Arroyo et al, 1996; Salerno et al, 2007;
Angeli et al, 2015).
6
Objective
The objective of this study is to confirm the efficacy and safety of intravenous terlipressin vs
placebo in the treatment of adult subjects with HRS Type 1 receiving standard of care 
albumin therapy.
6.1
Efficacy Variables
The efficacy variables are summarized below and further details are provided in Section 13.6.
6.1.1
Primary Efficacy Variables
The primary efficacy evaluation will be based on the following:
Incidence of verified HRS reversal, defined as the percentage of subjects with 2 consecutive 
SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or 
discharge (on treatment defined as up to 24 hours after the final dose of study drug). Subjects
must be alive without RRT for at least 10 days after achieving verified HRS reversal. SCr 
values after RRT, transjugular intrahepatic portosystemic shunt (TIPS), liver transplant, or 
open-label vasopressor use will be excluded from primary end point analysis. SCr values 
obtained after midodrine administration will be included if midodrine was started on Day 1, 


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was administered for no more than 24 hours, and the subject was enrolled on or after 17 
August 2018. SCr values will also be included if obtained after the administration of a single 
dose of dobutamine.
Note: SCr data for primary end point will be collected at least daily until discharge 
or Day 14. The analysis will be based on the Intent to Treat (ITT) population.
6.1.2
Secondary Efficacy Variables
Secondary efficacy analyses will be based on the following:

Incidence of subjects with HRS reversal, defined as the percentage of subjects with 
a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will 
be excluded).

Durability of HRS reversal, defined as the percentage of subjects with HRS reversal 
without RRT to Day 30. HRS reversal is defined as the percentage of subjects with 
a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). RRT is defined as any procedure to replace non-endocrine kidney function 
and includes intermittent hemodialysis, ultrafiltration, continuous hemofiltration and 
hemodialysis, peritoneal dialysis and other dialysis and filtration techniques. The date 
RRT is instituted for the first time will be used to determine if a subject underwent 
RRT by Day 30.

Incidence of HRS reversal in the systemic inflammatory response syndrome (SIRS) 
subgroup, defined as the percentage of SIRS subjects with HRS reversal. HRS reversal 
is defined as the percentage of subjects with a SCr value no more than 1.5 mg/dL 
while on treatment by Day 14 or discharge (SCr values after RRT, TIPS, liver 
transplant, or open-label vasopressor use will be excluded).
Incidence of verified HRS reversal without HRS recurrence by Day 30. HRS Type 1 
recurrence is defined in Section 10.5. Incidence of verified HRS reversal, defined as the 
percentage of subjects with 2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours 
apart, while on treatment up to 24 hours after the final dose of study drug, by Day 14 or 
discharge. Subjects must be alive without RRT for at least 10 days after achieving verified 


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HRS reversal. SCr values after RRT, transjugular intrahepatic portosystemic shunt (TIPS), 
liver transplant, or open-label vasopressor use will be excluded from primary end point 
analysis. SCr values obtained after midodrine administration will be included if midodrine 
was started on Day 1, was administered for no more than 24 hours, and the subject was 
enrolled on or after 17 August 2018. SCr values will also be included if obtained after the 
administration of a single dose of dobutamine.
 
 
 
 
 
 
 
 
 
 


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6.1.5
Safety:
Safety assessments will include the following:

Non-serious adverse events up to 7 days after end of treatment.

Serious adverse events up to 30 days after end of treatment.

General safety profile, including physical examinations, vital signs and laboratory 
tests.

Mortality up to 90 days after the first dose of study drug.
7
Investigational Plan
7.1
Overall Study Design and Plan: Description
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study 
of intravenous terlipressin administered to subjects with HRS Type 1. All subjects
who consent to study participation must undergo an in-hospital screening/qualification period 
of no less than 48 hours prior to enrollment in order to establish the diagnosis of HRS Type 1. 
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. Qualified subjects will then be randomized in a 2:1 ratio to receive 


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either terlipressin or placebo, stratified by qualifying SCr (less than 3.4 mg/dL or at 
least 3.4 mg/dL) and pre-enrollment large volume paracentesis (LVP; at least one single event 
of at least 4 L or less than 4 L within 14 days prior to randomization). The qualifying SCr will 
be the last SCr that was on the screening/qualification eCRF. A total of 300 subjects are 
planned to be enrolled at approximately 70 sites in the US and Canada.
Subjects will receive up to 14 days of study treatment IV every 6 hours (± 30 minutes) 
(maximum of 15 days allowed if HRS reversal is first achieved on Day 14). Subjects will be 
contacted on Days 30 (±10), 60 (± 14), and 90 (± 14) for assessment of survival, RRT, TIPS, 
and liver transplant status (Figure 1).
Subjects will participate in 4 assessment periods, which includes screening, pre-treatment, 
active, and follow-up assessment (see Section 13.2).
Figure 1:
Schematic Diagram of Study Design
8
Study Population
8.1
Population Rationale
The study population consists of adult subjects with cirrhosis, ascites, and a diagnosis of HRS 
Type 1 based on the IAC diagnostic criteria (Arroyo et al, 1996; Salerno et al, 2007;
Angeli et al, 2015).


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Subjects with a baseline SCr level greater than 7.0 mg/dL will be excluded from the study.
The threshold for upper cut-off of SCr in entry criteria is derived from the results of previous 
NDA studies. In OT-0401, none of the subjects with a baseline SCr level greater than
7.0 mg/dL achieved HRS reversal. Subjects will be stratified by qualifying SCr (less than
3.4 mg/dL or at least 3.4 mg/dL).
Qualifying SCr is a prognostic factor for survival and HRS reversal. Excluding subjects with 
a baseline SCr of greater than 7 mg/dL and LVP at least 4 L within 2 days prior to 
randomization (both are exclusion criteria for this study), 3.4 mg/dL (N = 253) was the 
median baseline SCr of subjects enrolled in the OT-0401 and REVERSE studies combined.
Subjects will also be stratified by pre-enrollment LVP (at least one single event of at least 4 L 
or less than 4 L within 3 to 14 days prior to randomization). Note, subjects with a LVP of at 
least 4 L are excluded if it occurs within 2 days prior to randomization (refer to Section 8.4).
As per the literature, a paracentesis was considered a LVP if at least 4 L of fluid was 
withdrawn in a given procedure (Choi et al, 2005; Kao et al, 1985; Ginès et al, 1987; Pinto et 
al, 1988; Tito et al, 1990). In REVERSE, there were significantly more placebo subjects who 
had at least 1 LVP (at least 4 L in a single procedure) within 14 days prior to enrollment 
(54 [54.5%] placebo subjects vs 36 [37.1%] terlipressin subjects, p = 0.0143) (prior LVP data 
were not collected in OT-0401). Subjects with a history of prior LVP exhibited an almost 
3-fold greater verified HRS reversal rate with placebo compared to placebo-treated subjects 
without a history of prior LVP (18.5% vs 6.7%). The baseline imbalance increased the overall 
placebo response rate, contributing to the lower observed treatment effect.
The investigator must review any paracentesis performed in the pre-enrollment period 
and volume status after paracentesis must be considered carefully; as per standard of care, 
adequate replacement of fluid removed with albumin is required.
8.2
Number of Subjects to be Studied
A total of 300 subjects are planned to be enrolled at approximately 70 sites in the US 
and Canada. Discontinued subjects will not be replaced.
8.3
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible to enrollment:


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1. Written informed consent by subject or legally authorized representative.
2. At least 18 years of age.
3. Cirrhosis and ascites.
4. Rapidly progressive worsening in renal function to a SCr at least 2.25 mg/dL and meeting 
a trajectory for SCr to double over 2 weeks:
oNote: Refer to Section 21 for a nomogram intended for use in situations when the 
SCr value has increased rapidly over a short period of time but has not yet doubled 
within 2 weeks. The nomogram may be used to determine whether the subject’s 
SCr values are consistent with a trajectory likely to be representative of at least a 
doubling within 2 weeks (SCr values must be documented for a minimum of 4 days).
oIn situations where the time elapsed between SCr values is greater than 2 weeks, 
the investigator must contact the Medical Hotline maintained by the sponsor to 
discuss subject eligibility. The qualification form, including all available SCr data,
must be completed by the investigator or qualified designee and forwarded to 
the sponsor for review and approval prior to enrollment. All communications 
between investigators and the sponsor regarding a subject’s eligibility, including 
reasons supporting inclusion in the study, will be documented.
5. No sustained improvement in renal function (less than 20% decrease in SCr and SCr at 
least 2.25 mg/dL) at least 48 hours after diuretic withdrawal and the beginning of plasma 
volume expansion with albumin:
oNote: Albumin doses recommended by the IAC are 1 g/kg on the first day (maximum 
100 g) and 20 g/day to 40 g/day thereafter as clinically indicated (Salerno et al,
2007; Angeli et al, 2015).

Note: The qualifying SCr value is the SCr value at least 48 hours after both diuretic 
withdrawal (if applicable) and the beginning of albumin fluid challenge.
The qualifying serum creatinine for subjects on prior vasopressors will be taken after 
completion of vasopressor washout. The qualifying SCr value must be at least
2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) SCr value.
No subjects should be randomized unless their SCr has been obtained within 8 hours
prior to randomization and start of study drug. If there is a delay in subject 
randomization, then the qualifying/baseline SCr value must be redrawn so that the 


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value is collected within 8 hours prior to randomization and start of study drug to 
verify that the subject still meets the inclusion criterion for baseline SCr.
8.4
Exclusion Criteria
If any of the following exclusion criteria are met, the subject will not be enrolled:
1. Serum creatinine level greater than 7.0 mg/dL.
2. At least 1 event of LVP at least 4 L within 2 days of randomization.
Note: The investigator must review any paracentesis performed in the pre-enrollment 
period and volume status after paracentesis must be considered carefully; as per 
standard of care, adequate replacement of fluid removed with albumin is required.
3. Sepsis and/or uncontrolled bacterial infection (eg, persisting bacteremia, persisting 
ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability).
Note: Sepsis is defined as documented active, untreated infection and presence 
of SIRS. SIRS is defined as the presence of 2 or more of the following findings: 
temperature greater than 38°C or less than 36°C; heart rate greater than 90/min; 
respiratory rate greater than 20/min or partial pressure of arterial carbon dioxide 
(PaCO2) less than 32 mm Hg; white blood cell (WBC) count greater 
than 12,000 cells/μL or less than 4,000/ μL).
Note: Patients with decompensated liver disease frequently have SIRS criteria in the 
absence of uncontrolled infection or sepsis. Subjects with SIRS criteria, in the absence 
of active, untreated infection, and reasonably attributed to decompensated liver disease 
or alternate causes (eg, hepatic hydrothorax, acute alcoholic hepatitis) should be 
enrolled after discussion with the sponsor via the Medical Hotline, assuming they meet 
all subject selection criteria.
4. Less than 2 days anti-infective therapy for documented or suspected infection.
5. Shock.
Note: Shock is defined as hypotension (MAP less than 70 mm Hg or a decrease greater 
than 40 mm Hg in systolic blood pressure from baseline) with evidence of 
hypoperfusion abnormalities (eg, peripheral cyanosis, hypothermia, marked asthenia, 
pallor, obtundation not attributable to hepatic encephalopathy).


