Conditions: Decompensated Cirrhosis and Ascites
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 410
Healthy volunteers: no

Brief summary:
This is a phase 3, multicenter, randomized, controlled, parallel-group, and open-label clinical study to evaluate the efficacy of standard medical treatment (SMT) + Albutein 20% administration versus SMT alone in participants with decompensated cirrhosis and ascites. The study population will consist of participants being discharged after hospitalization for acute decompensation of liver cirrhosis with ascites (or with prior history of ascites requiring diuretic therapy) with or without acute-on-chronic liver failure (ACLF) at admission or during hospitalization but without ACLF at discharge.

Detailed description:

Arms:
arm 1: Participants received Albutein 20%, at a dose of 1.5 grams/kilograms (g/kg), based on their body weight (maximum 100 grams per participant), as an intravenous (IV) infusion on Day 1, followed by the same dose of Albutein 20% every 10±2 days along with standard medical treatment (SMT) administered as per institution standards for the management of decompensated cirrhosis up to 12 months. arm 2: Participants received SMT up to 12 months as per institution standards for the management of decompensated cirrhosis.

Interventions: intervention 1: Albutein 20% intervention 2: SMT
Intervention descriptions: intervention 1: Injectable solution intervention 2: Participants received SMT according to institution standards for the management of decompensated cirrhosis.

Protocol document:
Prot_000.pdf: 
Official Title: 
Prevention of Mortality With Long-Term Administration of Human 
Albumin in Subjects With Decompensated Cirrhosis and Ascites 
NCT Number: 
NCT03451292 
Document Date: 
Protocol, Version 6: 24-Sep-2020 


Signed by:  
Reason:  
Date / Time (UTC):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Completion of the signature block below signifies the review and approval of this document.  
24-Sep-2020 06:32:42
Owner
23-Sep-2020 18:07:40
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Clinical Study Protocol
Protocol Title:
Prevention of Mortality with Long-Term 
Administration of Human Albumin in Subjects with 
Decompensated Cirrhosis and Ascites
Investigational Product:
Albutein® 20%
Sponsor’s Name and Address:
Instituto Grifols, S.A.
Can Guasch, 2
08150, Parets del Vallès
Barcelona
Spain
Additional Identifier:
PRECIOSA
EUDRACT Number:
2016-001789-28
IND/CTA Number:
17549
Development Phase:
3
Sponsor Signatories:
MD
Grifols Therapeutics LLC
Email address:
Telephone number:
Grifols Bioscience Industrial Group
Email address:
Telephone number:
See Sponsor Signatures on the cover page of the 
protocol
Confidentiality Statement:
The following confidential information is the property of Grifols. As long 
as the information contained in this protocol has not been published, it 
may only be used after permission has been obtained from Grifols. It is 
not possible to make reproductions of all or sections of this protocol. 
Commercial use of the information is only possible with the permission of 
the proprietor and is subject to a license fee.
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Summary of Changes for Amendment 5
Protocol Version
Date of Approval/Effective Date
6
Amendment 5 + Integrated Protocol
See Left Margin
5
Amendment 4 + Integrated Protocol
11 Mar 2020
4.0
Amendment 3 + Integrated Protocol
19 Dec 2018
3.0
Amendment 2 + Integrated Protocol
05 Jul 2018
2.0
Amendment 1 + Integrated Protocol
13 Oct 2017
1.0
Original
07 Jul 2017
Amendment 4
The protocol for IG1601 (Version 5, dated 11 Mar 2020) has been amended and reissued as 
Protocol Amendment 5, Version 6. See Appendix 11 for a summary of changes for 
Amendment 5.
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Investigator Signature Page
The undersigned confirms that he/she agrees to conduct the study under the conditions 
described in this protocol and comply with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) and all applicable regulatory requirements:
___________________________________
______________________
INVESTIGATOR NAME (Please Print)
LOCATION
___________________________________
______________________
INVESTIGATOR SIGNATURE
DATE
Title of the Investigator:
Address of the Site:
Telephone Number:
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PROTOCOL SYNOPSIS
Title of Study:
Prevention of Mortality with Long-Term Administration of Human Albumin in Subjects with 
Decompensated Cirrhosis and Ascites
Study Number: IG1601
Phase: 3
Study Objectives:
Primary Efficacy Objective 
•
To evaluate the effect of standard medical treatment (SMT) plus long-term Albutein 20% 
(SMT + Albutein 20%) administration on 1-year transplant-free survival versus SMT 
alone. 
Secondary Efficacy Objectives 
•
To evaluate the effects of SMT + Albutein 20% administration on 3- and 6-month 
transplant-free and overall survival versus SMT alone
•
To evaluate the effects of SMT + Albutein 20% administration on 1-year overall survival 
versus SMT alone
•
To evaluate the total number of paracenteses and the incidence of refractory ascites 
according the International Club of Ascites (ICA) criteria 
Exploratory Objectives
The effects of SMT + Albutein 20% administration versus SMT alone on the following 
parameters will be evaluated:
•
3-, 6-, and 12-month incidence of acute-on-chronic liver failure (ACLF) according to the 
European Association for the Study of Liver- Chronic Liver Failure (EASL-CLIF) 
Consortium definition
•
Incidence of individual organ failures: liver, renal, cerebral, coagulation, respiration, and 
circulation as defined by the CLIF-Consortium Organ Failure (CLIF-C OF) score and the 
total CLIf-C OF score
•
Readmissions to the hospital due to an acute complication of cirrhosis
•
Admissions to intensive care units (ICU)
•
Incidence of disease-related complications (see Section 8.3.10)
•
Serum albumin concentration and albumin functional capacity in serum (albumin binding 
capacity)
•
Incidence of transjugular intrahepatic portosystemic shunt (TIPS) insertion for refractory 
ascites
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•
CLIF-C Acute-on-chronic liver failure (CLIF-C ACLF) score, CLIF-C Acute 
Decompensation (CLIF-C AD) score, Model for End-stage Liver Disease (MELD) score, 
and Child-Pugh score
•
Subject’s quality of life according to the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
health questionnaire.
Safety Objective
•
To determine the safety and tolerability profile of SMT + Albutein 20% administration in 
subjects with decompensated cirrhosis and ascites
Overall Study Design and Description:
Approximately 410 subjects with decompensated cirrhosis and ascites will be included in this 
study after obtaining written informed consent. The study population will consist of subjects 
who have been hospitalized for acute decompensation of liver cirrhosis with ascites (or with 
prior history of ascites requiring diuretic therapy) with or without ACLF at admission or 
during hospitalization, but without ACLF at Screening. 
There will be a screening period for enrollment of each hospitalized subject in the study. 
Screening should occur while the subject is hospitalized. Randomization must occur within 
72 hours of screening, and it can occur while the subject is hospitalized or after discharge 
from the hospital. The first dose of Albutein 20%  is administred on the same day as 
randomization.  
Randomization of subjects will be stratified by region (Europe or North America [NA]) and 
by whether or not subjects have been previously hospitalized for acute decompensation of 
liver cirrhosis prior to the most recent hospitalization for acute decompensation of liver 
cirrhosis with ascites as required by Inclusion Criterion #3v4 (below). Within each stratum 
(ie, each unique combination of region and history of hospitalization for acute 
decompensation of liver cirrhosis), eligible subjects will be randomized in a 1:1 ratio into 
1 of 2 treatment groups:
•
SMT + Albutein 20% 
•
SMT (control group)
SMT + Albutein 20% Treatment Group
Approximately 205 subjects will be randomized to the SMT + Albutein 20% treatment 
group. Screening should occur while the subject is hospitalized. Randomization must occur 
within 72 hours of screening, and it can occur while the subject is hospitalized or after 
discharge from the hospital. The first dose of Albutein 20%  is administred on the same day 
as randomization  at the dose of 1.5 g/kg body weight (maximum 100 grams per subject). 
Thereafter, subjects will receive Albutein 20% infusions at the dose of 1.5 g/kg body weight 
(maximum 100 grams per subject) every 10 ± 2 days for the rest of the study (up to a 
maximum of 12 months). Subjects in this treatment group will also receive SMT.
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SMT Group
Approximately 205 subjects will be randomized to the control group and receive SMT. 
Screening should occur while the subject is hospitalized. Randomization must occur within 
72 hours of screening, and it can occur while the subject is hospitalized or after discharge
from the hospital. Following randomization, subjects randomized to this group will receive 
SMT, which will be administered per institution standards.
The treatment period in the study will be up to 12 months. Subjects in both treatment groups 
(SMT + Albutein 20% and SMT alone) will be followed for up to 12 months. During the 
entire study, the safety of both treatment groups will be monitored by a Data Safety 
Monitoring Board.
Primary Endpoint and Secondary Endpoints:
The primary efficacy endpoint is to compare the 1-year transplant-free survival in the intent-
to-treat (ITT) population between the SMT + Albutein 20% treatment group and the SMT 
alone group.
The secondary efficacy endpoints are to assess the effects of SMT + Albutein 20% treatment 
versus SMT alone on: (1) 3- and 6-month transplant-free and overall survival, (2) 1-year 
overall survival, and (3) total number of paracenteses and the incidence of refractory ascites.
Number of Subjects Planned:
Approximately 410 subjects will be enrolled in this study. These subjects will be randomized 
in a 1:1 ratio into the SMT + Albutein 20% treatment group or the SMT control group.
Study Centers Planned:
Approximately 40 study centers in the United States and Europe will participate in this study.
Diagnosis and Main Criteria for Inclusion:
Note that any criterion number containing v5 was modified in the protocol (eg, 2v5 indicates 
that the original criterion #2 was last modified in Protocol Version 5).
Inclusion Criteria:
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study.
1.
Male or female subject ≥18 years of age.
2v5.
Subjects with diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic,      
and ultrasonographic features or on histology).
3v5.
Subjects who have been hospitalized for acute decompensation of liver cirrhosis with 
ascites (or with prior history of ascites requiring diuretic therapy) with or without 
ACLF at admission or during hospitalization but without ACLF at Screening.
4v5.
This criterion has been removed in protocol Version 5.
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5.
In subjects with cirrhosis due to hepatitis B virus, decompensation must occur in the 
setting of continuous (no less than 3 months) appropriate antiviral therapy.
6.
In subjects with cirrhosis due to hepatitis C virus, only decompensated patients who 
will not receive antiviral therapy during the study period will be included (Subjects 
receiving antiviral therapy within 14 days prior to enrollment cannot be included in 
the study).
7.
In subjects with cirrhosis due to autoimmune hepatitis, decompensation must occur 
in the setting of continuous immunosuppressive therapy.
8.
Subjects must be willing and able to provide written informed consent or have an 
authorized representative able to provide written informed consent on behalf of the 
subject in accordance with local law and institutional policy.
9.
CLIF-C AD score > 50 points at screening.
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1v5.
Subjects with ACLF at Screening
2v5.
Subjects with type 1 HRS currently on treatment with vasoconstrictors or 
hemodialysis. 
3.
Subjects with TIPS or other surgical porto-caval shunts.
4v5.
Subjects with refractory ascites as defined by ICA criteria without any other event of 
acute decompensation.
5v5.
This criterion has been removed in protocol Version 5.
6v5.
Subjects receiving dual anti-platelet therapy or anti-coagulant therapy  (exception: 
DVT prophylaxis).
7v5.
Subjects with ongoing endoscopic eradication of esophageal varices with ≤2    
endoscopic sessions completed before screening.
8.
This criterion has been removed from protocol Version 5 
9.
Subjects with evidence of current locally advanced or metastatic malignancy. Subjects 
with hepatocellular carcinoma within the Milan criteria (1 nodule ≤5 cm or 3 nodules 
≤3 cm), non-melanocytic skin cancer, or controlled breast or prostate cancer can be 
included.
10v4. Subjects with acute or chronic heart failure (New York Heart Association [NYHA]).
11.
Subjects with severe (grade III or IV) pulmonary disease (Global Obstructive Lung 
Disease [GOLD]).
12v5. Subjects with nephropathy with renal failure with serum creatinine  >2 mg/dL or 
systemic hypertension.
13v5. This criterion has been removed from protocol Version 5. 
14.
Subjects with severe psychiatric disorders.
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15.
Subjects with a known infection with human immunodeficiency virus (HIV) or have 
clinical signs and symptoms consistent with current HIV infection.
16.
Females who are pregnant, breastfeeding, or if of childbearing potential, unwilling to 
practice effective methods of contraception (oral, injectable, or implanted hormonal 
methods of contraception, placement of an intrauterine device or intrauterine system, 
condom, or occlusive cap with spermicidal foam/gel/cream/suppository, male 
sterilization, or true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods], declaration of abstinence for the duration of the clinical study, 
and withdrawal are not acceptable methods of contraception).
17.
Subjects with previous liver transplantation.
18.
Subjects with known or suspected hypersensitivity to albumin.
19.
Subjects participating in another clinical study within 3 months prior to screening.
20v4. Subjects with active drug addiction (exceptions: active alcoholism or marijuana).
21.
In the opinion of the investigator, the subject may have compliance problems with the 
protocol and the procedures of the protocol.
22.
Subjects with ongoing or recent variceal bleeding (subjects can be included 2 weeks 
after hemorrhagic episode). 
23.
Subjects with septic shock at screening. 
24.
Subjects with ongoing SBP infection (subjects can be included upon resolution).
25.
Subjects with current infection of COVID19, those who are less than 14 days post 
recovery, or those who have clinical signs and symptoms consistent with COVID19
infection.
Investigational Product, Dose and Mode of Administration
Albutein 20% is the investigational product (IP).
Following randomization, subjects will receive the first Albutein 20% infusion at the dose of 
1.5 g/kg body weight (maximum 100 grams per subject). Thereafter, subjects will receive 
Albutein 20% infusions at the dose of 1.5 g/kg body weight (maximum 100 grams per 
subject) every 10 ± 2 days for the rest of the study (up to a maximum of 12 months). Subjects 
in this treatment group will also receive SMT.
Duration of Treatment:
Subject participation is up to 12 months after the screening period.
Reference Therapy, Dose, and Mode of Administration
Control Group: SMT per institution standards
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Key Study Variables:
Primary Efficacy Variable:
•
Time to liver transplantation or death through 1 year after randomization.
Secondary Efficacy Variables:
•
Time to liver transplantation or death through 3 and 6 months after randomization, and 
time to death through 3 and 6 months after randomization 
•
Time to death through 1 year after randomization
•
Total number of paracenteses and incidence of refractory ascites according the ICA
criteria
Exploratory Efficacy Variables
•
Incidence of ACLF (3, 6, and 12 months)
•
Organ function subscores (liver, renal, cerebral, coagulation, circulation, and respiration), 
according to the CLIF-C OF score and the total CLIF-C OF score
•
Number and length of hospital readmission for an acute complication of cirrhosis 
•
Number and length of ICU admission
•
Incidence of disease-related complications (see Section 8.3.10)
•
Serum albumin concentration and albumin functional capacity in serum (albumin binding 
capacity)
•
Incidence of insertion of TIPS for refractory ascites
•
CLIF-C ACLF score, CLIF-C AD score, MELD score, and Child Pugh score
•
Quality of life: EQ-5D-5L health questionnaire
Safety Variables:
•
The number of suspected adverse drug reactions (ADRs), including adverse reactions, 
and incidence rate of subjects with suspected ADRs during the treatment period and 
within 72 hours after Albutein 20% infusion completion (or after Albutein 20% infusion 
stops) will be considered as the main safety variables. The number and incidence rate of 
overall AEs and serious adverse events, as well as deaths and discontinuations due to 
AEs will be also collected and analyzed. 
•
Vital signs will be recorded at each scheduled visit and in particular before and after each 
Albutein 20% infusion. 
•
Clinical laboratory test parameters (blood cell counts, platelet count, international 
normalized ratio, fibrinogen, etc.) will be assessed according to the study schedule.
•
Physical examinations will be assessed according to the study schedule.
•
According to the investigator’s assessment, all clinically relevant changes in vital 
function and laboratory testing parameters findings will be considered AEs.
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Study Assessments and Procedures:
Screening Visit:
Following signature of the informed consent form (ICF), subjects will be screened while 
hospitalized. Local laboratory testing will be used for screening to determine inclusion and 
exclusion criteria have been met, prior to initiating treatment. Local laboratory tests 
performed for screening purpose only will be kept in subjects’ source documents but will not 
be entered into the eCRF. In addition, Central Laboratory testing will be collected for the 
purpose of safety assessment and data analyses.
•
Review of the inclusion and exclusion criteria to determine subject’s eligibility
•
Documentation of demographics: date of birth, gender, race, and ethnic origin
•
Documentation of medical history, including etiology of cirrhosis, history, and significant 
concomitant disease conditions
•
Urine pregnancy test (human chorionic gonadotrophin-based urine assay) for women of 
childbearing potential (to be performed locally at the investigative study center)
•
Full physical examination (excluding breast and genitourinary examination)
•
Ascites assessment according to the ICA criteria
•
Hepatic encephalopathy evaluation
•
Hemodynamics assessment (mean arterial pressure [MAP])
•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Blood sample collection for:
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score.