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6. Current or recent (within 4 weeks) treatment with or exposure to nephrotoxic agents: 
eg, aminoglycosides, amphotericin, cyclosporine A, cisplatin, nonsteroidal 
anti-inflammatory drugs (NSAIDs: eg, ibuprofen, naproxen, diclofenac), significant 
exposure to radiographic contrast agents (large doses or multiple injections of 
iodinated contrast media, eg, during coronary or abdominal angiogram.
Note: Up to 3 doses of an NSAID within the prior month is acceptable.
Note: Use of short-term (less than 2 weeks) oral neomycin for acute encephalopathy 
is acceptable.
7. Estimated life expectancy of less than 3 days.
8. Superimposed acute liver injury due to drugs (eg, acetaminophen), dietary 
supplements, herbal preparations, viral hepatitis, or toxins (eg, Amanita toxin with 
mushroom poisoning, carbon tetrachloride), with the exception of acute alcoholic 
hepatitis.
Note: subjects meeting criteria for drug, dietary supplement or herbal preparation 
induced liver injury (http://livertox.nih.gov/; Chalasani et al, 2014) should be excluded
9. Proteinuria greater than 500 mg/day.
10. Evidence of obstructive uropathy or parenchymal renal disease on ultrasound or other 
imaging.
11. Tubular epithelial casts, heme granular casts, hematuria or microhematuria (greater 
than 50 red blood cells per high power field in the absence of recent catheterization) 
on urinalysis.
Note: Urine sediment examination is required to exclude presence of heme granular 
casts and other clinically significant casts.
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 requiring increasing doses of drug therapy, 
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.
14. Current or recent (within 4 weeks) RRT.


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15. Participation in other clinical research involving investigational medicinal products 
within 30 days of randomization.
16. TIPS within 30 days of randomization.
17. Use of vasopressors (eg, norepinephrine, epinephrine or vasopressin, dopamine or 
other vasopressors) of at least 3 consecutive days within prior 14-day screening period.
Patients receiving a vasopressor other than midodrine within 24 hours of qualifying 
SCr are excluded, ie, 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 randomization.
18. Known allergy or sensitivity to terlipressin or another component of the 
study treatment.
NOTE: It is recognized that clinical judgment is a component of individual subject 
assessment, particularly in critically ill subjects with multi-organ disease. If, in the opinion 
of the investigator, a subject meets the criteria for HRS Type 1 but appears to demonstrate 
a potential deviation from the inclusion or exclusion criteria listed above, the investigator 
must contact the sponsor or designee via the Medical Hotline to discuss subject eligibility. 
All communications via the Medical Hotline, including reasons supporting inclusion 
in the study, will be documented.
8.5
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. 
If study treatment or protocol-specified assessments are discontinued, the reason will be 
recorded and the sponsor should be notified promptly. If a subject withdraws from the study, 
the reason will be recorded on the eCRF. Reasons for terminating participation in the clinical 
study may include the following:

Adverse event(s).

Abnormal laboratory value(s).

Abnormal test procedure result(s).

Protocol-noncompliance.

Withdrawal of consent.


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
Lost to follow-up.

Administrative problems.
It is imperative to obtain complete follow-up data for all randomized subjects, whether or not 
they received their assigned study treatment, altered or discontinued study drug prematurely. 
Every attempt should be made to collect follow-up information, including required laboratory 
tests, serious adverse events (SAEs) and mortality assessments, except for those subjects
who specifically withdraw consent for release of such information. Sites should contact 
subject/family member via telephone, mail or both to obtain this information. At least 
3 documented attempts should be made by the site. Subjects withdrawn from treatment due 
to an adverse event should be followed until the event resolves, is no longer clinically 
significant, has stabilized, or is otherwise explained. Withdrawal of consent for follow-up 
should be accompanied by documentation of the reason for withdrawal. Withdrawal of 
consent for treatment should be distinguished from withdrawal of consent for follow-up 
contact and from withdrawal of consent for non-subject contact follow-up (eg, medical 
records checks). Sites should do the utmost to obtain the withdrawal of consent in writing and, 
if the subject or the subject’s representative refuses or is physically unavailable, the site 
should document and sign the reason for the subject’s failure to withdraw consent in writing.
9
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 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.


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10 Treatment of Subjects
10.1 Blinding
This study will be double-blinded using matching 6-mL placebo glass vials containing 
lyophilized mannitol without the active ingredient terlipressin, and 6-mL vials with 
lyophilized mannitol as the inert carrier compound containing 1 mg terlipressin acetate. 
Refer to Section 11.1 for details of the study drug and placebo.
10.2 Randomization
Subjects will be randomly assigned centrally using an interactive voice and web response 
system (IXRS) to treatment groups in order to minimize bias based upon subject selection 
and baseline characteristics. Subjects will be stratified by qualifying SCr (less than 3.4 mg/dL 
or at least 3.4 mg/dL) and pre-enrollment LVP (at least one single event of at least 4 L or less 
than 4 L within 3 to 14 days prior to randomization), and randomized (2:1) to receive either 
active terlipressin or matching placebo. Note, subjects with a LVP of at least 4 L are excluded 
if it occurs within 2 days prior to randomization (refer to Section 8.4).
Each investigational site will receive kits of blinded, labeled active and placebo vials each 
numbered with unique, randomized identification numbers. The method of unblinding will be 
through the IXRS. The randomization codes will be generated by an independent statistician 
and will not be accessible to blinded personnel (unless required during a medical emergency) 
during the study period.
10.3 Dosing With Study Drug
Each subject will be assigned blinded study drug. Under no circumstance is it permitted 
to treat a subject with study drug that was not specifically assigned to that subject.
10.3.1 Initial Dosing
Blinded terlipressin or placebo will be administered intravenously as a bolus injection over 
2 minutes at a dose of 1 mg (1 vial) every 6 hours (± 30 minutes). After study drug 
administration, the line should be flushed with saline. 


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10.3.2 Dose Modifications

If SCr has decreased, but by less than 30% from the baseline value on Day 4 after a 
minimum of 10 doses of study drug, the dose of study drug will be increased to 2 mg 
every 6 hours (± 30 minutes) (8 mg/day). 

The dose should not be increased in subjects with coronary artery disease or 
in the setting of circulatory overload, pulmonary edema, or bronchospasm.

If dosing is interrupted due to an adverse event, study drug may be re-started, 
at the discretion of the investigator, at the same or lower dose as per protocol
(refer to Section 10.3.2.1). Study drug will not be restarted if dosing was interrupted 
due to cardiac ischemia or mesenteric ischemia.

If in the investigator’s judgment, a dose increase is not advisable or otherwise justified 
in the individual subject, the reason(s) for not increasing the dose of study drug will be 
documented on the electronic case report form (eCRF).
10.3.2.1 Management of Adverse Events
With the exception of presumed cardiac or intestinal ischemia, the initial management of AEs 
may include dose reduction or temporary interruption of study drug dosing. After dose 
interruption, study drug may be restarted at a reduced dose of 0.5 mg or 1 mg every 6 to 
12 hours. At the discretion of the investigator, the dose may then be increased to the previous 
dose level. Careful assessment of concomitant medications and treatment (particularly 
albumin dosing) and their potential relationship to the AE should be undertaken and adjusted 
as per standard of care and investigator discretion. If possible, study drug dosing should be 
restarted promptly and/or maintained at usual or reduced dosing particularly for the first 
4 days of study drug administration. Investigators are encouraged to discuss any dosing 
questions with the Medical Hotline.
10.3.2.1.1 Management of Fluid Overload
Volume overload in this context refers to intravascular volume overload manifested 
as pulmonary congestion or overt pulmonary edema. Subjects with increasing dyspnea, cough, 
orthopnea, or tachypnea should be carefully evaluated for evidence of pulmonary edema 
(physical examination and, as judged by the investigator to be indicated, chest X-ray or other 
investigations). In subjects with fluid overload, especially those with respiratory events 


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(dyspnea, respiratory distress), careful assessment of concomitant albumin and temporary 
albumin dose reduction or discontinuance may be the most appropriate initial management. 
Judicious, short term use of temporary diuretic therapy as per standard of care may be 
undertaken at the discretion of the investigator in some subjects in whom a response to 
diuretic therapy is expected. If fluid overload requiring intervention persists after these initial 
measures, further management should include dose reduction or temporary interruption 
of study drug dosing as above.
10.4 Treatment Discontinuation

Treatment should be continued until 24 hours after 2 consecutive SCr values no more 
than 1.5 mg/dL have been obtained, OR up to a maximum of 14 days 
(maximum of 15 days if SCr first reaches 1.5 mg/dL on Day 14). 

If on Day 4 (after a minimum of 10 doses) SCr is at or above baseline value, 
study drug should be discontinued.

Treatment must be discontinued when the subject is to undergo RRT, 
liver transplantation, TIPS or vasopressor therapy.

Dosing must be permanently discontinued if an event of cardiac ischemia 
or mesenteric ischemia occurs.
10.5 Assessment of Recurrence
Any subject with a SCr value of at least 2.25 mg/dL after achieving verified HRS reversal, but 
prior to transplant/discharge/Day 14, will be assessed for HRS Type 1 recurrence. HRS 
recurrence by Day 30 is defined as another episode of HRS Type 1, by Day 30, after achieving 
verified HRS reversal, characterized by rapidly progressive worsening in renal function to a 
SCr at least 2.25 mg/dL, without sustained improvement in renal function (less than 20% 
decrease in SCr and SCr at least 2.25 mg/dL) at least 48 hours after diuretic withdrawal and 
the beginning of plasma volume expansion with albumin, and meeting all applicable inclusion 
and exclusion criteria (as outlined in Section 8.3 and Section 8.4) defining the initial diagnosis 
of HRS Type 1.


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Specifically, these criteria are as follows:
1. The subject had rapidly progressive worsening in renal function to a SCr at 
least 2.25 mg/dL and met a trajectory for SCr to double over 2 weeks.
2. The subject had no sustained improvement in renal function (less than 20% decrease in 
SCr and SCr at least 2.25 mg/dL) at least 48 hours after diuretic withdrawal and the 
beginning of plasma volume expansion with albumin.
3. The subject had no sepsis or uncontrolled bacterial infection.
4. If there is documented or suspected infection, the subject has at least 2 days of 
anti-infective therapy.
5. The subject does not have shock.
6. The subject does not have current or recent (within 4 weeks) treatment with or 
exposure to nephrotoxic agents: eg, aminoglycosides, amphotericin, cyclosporine A, 
cisplatin, nonsteroidal anti-inflammatory drugs (NSAIDs: eg, ibuprofen, naproxen, 
diclofenac), significant exposure to radiographic contrast agents (large doses or 
multiple injections of iodinated contrast media, eg, during coronary or abdominal 
angiogram.
Note: Up to 3 doses of an NSAID within the prior month is acceptable.
Note: Use of short-term (less than 2 weeks) oral neomycin for acute encephalopathy is 
acceptable.
7. The subject had no superimposed acute liver injury or exposure to nephrotoxic agents.
8. Proteinuria was less than 500 mg/day.
9. The subject does not have evidence of obstructive uropathy or parenchymal renal 
disease on ultrasound or other imaging.
10. The subject does not have tubular epithelial casts, heme granular casts, hematuria or 
microhematuria (greater than 50 red blood cells per high power field in the absence of 
recent catheterization) on urinalysis.


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Note: Urine sediment examination is required to exclude presence of heme granular 
casts and other clinically significant casts.
The investigator will determine whether the subject has had a recurrence of HRS Type 1. 
If the investigator cannot exclude a recurrence of HRS Type 1, then the subject will be 
considered to have HRS Type 1 recurrence. HRS Type 1 recurrence will be monitored 
as follows: Recurrence of HRS Type 1 during the follow-up period (after discharge or Day 14) 
will be assessed based upon the investigator’s opinion and serious AE data collected up to 
30 days after end of treatment. Following the initial hospital discharge, all re-hospitalizations 
within 30 days after end of treatment (except for planned hospital admissions or procedures 
as described in the protocol) are to be recorded as an SAE. Re-hospitalizations will require 
an investigator assessment and opinion regarding possible recurrence of HRS Type 1.
All available relevant medical records, MedWatch forms, discharge summaries or 
other relevant source documents should be requested and reviewed for all SAEs, including 
all hospitalizations, until 30 days after discontinuation of study drug.
HRS Type 1 recurrence beyond 30 days after end of treatment will be further monitored based 
on requests for retreatment as outlined in Section 10.6 of the protocol.
10.6 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 30% reduction in SCr) who 
develop recurrence of HRS Type 1 during the study or follow-up period may be retreated with 
initially assigned blinded study drug for a maximum of 14 days (from the beginning of the 
retreatment, treatment and study procedures will be identical to the initial therapy). To qualify 
for retreatment, the subject must again meet the study inclusion/exclusion criteria (Section 8.3
and Section 8.4) and the sponsor must be contacted prior to initiation of retreatment. 
Retreatment may occur within 90 days of the subject’s first dose of study drug. Subjects will 
not be re-randomized or re-stratified for the retreatment cycle. Retreated subjects should 
follow the same schedule of assessment as performed in the original treatment period. 
The follow-up schedule will be based upon the original randomization. AEs for retreated 
subjects will be followed for 7 days postdose or discharge, whichever comes first.


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10.7 Concomitant Medication
10.7.1 Recommended Concomitant Medication
10.7.1.1 Albumin
In keeping with standard medical practice and current guidelines, it is strongly recommended 
that albumin be administered to all subjects in both study arms. Albumin doses recommended 
by the IAC following the albumin fluid challenge are 20 g/day to 40 g/day as clinically 
indicated (Salerno et al, 2007; Angeli et al, 2015). It is recommended (if clinically 
appropriate) that the albumin dose is kept constant during the study drug administration 
period. For management of fluid overload, refer to Section 10.3.2.1.1.
10.7.1.2 Prohibited or Discouraged Concomitant Medications
The following medications are prohibited or strongly discouraged during treatment with 
study drug (Table 10–1).
Table 10–1
Prohibited/Discouraged Concomitant Medications
Prohibited Concomitant Medications
Midodrine and other vasopressive drugs including vasopressin, dopamine, dobutamine, norepinephrine.
Prostaglandin analogs (eg, misoprostol).
NSAIDs (eg, ibuprofen, naproxen, diclofenac).
Octreotide.
Discouraged Concomitant Medications
Diuretics are strongly discouraged unless medically required for fluid overload; limited use of diuretics for the 
management of fluid overload as per standard of care may be employed and must be documented
(Section 10.3.2.1.1).
10.8 Treatment Compliance
The treatment, dosage and time of administration for each dose of study drug will be 
documented. A monitor will review subject source documents and drug accountability records 
to assess treatment compliance on an ongoing basis during site visits. 




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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.
11.1.2 Placebo
Matching placebo vials (containing 11 mg mannitol) are identical in appearance to terlipressin 
for injection vials. Each vial will be reconstituted with 5 mL of sterile 0.9% sodium chloride 
solution.
11.2 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) with mannitol or matching placebo (mannitol 
only) will be provided to the sites. Study drug labels will comply with local regulatory 
requirements, including sponsor name and address, protocol number, kit number, 
storage conditions and US Investigational New Drug (IND) caution statement.
11.3 Study Drug Storage and Preparation
Study drug should be stored in a secure location at 2ºC to 8ºC until reconstitution and can be 
stored up to 48 hours at refrigerated storage conditions (2ºC to 8ºC) once reconstituted 
with sterile 0.9% NaCl solution.
Access will be strictly limited to the investigators and their designees.
11.3.1 Reconstitution
Each vial of study drug will be reconstituted with 5 mL of sterile 0.9% sodium chloride 
solution.


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11.3.2 Administration
Reconstituted study drug should be administered via a slow bolus (IV push over 2 minutes). 
See Section 10.1 for details.
After study drug administration the line should be flushed with saline.
11.4 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 named sub-investigators and may not be used for any purpose other than that outlined 
in this protocol.
All unused investigational product will be handled as outlined in the pharmacy manual. 
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.
12 Randomization, Breaking of Blinded Codes
12.1 Randomization and Blinding
12.1.1 Randomization
After the subject has signed the informed consent form (ICF), the investigator or qualified 
designee will complete the subject qualification form, along with the required supportive 
documentation (including SCr values during hospitalization and details of albumin fluid 
challenge administration and diuretic withdrawal), and forward to the sponsor for review 
and approval of subject enrollment.
Randomization will occur only after a diagnosis of HRS Type 1 is established, written 
informed consent has been obtained from the subject or representative, and subject eligibility 
is confirmed. Once a subject is randomized, the subject is considered a study participant. 


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Even if study drug is not subsequently administered, the subject must be followed-up 
for mortality assessments.
A total of 300 subjects are planned to be randomized via an IXRS. Each successive subject
will be assigned a unique identification number. Allocation will be made to 1 of 2 treatment 
groups, ie, terlipressin or placebo, in a 2:1 ratio. Both treatment groups will be studied 
concurrently. Randomization will be stratified by qualifying SCr (less than 3.4 mg/dL or at 
least 3.4 mg/dL) and pre-enrollment LVP (at least one single event of at least 4 L or less than
4 L within 3 to 14 days prior to randomization). Note, subjects with a LVP of at least 4 L are 
excluded if it occurs within 2 days prior to randomization (refer to Section 8.4).
12.1.2 Blinding of Study Drugs 
The active and placebo vials will be labeled with single panel labels comprised of randomized 
identification numbers for each kit to maintain the blinding of the randomized treatments. 
Refer to the pharmacy manual for additional details. 
12.1.3 Unblinding of Treatment Assignment
Unblinding of treatment assignment should be done only in the event that definite knowledge 
of the study drug is essential for the medical treatment of the subject. If possible, 
the investigator should contact the sponsor via the Medical Hotline prior to unblinding. In the 
event that unblinding of an individual subject is required, the investigator will be able to call 
into the IXRS system to unblind a subject. 
The sponsor must be immediately informed of any unblinding and the site must document the 
date and reason for unblinding in writing, as well as the method used.
13 Assessments and Procedures
13.1 Schedule of Assessments and Procedures
Table 13–1 presents the schedule of assessments and procedures to be performed during 
the study.


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Table 13–1
Schedule of Assessments
Study Assessment
Screening 
Period
Pre-
Treatment 
Period
Active Study Period
Follow-up Period
(Days from 1st Dose)c
Baseline 
Assessment
Days 1 to 14a (as applicable)
End of 
Treatment
10
Days 
After 
2nd
SCR ≤ 
1.5 
mg/dL
Day 14 b
or 
Discharge
whichever 
occurs 
first
30
days
± 10 dt
60 
days
± 14 d
90 
days
± 14 d
1
2
3
4
5
6
7
8 to 14a
Diagnosis of HRS 
Type 1
X
Informed consent 
X
Inclusion/exclusion 
criteria
X
X
Verification of 
study qualification
X
Demographics
X
Height and body 
weight
X
Pregnancy testd
X
Prior medications
X
X
Record all pre-
enrollment 
paracentesis prior 
to randomizatione,f
X
X
Baseline SCr prior 
to randomizationf
X
Xg
Randomization
X
Medical historyh
X
X
X








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Study Assessment
Screening 
Period
Pre-
Treatment 
Period
Active Study Period
Follow-up Period
(Days from 1st Dose)c
Baseline 
Assessment
Days 1 to 14a (as applicable)
End of 
Treatment
10
Days 
After 
2nd
SCR ≤ 
1.5 
mg/dL
Day 14 b
or 
Discharge
whichever 
occurs 
first
30
days
± 10 dt
60 
days
± 14 d
90 
days
± 14 d
1
2
3
4
5
6
7
8 to 14a
Record all 
paracentesis events
Record all paracentesis performed after study drug treatment discontinued to 30-day follow-up
Abbreviations: ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen,
CBC = complete blood count, d = day; ECG = electrocardiogram, HRS = hepatorenal syndrome, INR = international normalized ratio, LVP = large volume 
paracentesis, RRT = renal replacement therapy, SCr = serum creatinine, TIPS = transjugular intrahepatic portosystemic shunt.
aSame procedures and assessments on Day 15 if response first occurs on Day 14.
bDay 15 if response first occurs on Day 14.
cFollow-up assessments must also be completed for subjects randomized but not treated with study drug. Study days will be counted from first day of study drug
administration (or from randomization for those subjects who do not receive study drug).
dFemale 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.
eDate and volume of all pre-enrollment paracentesis will be recorded in the eCRF.
Note, subjects with a LVP of at least 4 L are excluded if it occurs within 2 days prior to randomization (refer to Section 8.4).
The investigator must review any paracentesis in the pre-enrollment period and volume status after paracentesis must be considered carefully; as per standard of 
care, adequate replacement of fluid removed with albumin is required. A paracentesis is considered a LVP if at least 4 L of fluid is withdrawn in a given procedure 
(Choi et al, 2005; Kao et al, 1985; Ginès et al, 1987; Pinto et al, 1988; Tito et al, 1990).
fAll pre-enrollment paracentesis and baseline SCr to be recorded before randomization (and required for IXRS).
gThe qualifying SCr value (SCr value at least 48 hours after both diuretic withdrawal and the beginning of albumin fluid challenge) is considered the baseline SCr 
and must be drawn no more than 8 hours prior to start of study drug. The qualifying SCr value must be at least 2.25 mg/dL AND at least 80% of the diagnostic 
(pre-fluid challenge) SCr value. 
No subjects should be randomized unless their SCr has been obtained within 8 hours prior to randomization and start of study drug. 
If there is a delay in subject randomization, then the qualifying/baseline SCr value must be redrawn so that the value is collected within 8 hours prior to 
randomization and start of study drug to verify that the subject still meets the inclusion criterion for baseline SCr.