•
Record endoscopic findings (if performed in the last 6 months)
•
Record abdominal ultrasound (if performed in the last 6 months)
•
Record ACLF grade 
•
Record prior (within the last 30 days) concomitant medications
•
Record AEs
Treatment Period Day 1
Randomization must occur within 72 hours of screening, and it can occur while the subject is 
hospitalized or after discharge from the hospital. The first dose of Albutein 20% is 
administred on the same day as randomization. All assessments and activities will be 
performed prior to treatment. In the SMT + Albutein 20% treatment group, vital signs and 
serum albumin concentration will also be recorded after treatment. Study assessments and 
activities will include:
•
Randomization (after confirmation of subject eligibility and prior to treatment)
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•
Record vital signs (systolic and diastolic blood pressure [BP], heart rate [HR], respiratory 
rate [RR], temperature [T]) (measured immediately prior to and immediately after the end 
of the Albutein 20% infusion in the SMT + Albutein 20% treatment group)
•
Ascites assessment according to the ICA criteria 
•
Record weight
•
Blood sample collection for:
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group
-
Systemic inflammatory assessment 
-
Albumin functional capacity assessment (albumin binding capacity)
-
Blood biomarker retains (all clinical blood samples will need to be drawn first)
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire) 
•
Record AEs
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
Treatment Period Day 11 and Monthly Visits (Month 1 through Month 11)
Subjects will have assessments on Day 11 (±2 days), Month 1 (±2 days), and then monthly 
(±2 days) for up to 11 months: Days 31, 61, 91, 121, 151, 181, 211, 241, 271, 301, 331. 
All assessments and activities will be performed prior to treatment. In the SMT + 
Albutein 20% treatment group, vital signs and serum albumin concentration will also be 
recorded after treatment. Study assessments and activities will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to 
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
•
Ascites assessment according to the ICA criteria 
•
Hepatic encephalopathy evaluation 
•
Hemodynamics assessment (MAP)
•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Assessment of TIPS insertion 
•
Record weight
•
Blood sample collection for:
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group
-
Systemic inflammatory assessment 
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-
Albumin functional capacity assessment (albumin binding capacity [Day 11, Months 
1, 3, 6, and 9 only])
-
Blood biomarker retains (optional, all clinical blood samples will need to be drawn 
first) (Months 1, 3, 6, and 9 only) 
•
Record ACLF grade
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score
•
Physical examination (Month 6 only)
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire) (Months 1, 3, 6, and 9 only)
•
Record AEs 
•
Record data on liver transplantation, subject survival, and cause of death (Months 3 and 6 
only) 
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
SMT + Albutein 20% Treatment Period Days 21, 41, 51, 71, 81, 101, 111, 131, 141, 161, 
171, 191, 201, 221, 231, 251, 261, 281, 291, 311, 321, 341, 351
Subjects in the SMT + Albutein 20% treatment group will receive infusions every 10 (± 2) 
days for up to 12 months in the study. Study assessments and activities will include:
All treatment day assessments and activities will be performed prior to treatment in the 
SMT + Albutein 20% treatment group only. Vital signs will also be recorded in the 
SMT + Albutein 20% treatment group only after treatment. Study assessments and activities 
will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to 
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
•
Record weight
•
Record concomitant medications
•
Record AEs
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
Month 12 Visit/ Early Discontinuation Visit
All assessments and activities at the Month 12 (Day 361 ±2 days)/Early Discontinuation 
Visit will be performed prior to treatment. In the SMT + Albutein 20% treatment group, vital 
signs and serum albumin concentration will also be recorded after treatment. Study 
assessments and activities will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to 
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
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•
Ascites assessment according to the ICA criteria 
•
Hepatic encephalopathy evaluation
•
Hemodynamics assessment (MAP)
•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Assessment of TIPS insertion 
•
Record weight
•
Blood sample collection for: 
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group [Month 12 Visit only])
-
Systemic inflammatory assessment 
-
Albumin functional capacity assessment (albumin binding capacity)
-
Blood biomarker retains (optional, all clinical blood samples will need to be drawn 
first)
•
Record ACLF grade 
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score
•
Physical examination 
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire) 
•
Record AEs 
•
Record data on liver transplantation, subject survival, and cause of death 
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only [Month 12 Visit 
only])
End of Study Visit for Subjects who Complete Study Treatment
Subjects will return to the study center within 1 week of study completion. End of study 
assessments in subjects who complete study treatment (up to 12 months) will include:
•
Record concomitant medications
•
Record AEs
Follow-Up for Early Discontinued Subjects (Months 3, 6, 12)
In subjects who discontinue from the study early, the following assessments will be 
performed at Months 3, 6, and 12 with a +/- 5 day window each visit:
•
Record data on liver transplantation, subject survival, and cause of death
Statistical Methods:
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Study Population
There will be 3 analysis populations in this study; 2 populations for efficacy assessment and 
1 population for safety evaluation.
The ITT population is defined as all subjects who are randomized. The ITT population will 
be used for all efficacy analyses. Subjects will be grouped according to the treatment to 
which they are randomized in all efficacy analyses.
The Per-Protocol (PP) population is defined as the subset of subjects included in the ITT 
population who do not present major protocol violations which might have an impact on the 
primary efficacy analysis, complete at least 80% of the scheduled treatments and are not 
excluded from the study for interrupting the Albutein 20% treatment for more than 4 
consecutive weeks (SMT + Albutein 20% treatment group subjects). The primary efficacy 
analyses will be carried out using the PP population in order to confirm the results based on 
the ITT population.
The Safety population is defined as the subset of patients who receive at least one 
SMT + Albutein 20% administration or SMT alone. Safety analyses will be based on this 
population. Subjects will be grouped according to the treatment they actually received in all 
safety analyses.
Primary Efficacy Analyses
This is a study to demonstrate superiority of SMT + Albutein 20% to SMT alone on 1-year 
transplant-free survival. The null hypothesis is that the hazard functions for liver 
transplantation or death are the same for the 2 treatment groups, or equivalently, the hazard 
ratio is equal to 1. The alternative hypothesis is that the hazard functions for liver 
transplantation or death are not the same for the 2 treatment groups, or equivalently, the 
hazard ratio is not equal to 1. The effect of SMT + Albutein 20% administration on the 
transplant-free survival at 1 year after randomization versus SMT alone will be summarized 
by means of Kaplan-Meier survival estimates and curves and compared between treatment 
groups by means of the Log-rank test stratified by region (Europe or NA) and history of 
hospitalization for acute decompensation of liver cirrhosis (yes or no). An un-stratified 
analysis will be performed as a sensitivity analysis.
In the event that clinically and statistically significant imbalances are observed between 
treatment groups in any of subjects’ baseline characteristics, sensitivity analyses will be 
performed in which treatment effects will be adjusted by those characteristics by fitting an 
appropriate Cox Proportional-Hazards (PH) model. In addition, subgroup analyses by age 
group, sex, race, region (Europe vs NA), and history of hospitalization for acute 
decompensation of liver cirrhosis (yes vs no) will be carried out for the primary endpoint.
The primary efficacy analysis will be carried out on the ITT population and repeated on the 
PP population. 
Secondary Efficacy Analyses
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The analysis of the secondary endpoints will be performed using the ITT population.
The effects of SMT + Albutein 20% administration on the overall survival at 3, 6, and 12 
months and transplant-free survival at 3 and 6 months after randomization versus SMT alone 
will be assessed by carrying out the same analyses for the primary efficacy variable described 
above.
Total number of paracenteses and incidence of refractory ascites will be listed for each 
subject, summarized by treatment group, and compared between treatment groups by means 
of analysis of covariance (ANCOVA) or Student’s t test (for normally-distributed variables), 
Poisson regression model (for count variables), and Fisher’s exact test or Chi-square test (for 
binomial variables).
The fixed-sequence testing method will be used to adjust for multiplicity in the analyses of the 
secondary efficacy endpoints.
Exploratory Analyses
As appropriate to the data, the original values or changes from baseline (last measurement 
taken prior to the start of study treatment on Day 1) of the following exploratory endpoints 
will be listed for each subject, summarized by treatment group, and compared between 
treatment groups by means of ANCOVA or Student’s t tests (for normally-distributed 
variables), non-parametric Mann-Whitney U test (for non-parametric variables), Kaplan-
Meier estimates and Log-rank test (for time-to-event variables), Poisson regression model (for 
count variables), and Fisher’s exact test or Chi-square test (for binomial variables): 
Incidence of ACLF, CLIF-C OF score, CLIF-C ACLF score, CLIF-C AD score, MELD score, 
Child Pugh score, number and length of hospital readmission for an acute complication of 
cirrhosis, number and length of ICU admission, incidence of disease-related complications, 
serum albumin concentration, albumin functional capacity (albumin binding capacity), 
incidence of insertion of TIPS for refractory ascites, and the EQ-5D-5L health questionnaire.
For the normally-distributed variables, the ANCOVA model will include change from 
baseline as the dependent variable, treatment as a fixed factor, and baseline value as a 
covariate. If any potential confounders are identified among subjects’ baseline characteristics, 
they will be included as additional covariates in the ANCOVA models to adjust treatment 
effects. In addition, for the longitudinal measurements taken repeatedly over time, the 
treatment effects may be explored by using the mixed-effect model repeated measures 
analysis.
Safety Analysis
The safety analyses will be addressed by listing and tabulation of AEs (including suspected 
ADRs), vital signs, physical assessments, and clinical laboratory tests. Data will be described 
using descriptive analyses and treatment comparisons will be based on review of descriptive 
statistics. The safety analyses will be based on the Safety population.