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hMedical history will include assessment of multi-organ dysfunction at baseline (refer to Section 13.3.5 and the Site/Investigator Study Manual for additional 
details).
iA general 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 physical examination will also include weight and height.
jA 12-lead 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 AE as clinically necessary.
kBoth urine and blood samples for biomarker evaluation will be collected once at baseline; participation in this project will not affect participation in the main 
study.
lTreatment should be continued until 24 hours after 2 consecutive SCr values no more than 1.5 mg/dL have been obtained, OR up to a maximum of 14 days 
(maximum of 15 days if SCr first reaches 1.5 mg/dL on Day 14, when the Day 14 assessments will be performed on Day 15). Window is (± 30 minutes).
mMust be performed at least once daily during active treatment AND until Day 14 (regardless of treatment status) or discharge, whichever occurs first. If SCr and/or 
BUN assessments are performed more than once daily as part of the subject’s medical care, all values are to be recorded on the eCRF. At 30-day follow-up visit, 
collect SCr only (no BUN).
nA blood sample for measurement of SCr must be drawn before discharge. The second verifying sample of SCr no more than 1.5 mg/dL must be taken at least 2 
hours apart and must be consecutive.
oIf a subject meets the primary end point (2 consecutive SCr values of no more than 1.5 mg/dL), the subject’s survival and RRT status must be confirmed 10 days 
after the date of the second SCr. This follow up is required regardless of whether the subject remains hospitalized or has been discharged. If the subject has been 
discharged, follow-up may be by phone. 
pRequired for evaluation of efficacy endpoints.
qVital sign measurements include body temperature, respiratory rate, systolic and diastolic blood pressure, SpO2 (pulse oximetric saturation), and heart rate. 
Time points for systolic and diastolic blood pressure and heart rate: predose and postdose at 5 (±2) min and 2 (±0.25) h for every dose. Time points for 
body temperature, respiratory rate, and pulse oximetric saturation (SpO2): once daily.
rConcomitant medications include IV solutions and blood products.
sAll subjects will be required to come back for Day 30 (± 10) visit and will be contacted by phone for Day 60 (± 14), and Day 90 (± 14) follow up to assess survival, 
RRT, TIPS and liver transplant status. Study days will be counted from first day of study drug administration (or from randomization for those subjects who do not 
receive study drug). All information regarding RRT, TIPS and liver transplant must be collected.
tFor the Day 30 follow-up visit, all subjects are required to provide a blood sample for SCr. The site staff must also collect an updated medical history, vital signs,
concomitant medications, SAE assessment, paracentesis events, RRT, and HRS recurrence.
uThe investigator should perform daily abbreviated physical examinations through the end of treatment to evaluate suspected AEs.


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13.2 Study Assessment Periods
13.2.1 Screening Period
The screening period occurs prior to enrollment and consists of establishing the diagnosis 
of HRS Type 1 as per guidelines and standard medical practice and confirming eligibility 
for study participation. The investigator or qualified designee will complete the subject 
qualification form along with the required supportive documentation (including SCr values 
during hospitalization and details of albumin fluid challenge administration and diuretic 
withdrawal) and forward to the sponsor for review and approval of subject enrollment. 
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.
Subjects screened but not enrolled in the study for any reason should be recorded on 
the screening log. These subjects are not considered study participants and no additional 
follow-up is required.
The investigator must review any paracentesis performed in the pre-enrollment period 
and volume status after paracentesis must be considered carefully; as per standard of care, 
adequate replacement of fluid removed with albumin is required.
13.2.2 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 the beginning of albumin fluid challenge) is considered the baseline SCr and must 
be drawn no more than 8 hours prior to start of study drug. The qualifying SCr value 
must be at least 2.25 mg/dL AND at least 80% of the diagnostic (pre-fluid challenge) 
SCr value. No subjects should be randomized unless their SCr has been obtained 
within 8 hours prior to randomization and start of study drug. If there is a delay 
in subject randomization, then the qualifying/baseline SCr value must be redrawn 
so that the value is collected within 8 hours prior to randomization and start of study 
drug to verify that the subject still meets the inclusion criterion for baseline SCr. 
The qualifying serum creatinine for subjects on prior vasopressors will be taken after 
completion of vasopressor washout. Other baseline assessments must be performed 
no more than 24 hours prior to start of study drug.


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13.2.3 Active Study Period (14 Days)
13.2.3.1 Dosing (Up to 14 Days)
The active study period extends from the initiation of study treatment through Day 14 
(Day 15 as described in Section 10.4) or discharge from the hospital for any reason, 
whichever occurs first. Study drug will be administered as described in Section 10.3. 
Concomitant medications will be collected during this active study period.
See Table 13–1 for the schedule of assessments during the active study period.
13.2.3.2 End of Treatment, Discharge or Day 14
Treatment should be continued until 24 hours after 2 consecutive SCr values no more than 1.5 
mg/dL have been obtained, OR up to a maximum of 14 days (maximum of 15 days if SCr first 
reaches 1.5 mg/dL on Day 14, when the Day 14 assessments will be performed on Day 15).
Following HRS reversal (SCr no more than 1.5 mg/dL), repeat values for SCr must be 
obtained a minimum of 2 hours after the first SCr value. Every effort must be made to collect 
these SCr values.
All information regarding paracentesis events, RRT, TIPS, liver transplant, or open-label 
vasopressor use must be collected.
The subject will be contacted to determine the status of survival without RRT at 10 days 
after the second SCr value no more than 1.5mg/dL is attained.
13.2.4 Follow-up Period
The follow-up period begins after the end of the study treatment and concludes 90 days 
following the start of treatment. Study days will be counted from first day of study drug 
administration (or from randomization for those subjects who do not receive study drug).
All subjects will have a follow up visit on Day 30 (±10 days) while Day 60 (± 14), and 
Day 90 (± 14) follow up can be done via telephone to assess survival, RRT, TIPS, and 
liver transplant status. Study days will be counted from first day of study drug administration 
(or from randomization for those subjects who do not receive study drug). In addition, during 
the Day 30 follow-up, a blood sample will be obtained to assess serum creatinine. A physical 
examination, updated medical history, vital signs, concomitant medications, and SAE 
assessments, paracentesis events, RRT, TIPS, and liver transplant status will also be collected. 


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13.2.4.1 Day 30 Blood Sample Collection
All subjects will be required to provide a blood sample at Day 30 (± 10 days) for analysis 
of SCr. This blood sample can be drawn during the Day 30 visit or by a visiting phlebotomist
if the subject is unable to return to the study site during the Day 30 follow-up window.
Every effort will be made to collect a blood sample at Day 30 for all subjects. No imputation 
will be made for missing values.
13.3 Detail of Baseline Assessments and Procedures
13.3.1 Physical Examination
A complete physical examination, including weight and height, will be conducted at baseline
and at the 30-day follow-up. This will include a general 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, 
neurological, back/spinal, and lymph nodes. This includes worsening of baseline conditions.
In addition, abbreviated physical examinations will be conducted every day during the 14-day 
active study period.
The investigator may perform additional unscheduled examinations to manage or evaluate 
a suspected AE as clinically necessary. The timing and scope of additional unscheduled 
examinations should be determined by the nature and severity of the AE being evaluated. 
In the case of suspected cardiac, intestinal or other ischemia, examination of the subject by 
a physician should be completed on an emergency basis (generally within 15 to 30 minutes). 
For suspected cardiac ischemia, examination should include assessment of vital signs, cardiac 
and pulmonary auscultation, and evaluation of jugular venous pressure by clinical 
examination and other components as determined by the physician's clinical judgment. For 
suspected cardiac ischemia, site must perform an ECG and cardiac enzymes (high sensitivity 
troponin) at the time of assessment and 3 hours later. Subjects with suspected intestinal 
ischemia should undergo careful examination of the abdomen to evaluate for the presence of 
diffuse or focal tenderness, rebound, or acute abdomen with diffuse rigidity. For suspected 
intestinal ischemia, venous (blood) lactate levels must be drawn and compared to baseline 
levels. Further investigations should be carried out based on clinical practice. All subjects 
should have evaluation of the skin of the trunk and extremities for mottling, cyanosis, 
blanching or pallor.
Clinically relevant abnormalities found upon physical examination will be reported 
and analyzed as AEs.


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13.3.2 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 AE 
as clinically necessary. Clinically relevant abnormalities found upon subsequent ECGs will be 
reported and analyzed as AEs. The dates of all subsequent ECGs will be reported on the 
ECG eCRF.
13.3.3 Child-Pugh Scores
Child-Pugh score will be calculated at baseline and entered in the eCRF.
13.3.4 Vital Signs
The proposed post-study-drug time points for collection of systolic/diastolic blood pressure 
and heart rate are based on PK data from the OT-0401 and REVERSE clinical trials. 
The 5 (±2) min and 2 (±0.25) h time points roughly coincide with peak plasma concentrations 
of terlipressin and lysine-vasopressin respectively. Refer to Section 13.4.1.
13.3.5 Assessment of Multi-Organ Dysfunction
With the advancement in intensive care medicine, multiorgan dysfunction syndrome (MODS) 
has replaced the term multiorgan failure since the completion of the REVERSE study. 
According to Al-Khafaji et al, 2015, MODS describes a continuum with incremental degrees 
of physiologic derangements in individual organs; a process rather than a single event. 
Alteration in organ function can vary widely from a mild degree of organ dysfunction 
to completely irreversible organ failure.
Multi-organ failure or dysfunction, a hallmark of acute on chronic liver failure (ACLF), 
common in the study patient population, is defined and quantified by the original CLIF-SOFA 
score or its simplified version Chronic Liver Failure Consortium (CLIF-C) Organ Failure 
score (Arroyo et al, 2015). The scoring system has been developed and validated 
for predicting mortality in patients with ACLF (Jalan et al, 2014).