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Determination of Sample Size
Based on the CANONIC study, the overall 1-year transplant-free mortality rate in the current 
study population is assumed to be about 46%. Assuming a potential drop-out rate of 20% and 
5% type-1 error for a 2-sided Chi-square test, a global sample size of 410 patients (205 per 
treatment group) will allow an 80% statistical power to detect an absolute reduction of 15% 
for the 1-year mortality rate in subjects treated with SMT + Albutein 20%.
Alternatively, the sample size was calculated based on the log-rank test as follows. Assuming 
the 1-year transplant or mortality rate is 46% for the control group, or equivalently, the 
transplant-free survival rate is 54%, which translates to a hazard rate of 0.0017 assuming an 
exponential distribution. Using a log-rank test at the 2-sided significant level of 5%, a total of 
125 events would provide at least 80% power to detect an absolute reduction of 15% in 
transplant or mortality rate (a 31% 1-year transplant or mortality rate, or equivalently, a 69% 
transplant-free survival rate) in subjects treated with SMT + Albutein 20%. This absolute 
difference in transplant or mortality rates translates to a hazard ratio of 0.6022, or an 
approximate 40% risk reduction. With all subjects followed for the entire 1-year duration of 
the study, a total of 322 subjects would be required to obtain 125 events. Assuming a dropout 
rate of 20%, a global sample size of 404 subjects (202 per treatment group) is required. This 
sample size calculation was performed using Proc Power with the Twosamplesurvival 
statement in SAS version 9.4.
Taking a conservative approach, the larger of the 2 sample sizes (ie, the one based on the Chi-
square test) will be used to ensure the study has sufficient power.
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................5
TABLE OF CONTENTS.........................................................................................................18
GLOSSARY AND ABBREVIATIONS..................................................................................23
1
GENERAL INFORMATION..........................................................................................25
2
BACKGROUND INFORMATION ................................................................................25
2.1
Name and Description of the Investigational Product ...........................................25
2.2
Relevant Findings from Nonclinical and Clinical Studies.....................................25
2.3
Known and Potential Risks and Benefits to Human Subjects ...............................26
2.4
Description of and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Periods..............................................................27
2.4.1
Administration of Investigational Products .................................................27
2.4.2
Justification for Selection of Doses/Timing of Investigational Products ....28
2.5
Compliance Statement ...........................................................................................29
2.6
Study Population....................................................................................................29
2.7
Relevant Data and Literature Review....................................................................29
2.7.1
Rationale for Selection of Study Population................................................31
3
STUDY OBJECTIVES AND PURPOSE .......................................................................31
3.1
Efficacy Objectives................................................................................................32
3.1.1
Primary Efficacy Objective..........................................................................32
3.1.2
Secondary Efficacy Objectives....................................................................32
3.1.3
Exploratory Efficacy Objectives..................................................................32
3.2
Safety Objectives ...................................................................................................32
4
STUDY DESIGN.............................................................................................................33
4.1
Primary Endpoint and Secondary Endpoints .........................................................33
4.2
Study Design and Plan...........................................................................................33
4.3
Measures Taken to Minimize/Avoid Bias .............................................................36
4.3.1
Subject Numbering ......................................................................................36
4.3.2
Randomization.............................................................................................36
4.3.3
Blinding........................................................................................................36
4.4
Study Treatments ...................................................................................................36
4.4.1
Treatments to Be Administered ...................................................................36
4.4.1.1
Standard Medical Treatment + Albutein 20% ...................................36
4.4.1.2
Standard Medical Treatment..............................................................37
4.4.2
Labeling and Packaging of Investigational Product ....................................37
4.4.3
Storage of Investigational Product...............................................................37
4.5
Expected Duration of Subject Participation in the Study ......................................37
4.6
Discontinuation Criteria for Individual Subjects and Study..................................38
4.6.1
Discontinuation Criteria for Individual Subjects.........................................38
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4.6.2
Premature Termination of Study/Closure of Center....................................38
4.7
Accountability Procedures for Investigational Product .........................................38
4.8
Maintenance of Treatment Randomization Codes.................................................38
4.9
Data to Be Recorded Directly on the Case Report Forms .....................................39
5
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................39
5.1
Inclusion Criteria ...................................................................................................39
5.2
Exclusion Criteria ..................................................................................................39
5.3
Subject Withdrawal Criteria ..................................................................................41
5.3.1
Screen Failures.............................................................................................41
5.3.2
Discontinuation of Subjects from Treatment...............................................41
5.3.2.1
Liver Transplantation Criteria............................................................42
5.3.3
Removal of Subjects ....................................................................................42
5.3.4
Subject Replacement....................................................................................43
5.3.5
Follow-up of Subjects Withdrawn from Study............................................43
6
TREATMENT OF SUBJECTS.......................................................................................43
6.1
Administration and Timing of Investigational Products for Each Subject............43
6.1.1
Albutein 20% Dosage, Procedures, and Treatment Regimen......................43
6.1.2
Standard Medical Treatment........................................................................43
6.2
Prior and Concomitant Therapy.............................................................................44
6.2.1
Prohibited Medications Prior to Study Participation ...................................44
6.2.2
Prohibited Concomitant Medications during the Study...............................44
6.2.3
Restricted Concomitant Medications during the Study ...............................44
6.2.4
Cardiac Overload/Pulmonary Edema Treatment.........................................44
6.3
Treatment Compliance...........................................................................................45
7
ASSESSMENT OF EFFICACY .....................................................................................45
7.1
Efficacy Variables..................................................................................................45
7.1.1
Primary Efficacy Variable ...........................................................................45
7.1.2
Secondary Efficacy Variables......................................................................45
7.1.3
Exploratory Variables ..................................................................................45
7.2
Methods and Timing for Assessing, Recording, and Analyzing Efficacy 
Parameters..............................................................................................................46
7.2.1
Observations and Measurements .................................................................46
7.2.1.1
Screening Visit...................................................................................46
7.2.1.2
Treatment Period (Day 1 through Month 12) ....................................47
7.2.1.3
End of Study Visit for Subjects who Complete Study Treatment .....50
7.2.1.4
Follow-Up for Early Discontinued Subjects (Months 3, 6, 12).........50
7.2.2
Description of Laboratory Tests and Procedures.........................................50
7.2.3
Drug Concentration Measurements .............................................................51
8
ASSESSMENT OF SAFETY..........................................................................................51
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8.1
Safety Variables.....................................................................................................51
8.2
Methods and Timing for Assessing, Recording, and Analyzing  Safety 
Parameters..............................................................................................................52
8.2.1
Adverse Events ............................................................................................52
8.2.2
Vital Signs....................................................................................................52
8.2.3
Clinical Laboratory Evaluations ..................................................................53
8.2.4
Physical Examinations.................................................................................53
8.3
Procedures for Eliciting Reports of and for Recording and  Reporting Adverse 
Event and Intercurrent Illnesses.............................................................................53
8.3.1
Warnings/Precautions ..................................................................................53
8.3.2
Adverse Event Monitoring...........................................................................53
8.3.3
Adverse Event Definitions...........................................................................54
8.3.3.1
Adverse Events ..................................................................................54
8.3.3.2
Suspected Adverse Drug Reactions/Adverse Reactions....................54
8.3.4
Assessment of Causality of Adverse Event .................................................54
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction...............55
8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ......55
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction .........55
8.3.8
Adverse Event Documentation ....................................................................56
8.3.9
Event of Special Interest..............................................................................57
8.3.10
Disease Progression .....................................................................................57
8.3.11
Reporting of Serious Adverse Events, Deaths, and Pregnancy ...................58
8.3.11.1
Reporting of Serious Adverse Events................................................58
8.3.11.2
Reporting of Deaths...........................................................................59
8.3.11.3
Reporting Pregnancy..........................................................................59
8.4
Type and Duration of the Follow-Up of Subjects after Adverse Events...............59
9
STATISTICS ...................................................................................................................59
9.1
Statistical Methods.................................................................................................59
9.1.1
Demographic and Baseline Characteristics .................................................60
9.1.2
Efficacy Analysis.........................................................................................60
9.1.2.1
Primary Endpoint...............................................................................60
9.1.2.2
Secondary Endpoints .........................................................................60
9.1.2.3
Exploratory Endpoints .......................................................................61
9.1.3
Safety Analysis ............................................................................................62
9.1.3.1
Adverse Events ..................................................................................62
9.1.3.2
Clinical Laboratory Values................................................................62
9.1.3.3
Vital Signs..........................................................................................63
9.1.3.4
Physical Assessment ..........................................................................63
9.2
Determination of Sample Size ...............................................................................63
9.3
Level of Significance to Be Used ..........................................................................63
9.4
Criteria for Termination of the Study ....................................................................64
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9.5
Procedure for Accounting for Missing, Unused, and Spurious Data.....................64
9.6
Reporting Deviations from the Statistical Analysis Plan.......................................64
9.7
Subject Population for Analysis.............................................................................64
10
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..............................................64
11
QUALITY CONTROL AND QUALITY ASSURANCE...............................................65
12
ETHICS............................................................................................................................65
12.1
Institutional Review Board/Ethics Committee ......................................................65
12.2
Ethical Conduct of the Study.................................................................................65
12.3
Regulatory Authority Approvals/Authorizations...................................................66
12.4
Subject Information and Consent...........................................................................66
12.5
Confidentiality .......................................................................................................66
13
DATA HANDLING AND RECORD KEEPING ...........................................................67
13.1
Data Handling........................................................................................................67
13.2
Record Retention ...................................................................................................67
14
FINANCING AND INSURANCE..................................................................................67
15
PUBLICATION POLICY ...............................................................................................68
16
REFERENCES ................................................................................................................69
17
APPENDICES .................................................................................................................72
LIST OF IN-TEXT TABLES
Table 2-1 Grades of Acute-on-Chronic Liver Failure .......................................................30
Table 2-2 Mortality Rates and Grades of ACLF in the CANONIC Study........................30
Table 7-1 Name, Description, and Location of Laboratory Tests and Procedures............51
LIST OF IN-TEXT FIGURES
Figure 4-1 Overall Study Schema......................................................................................35
LIST OF APPENDICES
Appendix 1
Schedule of Study Procedures and Events.........................................73
Appendix 2
European Association for the Study of the Liver Clinical Practice 
Guidelines on the Management of Ascites/International Club of Ascites...................75
Appendix 3
Illness Severity Scores .......................................................................77
Appendix 4
West Haven Criteria for Hepatic Encephalopathy.............................79
Appendix 5
EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) 
Health Questionnaire ...................................................................................................80
Appendix 6
Milan Criteria.....................................................................................82
Appendix 7
NYHA Classification – The Stages of Heart Failure.........................83
Appendix 8
GOLD Staging System for COPD Severity.......................................84
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Appendix 9
Algorithm For Cardiogenic Pulmonary Overload .............................85
Appendix 10
Management of Acute Pulmonary Edema.........................................86
Appendix 11
Summary of Changes for Amendment 4 ...........................................87
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GLOSSARY AND ABBREVIATIONS
ACLF
Acute-on-chronic liver failure
ADL
Activities of Daily Living
ADR
Adverse drug reaction
AE
Adverse event
AIFA
Agenzia Italiana del Farmaco
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AR
Adverse reaction
AST
Aspartate aminotransferase
BUN
Blood urea nitrogen
BP
Blood pressure
CI
Confidence interval
CJD
Creutzfeldt-Jakob disease
CLIF-C ACLF
Chronic Liver Failure-Consortium Acute-on-chronic liver failure
CLIF-C AD
Chronic Liver Failure-Consortium Acute Decompensation
CLIF-C OF
Chronic Liver Failure-Consortium Organ Failure
COVID-19
Coronavirus disease of 2019
CRP
C-reactive protein
DSMB
Data Safety Monitoring Board
EASL-CLIF
European Association for the Study of Liver- Chronic Liver Failure
EC
Ethics Committee
eCRF
Electronic case report form
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels 
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GI
Gastrointestinal
GOLD
Global Obstructive Lung Disease
HBV
Hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HE
Hepatic encephalopathy
HIV
Human immunodeficiency virus
HNA2
Human nonmercaptalbumin-2
HR
Heart rate
HRS
Hepatorenal Syndrome
IB
Investigator’s Brochure
ICA
International Club of Ascites
ICF
Informed consent form
ICH 
The International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICU
Intensive care unit
INR
international normalized ratio
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IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IV
Intravenous
LDH
Lactate dehydrogenase
MAP
Mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for End-stage Liver Disease
NA
North America
NYHA
New York Heart Association
OPTN
Organ Procurement and Transplantation Network
PH
Proportional-Hazards
PP
Per-protocol
PRA
Plasma renin activity
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Spontaneous bacterial peritonitis
SD
Standard deviation
SMT
Standard medical treatment
SOP
Standard operating procedures
SPO2
Peripheral capillary oxygen saturation
T
Temperature
TIPS
Transjugular intrahepatic portosystemic shunt
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WBC
White blood cells
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1
GENERAL INFORMATION
Protocol title and other key study information are provided on the title page. Information 
regarding additional key personnel and organizations involved in the conduct of the study, 
including names and contact details of participating investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on members of 
additional study committees, will be found in the study files of the sponsor and at the 
investigator study centers within the study reference manual/file.  
Investigators and staff will receive training either via an investigators meeting or other 
appropriate individual study center training session(s).
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be established for this clinical study to 
monitor the progress and the safety of the clinical study participants. The DSMB Charter will 
outline the DSMB composition, responsibilities, schedule of the DSMB meetings, and study 
stopping rules.
2
BACKGROUND INFORMATION
In addition to the information provided below, please also refer to the Investigator’s 
Brochure (IB) (1) and any additional data supplied by the sponsor.
2.1
Name and Description of the Investigational Product
The investigational product (IP) in this study is Albumin (human) USP, 20%
(Albutein® 20%), which will be administered as a treatment for decompensated cirrhosis and 
ascites. Albutein 20% is a solution containing 200 g/L of total protein of which at least 95% 
is albumin. See Section 4.4 for study treatments details.
Standard medical treatment (SMT) will be administered per institution standards. There are 
several published guidelines for the treatment and management of patients with 
decompensated cirrhosis (2-5).
2.2
Relevant Findings from Nonclinical and Clinical Studies
Effects of Long-term Human Albumin Treatment in Subjects with Decompensated Cirrhosis
Several studies assessing the effect of long-term human albumin treatment in subjects with 
decompensated cirrhosis have been reported (6-15). In one study, the effect of intravascular 
volume expansion with human albumin treatment in subjects with cirrhosis and ascites was
evaluated. Hospitalized subjects were randomized to receive diuretics alone or 
diuretics + human albumin (12.5 g/day during hospitalization followed by 25 g/week after 
discharge) and were followed for a median duration of 20 months. Overall, human albumin
treatment was more effective than diuretics alone in resolving ascites and reducing the length 
of the hospital stay; however, these results were only achieved in a subset of subjects 
receiving a low dose of diuretics (13).
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In a second study, the effects of long-term human albumin administration on survival, 
recurrence of ascites, and onset of other complications were examined. Subjects hospitalized 
for first-onset ascites were randomized to receive diuretics alone or diuretics + human 
albumin (25 g/week for the first year, then 25 g every 2 weeks) and were followed for a 
median time of 84 months (range 2 to 120 months). In the study, subjects receiving human 
albumin had a significantly reduced recurrence rate of moderate to severe ascites and reduced 
rate of mortality (14). 
A third study is a non-profit open-label, multicenter, randomized clinical study, sponsored by 
the Agenzia Italiana del Farmaco (AIFA) (Long-Term Use of Human Albumin for the 
Treatment of Ascites in Patients with Hepatic Cirrhosis: a Multicenter, Open-label 
Randomized Clinical Trial: The Interim Analysis of the ANSWER Study). In this study, the 
effectiveness of long-term human albumin administration on mortality, quality of life, and 
onset of other complications is being examined in subjects with cirrhosis and uncomplicated 
ascites (no renal failure or refractory ascites) receiving at least 200 mg per day of an 
anti-mineralocorticoid drug and 25 furosemide per day. Subjects are randomized to receive 
diuretics alone or diuretics + human albumin (40 g twice a week for 2 weeks, then 40 g/week 
for up to 24 months) (15).
Interim analysis of data from 386 out of a planned 420 subjects in the ANSWER study
suggests that long-term human albumin administration significantly improves the 
management of ascites and is also able to reduce the incidence of other severe clinical 
complications of the disease to prolong survival in subjects with decompensated cirrhosis
(15).
2.3
Known and Potential Risks and Benefits to Human Subjects
Administration of albumin has shown efficacy in prevention and treatment of circulatory 
dysfunction in cirrhosis (16). Paracentesis is the most used treatment in cirrhotic patients 
with ascites but can cause a worsening of circulatory dysfunction. Administration of albumin 
after paracentesis can prevent this circulatory dysfunction (17). In patients with spontaneous 
bacterial peritonitis (SBP), the administration of intravenous (IV) albumin improves their 
circulatory function, reduces the presence of hepatorenal syndrome (HRS) from 
approximately 30 to 10% (9), and improves patient survival (14). The administration of 
albumin together with vasoconstrictors reverses the circulatory dysfunction and normalizes 
the serum concentration of creatinine to 40 to 60% in patients with HRS type 1 and improves 
their survival (18,19). There are also data that suggest that long term albumin administration 
(25 g weekly) improves the control of ascites and reduces the incidence and intensity of the 
muscle cramps (20).
Based on these studies, long-term administration of human albumin has potential beneficial 
effects on circulatory dysfunction, inflammatory response, oxidative stress, organ 
dysfunction, and organ failure. Long-term treatment with human albumin was initially 
proposed for the management of patients with decompensated cirrhosis with ascites based on 
its oncotic properties. In patients with cirrhosis and portal hypertension, ascites formation is 
the consequence of effective hypovolemia, which promotes renal retention of sodium and 
water. The preservation of the central blood volume with human albumin represents a logical 
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approach for the management of cirrhotic patients with ascites since it would improve renal 
function and the response to diuretics (21).