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Table 13–2
CLIF-C Organ Failure Score
Organ System
Score = 1
Score = 2
Score = 3
Liver, bilirubin (mg/dL)
< 6
6 to ≤12
> 12
Kidney, creatinine (mg/dL)
< 2
2 to < 3.5
≥3.5 or renal replacement
Brain, grade (West-Haven)
0
1 to 2
3 to 4
Coagulation, INR
< 2.0
2.0 to < 2 .5
≥2.5
Circulation, MAP (mm Hg)
≥70
< 70
Vasopressors
Respiratory PaO2/FiO2
or SpO2/FiO2
> 300
> 357
≤300 and > 200
> 214 and ≤ 357
≤200
≤ 214
Source: Arroyo et al, 2015.
Abbreviations: FiO2 = fraction of inspired oxygen; INR = international normalized ratio; MAP = mean arterial 
pressure; PaO2 = partial pressure of arterial oxygen; SpO2 = pulse oximetric oxygen saturation.
During baseline information collection and adverse event reporting, the investigators 
are required to record the actual organs involved in MODS (ie, other organs involved 
in MODS in addition to the baseline hepatic and renal dysfunction, and the severity 
of dysfunction in each organ involved), as well as MODS, itself, as a disease state. The use of 
the simplified version CLIF-C Organ Failure scoring system in documenting MODS organ 
involvement and MODS severity is strongly encouraged. Assessment of MODS will be 
detailed in the Site/Investigator Study Manual.
13.4 Detail of Safety Assessments and Procedures
13.4.1 Vital Signs
Vital sign measurements will be recorded at baseline (with the physical examination), during 
study drug administration, at the end of treatment, and at the Day 30 follow-up.
Systolic and diastolic blood pressure and heart rate will be recorded at baseline, and pre-dose 
and post-dose at 5 minutes (± 2 min) and 2 hours (± 0.25h) for every dose.
Body temperature, respiratory rate, and pulse oximetric saturation (SpO2) will be recorded 
once daily at baseline and during study drug administration.
13.4.2 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 13–3.


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Table 13–3
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.
13.4.3 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 Days 1, 3, 7 and treatment 
termination.
13.4.4 Adverse Events 
All adverse events will be assessed and recorded beginning with study drug administration 
until 7 days after discontinuation of study drug. Adverse events considered serious will be 
assessed and recorded until 30 days after discontinuation of study drug; excluding deaths, 
which will be collected up to 90 days after the first dose of study drug.
Those events that are serious in nature must be reported to the sponsor or its designee 
for safety reporting in an expedited manner (see Section 14 for definitions and reporting 
requirements).
The adverse event collection schedule for the proposed study is adopted from the previous 
clinical studies in the same patient population and for the same drug. The time frames for 
collecting various types of adverse events are defined to focus on the collection of safety 
information pertinent to the study subjects in the proposed study, as the target patient 
population has an extensive health background and existing medical conditions.


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13.4.4.1 Adverse Events of Special Interest
Based on its known mechanism of action and pharmacodynamics effects, terlipressin treated 
subjects may develop central or peripheral ischemia and signs/symptoms of pulmonary 
congestion including bronchospasm, wheezing, etc. To better characterize and help conduct 
a thorough safety analysis for these events, additional information will be requested from 
study sites for subjects who report AEs of select MedDRA preferred terms. These AEs will be 
considered as adverse events of special interest and will include abdominal pain, chest pain or 
dyspnea/wheezing/bronchospasm/pulmonary edema. Sites will be required to complete an 
additional Adverse Events of Special Interest eCRF page and provide information, ie,
characteristics of the event (location, time course, aggravating/relieving factors) as well as 
clinical laboratory and other investigations including radiologic imaging studies conducted in 
relation to the reported event.
13.5 Detail of Laboratory Assessments and Procedures
13.5.1 Local Laboratory at Investigational Site
The laboratory tests specified in this section will be performed in the laboratory at 
the investigational site. All local laboratories must use the isotope dilution mass spectroscopy 
method for the serum creatinine assay. 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 personnel should not draw the blood sample from an existing 
peripheral venous access site or a line used for IV fluid administration. See Site/Investigator’s 
Study Manual for additional details regarding blood drawing technique. 
13.5.1.1 Serum Electrolytes & Biochemistry
The following assessments are required at baseline, then once daily during treatment 
(max 15 days), daily until Day 14 or hospital discharge (whichever occurs first), and at 
the 30-day follow-up visit, regardless of treatment status:

Creatinine level.

Blood urea nitrogen (BUN) (not collected at 30-day follow-up).
If SCr and/or BUN assessments are performed more than once daily as part of the subject’s 
medical care, all values are to be recorded on the eCRF.


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The following assessments are required at baseline, then once daily during treatment 
with study drug (max 15 days):

Sodium.

Potassium.

Chloride.

HCO3.
The following assessments are required at baseline, 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.

Magnesium.

Calcium.

Glucose.
13.5.1.2 Hematology
The following assessments are required at baseline, on Treatment Days 1, 3, 7, and whenever 
possible, at treatment termination:

International normalized ratio (INR).

Complete blood count (CBC) and differential.


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13.5.2 Total Volume of Blood Collected
The total volume of blood collected from each subject over the course of 14 days and end of 
study will be approximately 310 mL.
If subjects agree to participate in the biomarker study an additional blood sample of 
approximately 10 mL will be collected.
13.6 Detail of Efficacy Assessments and Procedures
Serum creatinine must be collected at baseline, once daily during treatment 
(see Section 13.5.1.1); and then once daily (regardless of treatment status) 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 eCRF. Serum creatinine values obtained after RRT, TIPS, liver transplant, or open-label 
vasopressor use will be excluded from the efficacy evaluation. The qualifying 
serum creatinine for subjects on prior vasopressors will be taken after completion 
of vasopressor washout.
13.6.1 Primary Efficacy Variable
Incidence of verified HRS reversal, defined as the percentage of subjects with 2 consecutive 
SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or 
discharge (on treatment defined as up to 24 hours after the final dose of study drug). Subjects
must be alive without RRT for at least 10 days after achieving verified HRS reversal. SCr 
values after RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded from 
primary endpoint analysis. SCr values obtained after midodrine administration will be 
included if midodrine was started on Day 1, was administered for no more than 24 hours, and 
the subject was enrolled on or after 17 August 2018. SCr values will also be included if 
obtained after the administration of a single dose of dobutamine.
SCr data for the primary end point will be collected at least daily until discharge or Day 14. 
The analysis will be based on ITT population. Treatment should be continued until 24 hours 
after a second confirmatory SCr value no more than 1.5 mg/dL has been obtained, OR up to a 
maximum of 14 days (maximum of 15 days if SCr first reaches 1.5 mg/dL on Day 14). The 
date and time of the first observed SCr value of no more than 1.5 mg/dL (HRS reversal) will 
be used for calculating the time window for the verifying SCr value. The next (consecutive)
SCr value of no more than 1.5 mg/dL must occur during the time window in order to have a 
verified HRS reversal. The date RRT is instituted for the first time will be used to determine if 
a subject underwent RRT by Day 30.


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13.6.2 Secondary Efficacy Variables

Incidence of subjects with HRS reversal, defined as the percentage of subjects with 
a SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr 
values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded).

Durability of HRS reversal: the percentage of subjects with HRS reversal without RRT 
to Day 30. HRS reversal is defined as the percentage of subjects with a SCr value no 
more than 1.5 mg/dL while on treatment by Day 14 or discharge (SCr values after 
RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded). RRT is 
defined as any procedure to replace non-endocrine kidney function and includes 
intermittent hemodialysis, ultrafiltration, continuous hemofiltration and hemodialysis, 
peritoneal dialysis and other dialysis and filtration techniques. The date RRT is 
instituted for the first time will be used to determine if a subject underwent RRT by 
Day 30.

Incidence of HRS reversal in the SIRS subgroup: the percentage of SIRS subjects 
with HRS reversal. HRS reversal is defined as the percentage of subjects with a 
SCr value no more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). The SIRS subgroup is defined as any subject with at least 2 of the 
following criteria: WBC less than 4,000 or greater than 12,000 cells/μL; heart rate 
greater than 90 bpm; temperature greater than 38°C or less than 36°C; respiratory rate 
greater than 20/min; HCO3 less than 21 mmol/L; the latter criterion represents an 
approximation of the SIRS criterion PaCO2 of less than 32 mm Hg, derived from 
the observed HCO3 in subjects with HRS in whom a PaCO2 value was available 
(from the TAHRS study) and the calculated HCO3 in subjects with decompensated 
liver disease and PaCO2 of less than 32 mm Hg.
Incidence of verified HRS reversal without HRS recurrence by Day 30 is defined in Section 
10.5. Incidence of verified HRS reversal, defined as the percentage of subjects with 2
consecutive SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment up 
to 24 hours after the final dose of study drug, by Day 14 or discharge. Subjects must be alive 
without RRT for at least 10 days after achieving verified HRS reversal. SCr values after RRT, 
transjugular intrahepatic portosystemic shunt (TIPS), liver transplant, or open-label 
vasopressor use will be excluded from primary end point analysis. SCr values obtained after 
midodrine administration will be included if midodrine was started on Day 1, was 
administered for no more than 24 hours, and the subject was enrolled on or after 17 August


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2018. SCr values will also be included if obtained after the administration of a single dose of 
dobutamine.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14 Adverse Events
The investigator will carefully collect a thorough first dose of study drug baseline information 
and history for each subject upon enrollment. Immediately after a subject receives the first 
dose of study drug, throughout the duration of the study treatment and at each evaluation, 
the investigator will determine whether any AE has occurred. The investigator will also 
instruct the subject to contact the investigator or designee in between study visits 
and throughout the entire study period to report any AEs, until otherwise instructed.