Long-term human albumin administration may improve circulatory and organ function not 
only by directly acting as plasma-expander, but also indirectly modulating the deleterious 
effects of immune dysfunction and chronic or acute inflammation on the systemic circulation 
and organ function. Intravenous human albumin administration in decompensated cirrhosis 
increases cardiac contractility and systemic vascular resistances through the effects related to 
its non-oncotic properties. Maintaining an effective blood volume may support adequate 
organ perfusion and avoid/delay the occurrence of organ impairment/failure (21). 
In addition, long-term human albumin administration may also modulate the deleterious 
effects of inflammatory mediators on mitochondrial and cell function and on organ 
microcirculation, thus protecting target organs against tissue damage and microcirculatory 
disturbances. These effects could potentially reduce the incidence of decompensation 
episodes (ie, ascites, renal or liver failure, hepatic encephalopathy (HE), severe sepsis, septic 
shock, and acute-on-chronic liver failure [ACLF]) and increase survival rates (21).
Albutein is made from pooled human plasma. Based on effective donor screening and 
product manufacturing processes, it carries an extremely remote risk for transmission of viral 
diseases, including a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD). 
Although no cases of transmission of viral diseases or CJD have ever been identified for 
albumin, the risk of infectious agents cannot be totally eliminated (1).
Albutein is contraindicated in patients with severe anemia or cardiac failure in the presence 
of normal or increased intravascular volume. The use of Albutein is contraindicated in 
patients with a history of allergic reactions to this product. The most serious adverse 
reactions (ARs) are anaphylactic shock, heart failure, and pulmonary edema. The most 
common ARs are anaphylactoid type reactions. For additional information on potential risks
and adverse events (AEs), please also refer to the IB (1) and any additional data supplied by 
the sponsor.
2.4
Description of and Justification for the Route of Administration,
Dosage, Dosage Regimen, and Treatment Periods
2.4.1
Administration of Investigational Products 
Albutein 20% will be infused at a dose of 1.5 g/kg body weight (maximum 100 g per subject) 
every 10 ± 2 days for the duration of study participation (up to 12 months).
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2.4.2
Justification for Selection of Doses/Timing of Investigational Products
Preliminary Results of Human Albutein 20% Dose-Finding Study 
The current albumin dosage in cirrhosis is based on empiric assumptions on the concept that 
it mainly acts as a plasma expander. However, albumin has other biological effects unrelated 
to its oncotic capacity (22). 
A Grifols-sponsored clinical study (IG0802) was designed to test the hypothesis that 
normalization of serum albumin concentration by long-term exogenous albumin 
administration can be a target to achieve in order to potentiate the beneficial effects related to 
the oncotic and non-oncotic properties (23). In this open-label study, subjects with 
decompensated cirrhosis who were prone to develop severe circulatory dysfunction and HRS
within a short period of time were treated with a low human albumin dose (1 g/kg body 
weight every 2 weeks for 12 weeks). Following interim analysis results, which did not 
demonstrate a change in plasma renin activity (PRA), human albumin was administered at a 
higher dose with an increased frequency (1.5 g/kg body weight every week for 12 weeks).
To assess dose effectiveness, serum human albumin levels were measured at the end of 
treatment. Treatment with low-dose human albumin was not sufficient to increase the serum 
albumin levels above 34 g/L (lower limit of normal). In this treatment group, 2 out of 7 
subjects with hypoalbuminemia at the baseline visit had serum human albumin levels within 
the normal range at end of treatment. In contrast, treatment with high-dose human albumin
was sufficient to increase serum human albumin levels to within the normal range. Eight of 8 
subjects with hypoalbuminemia at the baseline visit had serum human albumin levels within 
the normal range at end of treatment.
In clinical study IG0802, an increase in a subject’s PRA >30% with respect to baseline 
served to demonstrate a sustained impairment of effective blood volume. Overall, a sustained 
impairment of effective blood volume was observed in 29% of subjects (4 low-dose and 
2 high-dose subjects). However, extreme circulatory instability (as manifested by acute, 
reversible increases in PRA) was documented in subjects receiving low-dose human albumin, 
but not in subjects receiving high-dose human albumin. Mean changes in PRA and serum 
human albumin concentrations correlated inversely (r = – 0.459; p = 0.039), while inotropic 
cardiac function improved significantly and portal pressure did not change following long-
term human albumin administration. 
In the high-dose treatment group, the serum human albumin concentration normalized very 
rapidly in subjects with hypoalbuminemia and, once normalized, remained within the normal 
range throughout the study. No hyperalbuminemia was observed in any subject in the 
high-dose treatment group. The mean change of serum human albumin concentration during 
treatment correlated inversely with the baseline serum albumin concentration; subjects with 
the most severe hypoalbuminemia had the highest increases in serum human albumin.
In summary, clinical study IG0802 demonstrated that a weekly dose of 1.5 g/kg body weight 
was effective and tolerable in subjects with decompensated cirrhosis. In addition, the dose 
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appeared to be tolerable as no increase of portal pressure was documented and no cases of 
hyperalbuminemia developed.
2.5
Compliance Statement
This study will be conducted under the conditions described in this protocol and in 
compliance with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP), and all applicable 
regulatory requirements.
2.6
Study Population
The study population will consist of subjects who have been hospitalized for acute 
decompensation of liver cirrhosis and ascites (or with prior history of ascites requiring 
diuretic therapy) with or without ACLF at admission or during hospitalization, but without 
ACLF at Screening. Subjects may also present other acute complications (HE, 
gastrointestinal [GI] bleeding, and/or bacterial infections) at admission or during 
hospitalization.
Subjects will be screened while hospitalized for acute decompensation of liver cirrhosis due 
to:
1. Development of ascites alone or associated with other complications (GI, HE, acute 
bacterial infection).
2. Development of a non-ascitic complication in patients with prior history of ascites 
requiring diuretic treatment for prevention of ascites recurrence.
2.7
Relevant Data and Literature Review
Decompensated Cirrhosis
Cirrhosis is a progressive chronic liver disease characterized by diffuse fibrosis, severe 
disruption of the intrahepatic venous flow, portal hypertension, and liver failure. 
Epidemiological studies indicate that there is an increasing prevalence of liver cirrhosis 
related to chronic infection by hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol 
consumption, and non-alcoholic steatohepatitis worldwide (24). The natural course of 
cirrhosis is divided into 2 stages. The first stage is compensated cirrhosis, which is defined as 
the period between the onset of cirrhosis and the appearance of the first major complication 
of the disease. During this period, which is relatively long in most patients (>10 years), 
symptoms are absent or minor, but liver lesions steadily progress. The term decompensated 
cirrhosis defines the period following the development of ascites, variceal bleeding, HE and 
bacterial infection. This period is associated with short-term survival (3 to 5 years). It is 
increasingly evident that patients rarely die as a consequence of an end-stage irreversible 
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destruction of the liver. Rather, in most patients the cause of death is an acute deterioration in 
their clinical condition promoted by a precipitating event, a syndrome termed ACLF.
The syndrome of ACLF had not been well characterized until recently when the CANONIC 
study was completed (25). The aim of the CANONIC study was to define ACLF, to assess 
the prevalence and clinical course of the syndrome and to assess the prognosis. The 
CANONIC study was an initiative of the European Association for the Study of Liver -
Chronic Liver Failure (EASL-CLIF) Consortium. The EASL-CLIF Consortium defined 
ACLF as a syndrome that develops in patients with cirrhosis characterized by acute 
decompensation (AD), organ failure(s), and high short-term mortality.
Based on the CANONIC study, ACLF severity was characterized by grades based on the 
level of organ failure, ranging from grade 1 (single organ failure) to grade 3b (presence of 
≥4 organ failures [25]). Table 2-1 lists the criteria for ACLF grades.
Table 2-1 Grades of Acute-on-Chronic Liver Failure
No ACLF 
- No organ failure
- One organ failure (liver failure, coagulation, circulatory or 
respiratory failure) with creatinine <1.5 mg/dL and no HE
ACLF grade 1a
- Single kidney failure without mild or moderate HE
ACLF grade 1b
- Single organ failure with serum creatinine ranging from 1.5 mg/dL 
to 1.9 mg/dL and/or mild-to-moderate HE
ACLF grade 2 
- Presence of 2 organ failures 
ACLF grade 3a
- Presence of 3 organ failures
ACLF grade 3b 
- Presence of ≥ 4 organ failures
Source: (25)
Among patients with ACLF in the CANONIC study, 51% had ACLF-1, 35% had ACLF-2, 
and 13% had ACLF-3. The 90-day mortality rate ranged from 40 to 80%, with higher 
mortality associated with more severe ACLF (25,26). Mortality rates at Day 28 and Day 90 
are shown in Table 2-2.
Table 2-2 Mortality Rates and Grades of ACLF in the CANONIC Study
Mortality Rates
ACLF Grades
No ACLF 
(n=928)
Grade 1
(n=148)
Grade 2
(n=108)
Grade 3 
(n=47)
All Patients
(n=1231)
28-Day
1.9%
22.1%
32.0%
76.7%
33%
90-Day
9.7%
40.7%
52.3%
79.1%
51%
Source: (25,26)
Current treatment of decompensated cirrhosis
Diuretics, antibiotics, and human albumin are the most frequently used treatments for the 
management of patients with cirrhosis. Based on the CANONIC study, human albumin was 
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indicated in 60% of subjects during hospital stay (25). Albumin is a critical determinant of 
the plasma oncotic pressure and therefore of circulatory homeostasis (6,7). It is also an 
important vehicle for the transport of water insoluble substances in plasma (ie, bilirubin, bile 
salts, steroids, thyroid hormones, fatty acids, drugs) (6). Perhaps the most outstanding 
function of albumin is that it also captures many inflammatory inducers and mediators and by 
this mechanism it modulates systemic inflammation and oxidative stress (14).
Serum albumin in cirrhosis is saturated by a myriad of endogenous ligands resulting in severe 
impairment of its transport capacity (scavenger). Albumin is also markedly oxidized in 
patients with decompensated cirrhosis as a consequence of the increased systemic oxidative 
stress in these patients (27,28). Oxidation of albumin to human nonmercaptalbumin-2
(HNA2) is irreversible and causes intense modifications of the protein structure and function 
and rapid clearance from the extracellular compartment (29,30). 
Approximately 50% of circulating albumin in decompensated cirrhosis is oxidized and 10% 
is irreversible oxidized to HNA2 (31). The corresponding percentages in healthy subjects are 
21% and 1%, respectively. The percentage of oxidized albumin is significantly higher in
patients with ACLF than in those without ACLF. These data indicate there is a significant 
reduction in the scavenger capacity of serum albumin for inflammatory inducers and 
mediators. This reduction may participate in the exaggerated response to the pro-
inflammatory precipitating events observed in these patients (21). 
Therefore, substitution of the saturated and highly oxidized endogenous albumin molecules 
by exogenous albumin with higher functionality is therefore another potentially important 
beneficial effect of Albutein 20% in patients with decompensated cirrhosis. 
2.7.1
Rationale for Selection of Study Population
An analysis of subjects in the CANONIC study (25) was performed to determine if the 
subject population was distinct from the ANSWER study population (15) with respect to 
mid-term mortality. The CANONIC study data base was composed of 867 subjects who were 
hospitalized with decompensated cirrhosis and ascites (with or without ACLF) and 
discharged from hospital without ACLF. The 1-year transplant-free mortality rate in these 
subjects was 44.5%. This finding indicates that subjects hospitalized by acute 
decompensation with or without ACLF at admission or during hospitalization, but without 
ACLF at discharge represent a distinct cohort of subjects who have decompensated cirrhosis 
with an increased fatality rate within 1 year after discharge. Based on these findings, the 
PRECIOSA study will be performed in this cohort of patients.
3
STUDY OBJECTIVES AND PURPOSE
The current study aims to assess the effectiveness of long-term Albutein 20% administration 
in the treatment of subjects with decompensated cirrhosis and ascites.  
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3.1
Efficacy Objectives
3.1.1
Primary Efficacy Objective
•
To evaluate the effect of SMT plus long-term Albutein 20% (SMT + Albutein 20%) 
administration on 1-year transplant-free survival versus SMT alone. 
3.1.2
Secondary Efficacy Objectives
•
To evaluate the effects of SMT + Albutein 20% administration on 3- and 6-month 
transplant-free and overall survival versus SMT alone
•
To evaluate the effects of SMT + Albutein 20% administration on 1-year overall survival 
versus SMT alone
•
To evaluate the total number of paracenteses and the incidence of refractory ascites 
according the International Club of Ascites (ICA) criteria (Appendix 2)
3.1.3
Exploratory Efficacy Objectives
The effects of SMT + Albutein 20% administration versus SMT alone on the following 
parameters will be evaluated:
•
3-, 6-, and 12-month incidence of ACLF according to the EASL-CLIF Consortium 
(CLIF-C) definition (24)
•
Incidence of individual organ failures: liver, renal, cerebral, coagulation, respiration, and 
circulation as defined by the CLIF-C Organ Failure (CLIF-C OF) score and the total 
CLIF-C OF score (Appendix 3)
•
Readmissions to the hospital due to an acute complication of cirrhosis
•
Admissions to intensive care units (ICU)
•
Incidence of disease-related complications (see Section 8.3.10)
•
Serum albumin concentration and albumin functional capacity in serum (albumin binding 
capacity [Table 7-1])
•
Incidence of transjugular intrahepatic portosystemic shunt (TIPS) insertion for refractory 
ascites
•
CLIF-C Acute-on-chronic liver failure (CLIF-C ACLF) score,CLIF-C Acute 
Decompensation (CLIF-C AD) score, Model for End-stage Liver Disease (MELD) score, 
and Child Pugh score
•
Subject’s quality of life according to the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
health questionnaire (Appendix 5).
3.2
Safety Objectives
•
To determine the safety and tolerability profile of SMT + Albutein 20% administration in 
subjects with decompensated cirrhosis and ascites
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4
STUDY DESIGN
4.1
Primary Endpoint and Secondary Endpoints 
The primary efficacy endpoint is to compare the 1-year transplant-free survival in the intent-
to-treat (ITT) population (see Section 9.7 for definition) between the SMT + Albutein 20%
treatment group and the SMT alone group.
The secondary efficacy endpoints are to assess the effects of SMT + Albutein 20% treatment
versus SMT alone on: (1) 3- and 6-month transplant-free and overall survival, (2) 1-year 
overall survival, and (3) total number of paracenteses and the incidence of refractory ascites. 
4.2
Study Design and Plan
This is a phase 3, multicenter, randomized, controlled, parallel-group, and open-label clinical 
study to evaluate the efficacy of SMT + Albutein 20% administration versus SMT alone in 
subjects with decompensated cirrhosis and ascites. This clinical study is planned to be 
performed in approximately 40 study centers in the United States and Europe. The protocol 
must be approved by regulatory authorities and the Institutional Review Board (IRB) or 
Ethics Committee (EC) of each of the participating centers.
Approximately 410 subjects with decompensated cirrhosis and ascites will be included in this 
study after obtaining written informed consent. The study population will consist of subjects 
who have been hospitialized for acute decompensation of liver cirrhosis with ascites (or with 
prior history of ascites requiring diuretic therapy) with or without ACLF at admission or 
during hospitalization, but without ACLF at Screening. 
There will be a screening period for enrollment of each hospitalized subject in the study. 
Screening should occur while the subject is hospitalized. Randomization must occur within 
72 hours of screening, and it can occur while the subject is hospitalized or after discharge 
from the hospital. The first dose of Albutein 20%  is administred on the same day as 
randomization.
Randomization of subjects will be stratified by region (Europe or North America [NA]) and 
by whether or not subjects have been previously hospitalized for acute decompensation of 
liver cirrhosis prior to the most recent hospitalization for acute decompensation of liver
cirrhosis with ascites as required by Inclusion Criterion #3v4 (Section 5.1). Within each 
stratum (ie, each unique combination of region and history of hospitalization for acute 
decompensation of liver cirrhosis), eligible subjects will be randomized in a 1:1 ratio into 1 
of 2 treatment groups:
•
SMT + Albutein 20%
•
SMT (control group)
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SMT + Albutein 20% Treatment Group
Approximately 205 subjects will be randomized to the SMT + Albutein 20% treatment 
group. Screening should occur while the subject is hospitalized. Randomization must occur 
within 72 hours of screening, and it can occur while the subject is hospitalized or after 
discharge from the hospital. The first dose of Albutein 20% is administered on the same day 
as randomization at the dose of 1.5 g/kg body weight (maximum 100 grams per
subject).Thereafter, subjects will receive Albutein 20% infusions at the dose of 1.5 g/kg body 
weight (maximum 100 grams per subject) every 10 ± 2 days for the rest of the study (up to a 
maximum of 12 months). Subjects in this treatment group will also receive SMT (see 
Section 2.1).
SMT Group
Approximately 205 subjects will be randomized to the control group and receive SMT (see 
Section 2.1). Screening should occur while the subject is hospitalized. Randomization must
occur within 72 hours of screening, and it can occur while the subject is hospitalized or after 
discharge from the hospital. Following randomization, subjects randomized to this group will 
receive SMT, which will be administered per institution standards. Several guidelines are 
published for the management of decompensated cirrhosis (2-5).
The treatment period in the study will be up to 12 months. See Appendix 1 for detailed study 
schedules. Subjects in both treatment groups (SMT + Albutein 20% and SMT alone) will be 
followed for up to 12 months. 
The overall study schema is shown in Figure 4-1.