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The investigator will record the nature, causality, severity, treatment and outcome of the AE, 
and will determine whether there is a “reasonable probability” that the study drug treatment 
caused the event.
A data safety monitoring board (DSMB) will review safety data throughout the study,
as outlined in the DSMB charter.
14.1 Definitions
The following definitions are based on:

International Council for Harmonisation (ICH) E2A: International Conference on 
Harmonisation Tripartite Guideline: Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting (1994).

ICH E6: International Council for Harmonisation Tripartite Guideline: Guideline for 
Good Clinical Practice (1996) and Integrated Addendum [E6] (R2) June 2015.

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.
14.1.1 Adverse Event Definition
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product.
14.1.2 Adverse Reaction Definition
An adverse reaction (AR) is defined as any AE caused by a drug.
In the preapproval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered adverse drug 


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reactions. The phrase responses to a medicinal product means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out.
14.1.3 Suspected Adverse Reaction Definition
A suspected adverse reaction is defined as an AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility suggests a causal relationship between 
the study drug treatment and the AE. A suspected adverse reaction implies a lesser degree 
of certainty about causality than an AE.
14.1.3.1 Unexpected Adverse Drug Reaction Definition
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator's Brochure 
for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product).
14.1.4 Unexpected Adverse Event or Unexpected Suspected Adverse 
Reaction Definition
This is an AE 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 AE 
or 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.
14.1.5 Treatment Emergent Adverse Event Definition
An AE for which the start date is on or after the date that the intervention begins.


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14.1.6 Serious Adverse Event Definition
Serious adverse events (SAE) are a subset of adverse events. They 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.
14.1.7 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.
An AE not listed in the IB at the specificity or severity observed is considered unexpected.


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14.1.8 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.
Table 14–1 lists adverse events that are common in this subject population (ie, 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.
Adverse events will be analyzed in both an aggregate and individual manner. However, if it is 
deemed an AR, the sponsor will follow the appropriate procedures to communicate and report 
the AR.


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Table 14–1:
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.
14.1.9 Overdose
Overdose is defined as an accidental or intentional/infusion or excessive dose of a product.
14.2 Collection of Adverse Events/Serious or Unexpected
Any AE occurring prior to signing the ICF should be considered medical history or a 
pre-existing condition and will be collected on the Medical History eCRF. 
All AEs will be assessed and recorded beginning with study drug administration until 7 days 
after discontinuation of study drug and at each evaluation. Adverse events considered serious 
will be assessed and recorded until 30 days after discontinuation of study drug, excluding 
deaths, which will be collected up to 90 days after the first dose of study drug.
The investigator will collect and record all necessary data including investigations that were 
performed for any AE of special interest, ie, an ischemic abdominal event, ischemic cardiac 
event, or bronchospasm-related respiratory event.


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14.2.1 Laboratory Abnormalities
The investigator will review clinical laboratory test results in a timely fashion. Laboratory
abnormalities deemed clinically significant will be recorded as AEs (as defined above) on 
the eCRF. Those events considered serious should be reported to the sponsor as outlined 
in Section 14.3.1.
14.2.2 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 AEs
(eg, re-hospitalization for liver transplantation). However, a baseline condition which 
deteriorates during the clinical study may be considered an AE.
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 serious AE. Re-hospitalizations will require an investigator assessment 
and opinion regarding possible recurrence of HRS Type 1.
14.2.3 Complications of the Disease
Complications frequently associated with HRS Type 1 are expected to occur, but should be 
recorded as an AE or serious AE, as applicable, eg, EVH, hepatic encephalopathy, sepsis, 
pneumonia, urinary tract infection. 
Since HRS Type 1 is the indication under investigation, worsening or aggravation of HRS 
during the active treatment period (including non-response) will NOT be recorded as a serious 
AE unless HRS is the cause of death or results in a subsequent re-hospitalization due 
to suspected recurrence.
14.2.4 Pregnancy
Pregnancy occurring in a subject is NOT considered an AE. However, the investigator must 
collect pregnancy information for subject and/or subject’s partner if the fetus was exposed 
to the study drug.
14.3 Reporting of Adverse Events/Serious or Unexpected Adverse 
Reactions or Adverse Events
14.3.1 Site Reporting to Sponsor
Investigators must report all serious AEs to the sponsor (and applicable IRB) whether or not 
the events are study drug-related or expected. In the event of the death of a subject, 


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the investigator-reported immediate cause of death will be collected and recorded on 
the appropriate eCRF page.
All serious AEs must be reported on a serious AE form and faxed to Mallinckrodt within 
24 hours of an investigator becoming aware of the event: 
Drug and Device Safety and Pharmacovigilance
Fax: 
Email: globalpv@mallinckrodt.com
If no fax confirmation received within 1 business day by the reporter, notify Global 
Pharmacovigilance via phone or email: 800-778-7898 or globalpv@mallinckrodt.com.
The initial serious AE form does not need to be signed by the investigator; however, a signed 
serious AE form is required within 72 hours of faxing to Mallinckrodt. The initial fax by 
the investigator will include 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 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 an AE being classified as serious, the investigator 
should contact the Medical Hotline for this study. The hotline number will be provided in the 
Site/Investigator Study Manual. Refer to Section 10.9.
If there are any specific questions regarding the completion of the serious AE form, 
please contact the site monitor.
14.3.1.1 Overdose
In the event of an overdose, the investigator will be required to report this event to the sponsor 
using a serious AE form, following the SAE reporting timeline. 
14.3.1.2 Pregnancy
In the event of pregnancy, the investigator will be required to report this event to the sponsor 
using the Pregnancy Surveillance Form. Pregnancy should be followed up by the investigator
until delivery and the neonatal outcome must be reported. 


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14.3.2 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.
14.3.3 Sponsor Reporting to Regulatory Authorities and Investigators
All reportable AEs, 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 to the local regulations as described in the safety review plan 
for this study. The reporting of serious AEs 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 6.1 of the protocol that are serious adverse 
events will only be reported in the final clinical study report unless the event was unusual, 
unexpected, and there is evidence suggesting a causal relationship between the study drug 
and the event (eg, 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
This is a randomized, double-blind, placebo-controlled, multicenter study of intravenous 
terlipressin in subjects with HRS Type 1. All subjects who consent to study participation must 
undergo an in-hospital screening/qualification period of no less than 48 hours prior to 
enrollment in order to establish the diagnosis of HRS Type 1. 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. 
Qualified subjects are then randomized in a 2:1 ratio to receive either terlipressin or placebo, 
stratified by qualifying SCr (less than 3.4 mg/dL or at least 3.4 mg/dL) and LVP (at least one 
single event of at least 4 L or less than 4 L within 14 days prior to randomization). A total of 
300 subjects are planned to be enrolled at approximately 70 sites in the United States and 
Canada.
Randomization will be done centrally using an IXRS stratified by qualifying SCr (less 
than 3.4 mg/dL or at least 3.4 mg/dL) and pre-enrollment LVP (at least one single event of at 
least 4 L or less than 4 L within 3 to 14 days prior to randomization). Note, subjects with a 
LVP of at least 4 L are excluded if it occurs within 2 days prior to randomization (refer to 


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Section 8.4). Subjects will receive up to 14 days of study drug (maximum 15 days in pre-
specified cases, see Section 10.2), administered intravenously 4 times per day. 
15.1 Safety Variables 
Safety variables will include the following:

Adverse events.

Serious adverse events, including deaths.

Vital signs (body temperature, blood pressure, heart rate, respiratory rate, and SpO2).

MELD score.

Encephalopathy score.

Laboratory parameters other than SCr.
Adverse events will be collected from the start of study drug administration, during treatment 
and up to 7 days post end of treatment and at each evaluation. Adverse events considered 
serious will be collected up to 30 days after the end of treatment. Deaths up to 90 days will be 
reported as SAEs. Adverse events will be classified by Medical Dictionary for Drug 
Regulatory Activities (MedDRA) system organ class, preferred term, severity, and 
seriousness, as well as by the investigator's assessment of the relationship of the AE to 
the study drug.
15.2 Subject Accounting and Baseline Characteristics
A summary of the study completion status and reasons for discontinuation will be provided 
for each treatment 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.
15.3 Statistical Methodology
15.3.1 Sample Size Calculation
 
 
 
 
 


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Table 15–1:
Sample Size Estimates
 
NOTE: Based on REVERSE, subjects without a known event of pre-enrollment LVP at least 4 L within 2 days 
of randomization and OT-0401 subjects with baseline SCr no more than 7 mg/dL. SCr values were included 
while the subjects were on treatment, up to 24 hours after the final dose of study drug. SCr values were excluded 
after RRT and transplant. If a subject died within 10 days after the reversal, then the subject did not have a 
reversal. If a subject has an RRT by the 30-day follow-up visit, then the subject did not have a reversal. Three 
REVERSE terlipressin subjects who achieved a reversal after the 24 hour window were counted as reversals 
because they would have continued on study drug based on the CONFIRM trial design through the reversal.
With a 2:1 randomization of terlipressin to placebo and an interim analysis after 50% of the 
subjects have completed Day 14 or Discharge, 300 subjects will provide 89.76% power to 
detect a statistically significant difference between the groups, 200 subjects in the terlipressin 
group and 100 subjects in the placebo group.
15.3.2 Interim Analysis
An interim analysis will be performed after 50% of the subjects have completed Day 14 or 
discharge, 150 subjects with approximately 100 in the terlipressin group and 50 in the 
placebo group. An O’Brien-Fleming spending function is used for the interim analysis alpha 
spending. For the interim analysis, the methods described in Section 15.3.6.1 will be followed.
15.3.3 Subject Populations
The populations that will be utilized for this study are defined below.
15.3.3.1 Intention to Treat Population
The intention to treat (ITT) population is defined as all randomized subjects. Treatment 
classification will be based on the randomized treatment. The ITT population defined in this 
way complies with the ITT principle expressed in ICH E9. This will be the primary population 
for analysis of efficacy endpoints.


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15.3.3.2 Safety Population
The safety population is defined as all randomized subjects who received at least 1 dose of 
study drug (terlipressin or placebo). Treatment classification will be based on the actual 
treatment received.
15.3.4 Statistical Analyses
All statistical analyses will be performed and summary tables and data listings will be 
prepared using SAS® software version 9.2 or higher. All statistical tests will be 2-sided with a 
final significance level of 0.05, unless stated otherwise. When the assumptions for the planned 
testing methods do not hold, transformations or nonparametric methods may be employed.
15.3.5 Demographic and Baseline Characteristics
All variables concerning demographic and baseline characteristics will be summarized by 
treatment group and overall to describe the study population. Continuous variables will be 
summarized by N, mean, standard deviation, median, minimum and maximum. Categorical 
variables will be summarized by frequency and percentage of subjects. The summaries will be 
presented for all subjects in the safety and ITT populations.
15.3.6 Efficacy Analyses
All efficacy endpoints will be analyzed primarily in the ITT population. Data from the initial 
treatment course will be utilized in the analyses. Any retreatment courses will be evaluated 
separately.
15.3.6.1 Primary Efficacy Analysis
Incidence of verified HRS reversal is defined as the percentage of subjects with 2 consecutive 
SCr values no more than 1.5 mg/dL at least 2 hours apart, while on treatment by Day 14 or 
discharge (on treatment defined as up to 24 hours after the final dose of study drug). The 
subject must be alive without RRT for at least 10 days after achieving verified HRS reversal. 
SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be excluded 
from primary end point analysis. SCr values obtained after midodrine administration will be 
included if midodrine was started on Day 1, was administered for no more than 24 hours, and 
the subject was enrolled on or after 17 August 2018. SCr values will also be included if 
obtained after the administration of a single dose of dobutamine.
Verified HRS reversal will be summarized by treatment group and analyzed using a Z Score 
based on the upper alpha boundary values for the interim and final analyses. The upper alpha 
boundary value for the interim analysis is 2.79651. At the interim analysis, if the Z score 


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is greater than 2.79651 then the study will stop for early success. If the Z score is no more 
than 2.79651 then the study will continue to the final analysis. The final analysis will be 
successful if the Z score is greater than 1.97743.
Table 15–2 shows the number of subjects with HRS Type 1 reversal that will be needed to 
achieve success at the interim analysis if the estimate of the placebo rate is accurate
(approximately 12.5%).
Table 15–2:
Potential Scenarios for Success at the Interim Analysis with a Placebo 
Rate of Approximately 12.5%
Endpoint
Terlipressin
(N = 100)
n (%)
Placebo
(N = 50)
n (%)
Z Score
Scenario 1
34 (34.0)
6 (12.0)
2.8723
Scenario 2
36 (36.0)
7 (14.0)
2.8098
15.3.6.2 Secondary Efficacy Analyses
A Hochberg procedure for multiple testing and the alpha level corresponding to the Z score of 
the primary efficacy analysis will be used for testing the secondary efficacy analyses at either 
the interim analysis or the final analysis.
If the interim analysis for the primary endpoint is successful then the secondary efficacy 
analyses will be tested against a corresponding p-value of 0.005166 for a Z score of 2.79651. 
The p-values from the 4 secondary efficacy analyses will be ordered from largest to smallest 
and will be compared as in Table 15–3 below:
Table 15–3:
Multiple Testing for the Interim Analysis of the Secondary Efficacy 
Analyses
p-value 
Ordering
α Comparator
If p-value less than α 
then:
If p-value at least
α then:
Largest p-
value
0.005166
= 0.005166/(4 - 4 + 1)
All 4 analyses are 
significant
Test the second 
largest p-value
Second largest 
p-value
0.002583
= 0.005166/(4 - 3 + 1)
The remaining 3 
analyses are significant
Test the third 
largest p-value
Third largest 
p-value
0.001722
= 0.005166/(4 - 2 + 1)
The remaining 2
analyses are significant
Test the smallest 
p-value
Smallest p-
value
0.001292
= 0.005166/(4 - 1 + 1)
This analysis is 
significant
No analyses are 
significant


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If the interim analysis for the primary endpoint is not successful then the study will continue 
onto the final analysis. If the primary efficacy analysis is successful, then the secondary 
efficacy analyses will be tested against a corresponding p-value of 0.047993 for a Z score of 
1.97743, as shown in Table 15–4 below:
Table 15–4:
Multiple Testing for the Final Analysis of the Secondary Efficacy Analyses
p-value 
Ordering
α Comparator
If p-value less than α 
then:
If p-value ≥ α 
then:
Largest p-
value
0.047993
= 0.047993/(4 - 4 + 1)
All 4 analyses are 
significant
Test the second 
largest p-value
Second largest 
p-value
0.023997
= 0. 047993/(4 - 3 + 1)
The remaining 3 
analyses are significant
Test the third 
largest p-value
Third largest 
p-value
0.015998
= 0. 047993/(4 - 2 + 1)
The remaining 2
analyses are significant
Test the smallest 
p-value
Smallest p-
value
0.011998
= 0. 047993/(4 - 1 + 1)
This analysis is 
significant
No analyses are 
significant
The following are the secondary endpoints:

Incidence of subjects with HRS reversal, defined as the percentage of subjects with 
a SCr value not more than 1.5 mg/dL, while on treatment up to 24 hours after the final 
dose of study drug, by Day 14 or discharge. SCr values after RRT, TIPS, liver 
transplant, or open-label vasopressor use will be excluded. HRS reversal will be 
summarized by treatment group and analyzed using the Cochran-Mantel-Haenszel 
(CMH) chi-square test stratified by qualifying SCr (less than 3.4 mg/dL or at least
3.4 mg/dL) and pre-enrollment LVP (at least one single event of at least 4 L or less 
than 4 L within 3 to 14 days prior to randomization). If the proportion of subjects with 
HRS reversal is small (expected cell counts less than 5), an unstratified Chi-square test 
will be used instead of the CMH test. If the number of events per cell is still less than 
5, then a Fisher’s Exact test will be used.

Durability of HRS reversal, defined as the percentage of subjects with HRS reversal
without RRT to Day 30. HRS reversal is defined as the percentage of subjects with 
a SCr value not more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). RRT is defined as any procedure to replace non-endocrine kidney function 
and includes intermittent hemodialysis, ultrafiltration, continuous hemofiltration and 
hemodialysis, peritoneal dialysis and other dialysis and filtration techniques. The date 
RRT is instituted for the first time will be used to determine if a subject underwent 


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RRT by Day 30. This endpoint will be summarized by treatment group and analyzed 
similarly to HRS reversal.

Incidence of HRS reversal in the SIRS subgroup, defined as the percentage of SIRS 
subjects with HRS reversal. HRS reversal is defined as the percentage of subjects 
with a SCr value not more than 1.5 mg/dL while on treatment by Day 14 or discharge 
(SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use will be 
excluded). This endpoint will be summarized by treatment group and analyzed 
similarly to HRS reversal. The SIRS subgroup is defined as any subject with at least
2 of the following criteria: WBC less than 4,000 or greater than 12,000 cells/μL; 
HR greater than 90 bpm; temperature greater than 38°C or less than 36°C; respiratory 
rate of greater than 20/min; HCO3 less than 21 mmol/L; the latter criterion represents 
an approximation of the SIRS criterion PaCO2 of less than 32 mm Hg, derived from 
the observed HCO3 in subjects with HRS in whom a PaCO2 value was available 
(from the TAHRS study) and the calculated HCO3 in subjects with decompensated 
liver disease and PaCO2 of less than 32 mm Hg.
Incidence of verified HRS reversal without HRS recurrence by Day 30. HRS Type 1
recurrence is defined in Section 10.5. Incidence of verified HRS reversal, defined as the 
percentage of subjects with 2 consecutive SCr values no more than 1.5 mg/dL at least 2 hours 
apart, while on treatment up to 24 hours after the final dose of study drug, by Day 14 or 
discharge. Subjects must be alive without RRT for at least 10 days after achieving verified 
HRS reversal. SCr values after RRT, transjugular intrahepatic portosystemic shunt (TIPS), 
liver transplant, or open-label vasopressor use will be excluded from primary end point 
analysis. SCr values obtained after midodrine administration will be included if midodrine 
was started on Day 1, was administered for no more than 24 hours, and the subject was 
enrolled on or after 17 August 2018. SCr values will also be included if obtained after the 
administration of a single dose of dobutamine. This endpoint will be summarized by treatment 
group and analyzed similarly to HRS reversal.
 
 
 
 
 
 
 






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15.3.6.4 Safety Analyses
Continuous variables will be summarized by N, mean, standard deviation, median, minimum 
and maximum. These include:

Change from baseline in MELD score.

Change from baseline in encephalopathy score.

Change from baseline in BUN.

Daily values, daily averages, and change from baseline of vital signs of body 
temperature, systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate, SpO2, and MAP.

Change from baseline in laboratory values.
Laboratory shift tables will be created.
Adverse events will be summarized by frequency and percentage of subjects.
15.3.7 Definition of Baseline
For evaluations that are collected at multiple occasions prior to initiation of study drug, 
the latest non-missing evaluation will be considered the "Baseline" evaluation for analysis. 
In most cases baseline will be defined as Day 0 of the study period, but a prestudy period 
value will be utilized instead if the Day 0 value is missing. Study Day 1 will be defined as 
the first calendar day that study drug is administered during the study period.
15.3.8 Missing Data
Unless otherwise stated, no imputation will be made for missing data.
15.3.9 Procedure for Amendments to the Statistical Plan
It is intended that all statistical analyses specified in this protocol will be performed. 
However, study observations or analysis results may suggest the need for additional, 
or changes to the statistical analyses of the collected study data. In either case, deviations 
(subtractions or additions) from the planned statistical analysis will be fully described in 
the final clinical study report. The statistical plan can be amended and the reasons 
for amendments will be documented. Furthermore, any additional analyses performed beyond 
those specified in this protocol will be descriptive in nature and will not include hypothesis 
testing for the purposes of inferential conclusions.


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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 eCRFs must be fully 
completed and include all required data for all subjects enrolled. All eCRF data must be 
submitted to the sponsor throughout and at the end of the study.
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 
(eg, 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 eCRF data are stored in a database and processed electronically. The sponsor’s medical 
monitor reviews the data for safety information. The data are reviewed for completeness, 
and logical consistency. Automated validation programs will identify missing data, out-of-
range data, and other data inconsistencies. Requests for data clarification are forwarded to 
the study site for resolution.


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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
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any subjects in this study, sponsor personnel and the investigator 
review the protocol, the IB, the eCRFs and instructions for their completion, the procedure for 
obtaining informed consent, and the procedure for reporting AEs and SAEs. A qualified 
representative of the sponsor will monitor the conduct of the study. During these study site 
visits, information recorded in the eCRFs will be verified against source documents.
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 in ensuring that the study adheres to the protocol and GCP requirements.
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.


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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 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.
18.1.1 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 


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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.
18.2 Informed Consent
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.
18.3 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 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.


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18.4 Biological Samples
Blood samples will be used only for scientific research. Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the subject’s identity. 
After the study ends, the clinical laboratory samples will be destroyed. Bioanalytical samples 
(ie, plasma, whole blood, urine) for measurement of drug/metabolite content will be retained 
at a biological storage facility. The subject may request that his or her samples, if still 
identifiable, be destroyed at any time; however, any data already collected from that sample 
will still be used for this research.
18.5 Subject Injury
In general, subject to specific provisions in the clinical trial agreement, if a subject is injured 
as a direct result of an investigational medicinal product, the sponsor will pay for reasonable 
and necessary medical treatment for the injury, to the extent that such expenses are not 
covered by the subject’s medical insurance, a government program, or other responsible third 
party. If laws or regulations of the locality in which the study is taking place require additional 
payment of expenses, the sponsor shall comply with such laws or regulations. 
Where applicable, the sponsor has taken specific national insurance.
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.
18.6.1 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 


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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.

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 Mallinckrodt 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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20 References
Al-Khafaji, A.H.; Sharma, S; Eschun, G. Multiple Organ Dysfunction Syndrome in Sepsis. 
Medscape. March 2015 (http://emedicine.medscape.com/article/169640-overview).
Angeli, P.; Ginès, P.; Wong, F.; Bernardi, M.; Boyer, T. D.; Gerbes, A.; et al. Diagnosis and 
Management of Acute Kidney Injury in Patients with Cirrhosis: Revised Consensus 
Recommendations of the International Club of Ascites. J Hepatol. 2015, 62, 968-974.
Arroyo, V.; Ginès, P.; Gerbes, A.L.; Dudley, F. J.; Gentilini, P.; Laffi, G.; et al. Definition and 
Diagnostic Criteria of Refractory Ascites and Hepatorenal Syndrome in Cirrhosis. 
International Ascites Club. Hepatology. 1996, 23, 164-176.
Arroyo, V.; Jiménez, W. Complications of Cirrhosis. II. Renal and Circulatory Dysfunction. 
Lights and Shadows in an Important Clinical Problem. J Hepatol. 2000, 32, 157-170.
Arroyo, V.; Fernandez, J.; Gines, P. Pathogenesis and Treatment of Hepatorenal Syndrome. 
Seminars in Liver Disease. 2008, 29, 81-95.
Arroyo, V.; Moreau, R.; Jalan, R.; et al. On Behalf of the Investigators of the EASL-CLIF 
Consortium CANONIC Study. Acute-on-chronic Liver Failure: A New Syndrome That Will 
Re-classify Cirrhosis. J Hepatol. 2015, 62, S131–S143.
Cavallin, M.; Kamath, P. S.; Merli, M.; Fasolato, S.; Toniutto, P.; Salerno, F.; et al. 
Terlipressin Plus Albumin Versus Midodrine and Octreotide Plus Albumin in the Treatment of 
Hepatorenal Syndrome: A Randomized Trial. Hepatology. 2015, 62, 567-574.
Centers for Disease Control and Prevention, National Center for Health Statistics, Death: 
Final data for 2013, http://www.cdc.gov/nchs/fastats/liver-disease.htm, last updated 6 
February 2015.
Chalasani, N. P.; Hayashi, P. H.; Bonkovsky, H. L.; Navarro, V. J.; Lee, W. M.; Fontana, R. J.; 
et al. ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced 
Liver Injury. Am J Gastroenterol. 2014, 109, 950-966.
Choi, C. H.; Ahn, S.H.; Kim, D. Y.; Lee, S.K.; Park, J. Y.; Chon, C.Y.; et al. Long-term 
Clinical Outcome of Large Volume Paracentesis With Intravenous Albumin in Patients With 
Spontaneous Bacterial Peritonitis: A Randomized Prospective Study. J Gastroenterol Hepatol.
2005, 20, 1215-1222.


Terlipressin
Protocol MNK19013058
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de Franchis, R. Evolving Consensus in Portal Hypertension. Report of the Baveno IV 
Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.
J Hepatol. 2005, 43, 167-176. Corrigendum in J Hepatol. 2005, 43, 547.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the 
Management of Ascites, Spontaneous Bacterial Peritonitis, and Hepatorenal Syndrome in 
Cirrhosis. J Hepatol. 2010, 53, 397-417.
Ferenci, P.; Lockwood, A.; Mullen, K.; Weissenborn, K.; Blei, A. Hepatic Encephalopathy-
Definition, Nomenclature, Diagnosis, and Quantification: Final Report of the Working Party 
at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002, 35, 716-
721.
Ginés, P.; Arroyo, V.; Quintero, E.; Planas, R.; Bory, F.; Cabrera, J.; et al. Comparison of 
Paracentesis and Diuretics in the Treatment of Cirrhotics With Tense Ascites. Results of a 
Randomized Study. Gastroenterology. 1987, 93, 234-241.
Ginès, P.; Guevara, M.; Arroyo, V.; Rodés, J. Hepatorenal Syndrome. Lancet. 2003, 29, 
362(9398), 1819-1827.
Hochberg, Y. A Sharper Bonferroni Procedure for Multiple Tests of Significance. Biometrika. 
1988, 75, 800-802.
Ioannou, G. N.; Doust, J.; Rockey, D. C. Systematic Review: Terlipressin in Acute 
Oesophageal Variceal Haemorrhage. Aliment Pharmacol Ther. 2003, 17, 53-64.
Jalan, R.; Saliba, F.; Pavesi, M.; Amoros, A.; Moreau, R.; Gines, P.; et al. Development and 
Validation of a Prognostic Score to Predict Mortality in Patients With Acute-on-chronic Liver 
Failure. J Hepatol. 2014, 61, 1038-1047.
Kao, H. W.; Rakov, N. E.; Savage, E.; Reynolds, T. B. The Effect of Large Volume 
Paracentesis on Plasma Volume - a Cause of Hypovolemia? Hepatology. 1985, 5, 403-407.
Kiszka-Kanowitz, M.; Henriksen, J.H.; Hansen, E. F.; Møller, S.; Bendtsen, F. Effect of 
Terlipressin on Blood Volume Distribution in Patients With Cirrhosis. Scand J Gastroenterol.
2004, 39, 486-492.
Ma, J.; Ward, E.; Siegel, R.; Jemal, A. Temporal Trends in Mortality in the United States, 
1969-2013, JAMA. 2015, 314, 1731-1739.
Mallinckrodt, Inc., Terlipressin; Investigator’s Brochure: Hazelwood, MO, v7.1, May 2016.


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Marrero, J. A. Hepatorenal Syndrome. NORD Guide to Rare Disorders. Lippincott Williams 
& Wilkins: Philadelphia, PA, 2003; pp 344-345.
Muir, A.J. Medical Encyclopedia: Hepatorenal Syndrome. Medline Plus. Reprinted from: 
www.nlm.nih.gov/medlineplus/print/ency/article/000489.htm. April 25, 2002.
Murkerjee, S.; Roy, H.; Zetterman, R. K. Hepatorenal Syndrome. eMedicine. Reprinted from: 
www.emedicine.com/med/topic/1001.htm. July 12, 2002.
National Hospital Discharge Survey 2005. Annual Summary with Detailed Diagnosis and 
Procedure Data. Vital and Health Statistics; Series 13, Number 165. Table 45, Number of first-
listed diagnoses from short-stay hospitals, page 69 (ICD-9 code 571, cirrhosis); Table 47, 
Number of all-listed discharges from short-stay hospitals, page 138 (ICD-9 code 572.4, HRS). 
December 2007.
Pinto, P. C.; Amerian, J.; Reynolds, T. B. Large-Volume Paracentesis in Nonedematous 
Patients With Tense Ascites: Its Effect on Intravascular Volume. Hepatology. 1988, 8, 
207-210.
Rodriguez, E; Elia, C; Sola, E; Barreto, R; Graupera, I; Andrealli, A; et al. Terlipressin and 
Albumin for Type-1 Hepatorenal Syndrome Associated with Sepsis. J Hepatol. 2014, 60, 955-
961.
Rozov-Ung, I.; Panesar, M. The Use of Terlipressin in Hepatorenal Syndrome. Dialysis and 
Transplantation. 2010, Oct, 421-425.
Runyon, B. A. L. AASLD. Introduction to the Revised American Association for the Study of 
Liver Diseases Practice Guideline Management of Adult Patients With Ascites Due to 
Cirrhosis. Hepatology. 2013, 57, 1651-1653.
Salerno, F.; Gerbes, A.; Ginès, P.; Wong, F.; Arroyo, V. Diagnosis, Prevention and Treatment 
of Hepatorenal Syndrome in Cirrhosis. A Consensus Workshop of The International Ascites 
Club. Gut. 2007, 56, 1310-1318.
Titó, L.; Ginès, P.; Arroyo, V.; Planas, R.; Panés, J.; Rimola, A.; et al. Total Paracentesis 
Associated With Intravenous Albumin Management of Patients With Cirrhosis and Ascites. 
Gastroenterology. 1990, 98, 146-151.


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21 Appendix A: Study IK-4001-HRS-301: Nomogram to Determine the 
Criterion for SCR Doubling Over a 2-Week Period
The nomogram is intended for use in situations when the SCr value has increased rapidly 
over a shorter period of time but has not yet doubled within 2 weeks.
To fulfill inclusion criterion #4, subjects must have a rapidly progressive worsening in renal 
function to a SCr at least 2.25 mg/dL (meeting a trajectory for SCr to double over 2 weeks).
The qualifying serum creatinine for subjects on prior vasopressors will be taken after 
completion of vasopressor washout.
For ease of calculation, these trajectories are estimated by relating a certain required “fold 
increase in SCr” to the elapsed time in days between 2 measured values (see Figure 3
and Table 21–1); greater proportional increases in SCr are required for observations of shorter 
duration. As noted in the nomogram, a 1.5-fold increase between the SCr values must be 
achieved within 4 days of observation. The required fold increase in SCr between SCr values 
progressively rises from 4 days of observation up to a 2 fold increase by 14 days observation.
Figure 3:
Nomogram to Determine the Criterion for SCr Doubling Over a 2-Week
Period


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Table 21–1:
Elapsed Time in Days and Required Fold Increase in SCr
Elapsed Time (days)
Fold Increase in Creatinine
4
1.50
5
1.54
6
1.58
7
1.62
8
1.67
9
1.71
10
1.76
11
1.82
12
1.88
13
1.94
14
2.00


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22 Appendix B: CLIF-SOFA Score
Table 22-1
CLIF-SOFA Score
Reference: Rodriguez, E; Elia, C; Sola, E; Barreto, R; Graupera, I; Andrealli, A; et al. Terlipressin and Albumin 
for Type-1 Hepatorenal Syndrome Associated with Sepsis. J Hepatol. 2014, 60, 955-961, supplementary 
Table 2.