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Screeninga
Randomizationb,c
1:1 (Day 1)
Study Visit
Study Visit
End of Study/
Early 
Discontinuation
SMT + Albutein 20%
(1.5 g/kg body weight every 10 ± 2 days)
Day 
11
Month
1
Month
2
Month
3e
Month
4
Month
5
Month
6e
Month
7
Month
8
Month
9
Month
10
Month
11
Month
12e
Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
Xd Xd
SMT
End of Study/
Early 
Discontinuation
Month
1
Month
2
Month
3e
Month
4
Month
5
Month
6e
Month
7
Month
8
Month
9
Month
10
Month
11
Month
12e
Day 
11
X = Treatment Day
Treatment Period
Figure 4-1 Overall Study Schema
a
Screening must occur during hospitalization.
b
Randomization (Day 1) must occur within 72 hours of screening (all efforts should be made to randomize subject as soon as they are determined eligible) 
c
Subjects in the SMT + Albutein 20% treatment group will receive infusion following randomization. Randomization and first Albutein 20% infusion should 
occur on the same day.
d
Subjects in the SMT + Albutein 20% treatment group will receive infusions at the dose of 1.5 g/kg body weight (maximum 100 grams per subject) every 10 
± 2 days for duration of the study (up to a maximum of 12 months)
e
Overall and transplant-free survival will be assessed at 3, 6, and 12 months
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4.3
Measures Taken to Minimize/Avoid Bias
4.3.1
Subject Numbering
Within each study center, subjects in the study will receive a consecutive subject number. 
Subject numbers are generated beginning with the study center number (3 digits, assigned by 
the sponsor) followed consecutively with a unique number for each subject (4 digits,
beginning with the number “2”). For example, if the investigator’s center number is 301, 
subject number will be 3012001, 3012002, 3012003, etc., in consecutive order. Subject 
numbers, once assigned, will not be reused at any center.
4.3.2
Randomization
Subjects who satisfy the inclusion criteria and who do not present any of the exclusion 
criteria will be enrolled in the study. Randomization must occur within 72 hours (3 days) of 
Screening. Randomization will be stratified by region (Europe or NA) and by whether or not 
subjects have been previously hospitalized for acute decompensation of liver cirrhosis prior 
to the most recent hospitalization for acute decompensation of liver cirrhosis with ascites as 
required by Inclusion Criterion #3v4 (Section 5.1). Within each stratum (ie, each unique 
combination of region and history of hospitalization for acute decompensation of liver 
cirrhosis), subjects will be randomly assigned to 1 of 2 treatment groups
(SMT + Albutein 20% versus SMT alone) in a 1:1 ratio. Randomization will be centralized 
and will be performed via an Interactive Web Response System after subject inclusion. A 
computer-generated randomization list will be used for treatment allocation.
4.3.3
Blinding
Not applicable. This is an open-label study.
4.4
Study Treatments
4.4.1
Treatments to Be Administered
4.4.1.1
Standard Medical Treatment + Albutein 20%
Albutein 20% is the IP in this study and is purified from human plasma. The solution is 
normally clear to slightly opalescent. Do not use the IP if the solution is cloudy or has 
precipitated. The product must be warmed to room temperature before use.
Do not dilute with water for injection. Once the container is open, the content must be 
administered immediately. Unused content must be discarded.
For additional information, see the IB.
Subjects allocated to this treatment group will receive SMT + Albutein 20%.
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4.4.1.2
Standard Medical Treatment
Subjects allocated to the control group will receive SMT, which will be administered per 
institution standards. Several guidelines are published for the management of decompensated 
cirrhosis (2-5). Diuretic therapy and dose modifications will be permitted on the basis of the 
evolution of ascites decompensation. Total paracentesis can be performed in the presence of 
tense ascites or symptoms due to the accumulation of abdominal fluid and will be followed 
by the administration of albumin. A TIPS will be considered when there are no other 
contraindications for this procedure for subjects with GI bleeding, refractory ascites, or 
hydrothorax. Complications such as bacterial infections, including SBP, or acute kidney 
injury, including type 1 HRS, will be treated according to current indications, which may 
require albumin infusion.
The usual treatment for comorbidities (ie, cardiac and respiratory diseases and diabetes) will 
be allowed according to the investigator’s medical judgement. Any medication administered 
during the study (including any blood products) will be recorded in the electronic case report 
form (eCRF) as well as in the subject’s medical record.
4.4.2
Labeling and Packaging of Investigational Product
Investigational products will be labeled according to the requirements of local law and 
legislation. Label text will be approved according to agreed Grifols procedures, and a copy of 
the labels will be made available to the study center. Each vial and corresponding box will 
have a label stating the protocol number and will specify that the product is only to be used in 
the clinical study.
4.4.3
Storage of Investigational Product
Albutein is stable for 3 years providing storage temperature does not exceed 25ºC. Protect 
from freezing. Do not use if the solution is turbid or if there is sediment in the bottle.
The product should be warmed to room temperature before use. Do not dilute with sterile 
water for injection. Once the container is open, the contents must be administered 
immediately. Do not begin administration more than 4 hours after the container has been 
entered. No remaining product in an opened container can be stored in the refrigerator and 
used at a later time. This product must not be used beyond the expiry date stated on the 
labeling.
Access to the IP must be strictly limited. The pharmacist or designee is responsible for 
maintain storage temperature records and for immediately reporting deviations in 
temperature to the study monitor.
4.5
Expected Duration of Subject Participation in the Study
The expected study duration of each subject in the study (after enrollment) will be up to 
12 months.
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4.6
Discontinuation Criteria for Individual Subjects and Study
4.6.1
Discontinuation Criteria for Individual Subjects
See Section 5.3 Subject Withdrawal Criteria.
4.6.2
Premature Termination of Study/Closure of Center
The sponsor, IRB/EC, and/or regulatory authorities have the right to close this study or a 
study center, and the investigator/sponsor has the right to close a center, at any time, although 
this should occur only after consultation between involved parties. The IRB/EC must be 
informed. Should the study/center be closed prematurely, all study materials (except 
documentation that has to remain stored at study center) must be returned to the sponsor. The 
investigator will retain all other documents until notification is given by the sponsor for 
destruction.
A study center can be closed for the following reasons:
•
Lack of enrollment 
•
Non-compliance with the requirements of the study protocol
•
Non-compliance with ICH GCP
4.7
Accountability Procedures for Investigational Product
Albutein 20% is to be used only for the study in accordance with the directions given in this 
protocol. The study pharmacist or designee is responsible for the distribution of the IP in 
accordance with directions given in the protocol and pharmacy manual.
The study pharmacist or designee is responsible for maintaining accurate records of the IP for 
his/her study center. Investigational product inventory/dispensing documentation verifying 
the receipt, dispensing, destruction, and return must be maintained and kept current by the 
pharmacist or designee. The unused inventory must be made available for inspection during 
the study by the monitor. Any unused material may be destroyed at the center according to 
their standard operating procedures (SOPs) or may be returned to the sponsor if the study 
center’s SOPs do not allow local destruction.
Unused IP supplies must be accounted for by the monitor and inventory/dispensing logs must 
be verified by the monitor prior to IP destruction. Written documentation from Grifols or 
designee of any unused inventory is required. At the end of the study, a copy of the 
inventory/dispensing log(s) and Interactive Web Response System dispensing documents 
will be retrieved by the monitor and returned to Grifols.
4.8
Maintenance of Treatment Randomization Codes 
Access to the actual randomization schedules or codes must be strictly controlled during the 
course of the study. 
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4.9
Data to Be Recorded Directly on the Case Report Forms
Not applicable.
5
SELECTION AND WITHDRAWAL OF SUBJECTS 
Eligible participants for this study include male and female adult subjects who are 
hospitalized with decompensated cirrhosis and ascites without ACLF at Screening. Subjects 
who fail to meet the eligibility criteria may not be re-screened.
Note that any criterion number containing v5 was modified in the indicated protocol waws 
modified in the protocol (eg, 2v5 indicates that the original criterion #2 was last modified in 
Protocol Version 5).
5.1
Inclusion Criteria
Inclusion Criteria:
A subject must meet all the following inclusion criteria to be eligible for participation in this 
study:
1.
Male or female subject ≥18 years of age.
2v5.
Subjects with diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic, 
and ultrasonographic features or on histology).
3v5.
Subjects who have been hospitalized for acute decompensation of liver cirrhosis with 
ascites (or with prior history of ascites requiring diuretic therapy) with or without 
ACLF at admission or during hospitalization but, without ACLF at Screening.
4v5.
This criterion has been removed from Version 5 of the protocol.
5.
In subjects with cirrhosis due to HBV, decompensation must occur in the setting of 
continuous (no less than 3 months) appropriate antiviral therapy.
6.
In subjects with cirrhosis due to HCV, only decompensated patients who will not 
receive antiviral therapy during the study period will be included (subjects receiving 
antiviral therapy within 14 days prior to enrollment cannot be included in the study).
7.
In subjects with cirrhosis due to autoimmune hepatitis, decompensation must occur in 
the setting of continuous immunosuppressive therapy.
8.
Subjects must be willing and able to provide written informed consent or have an 
authorized representative able to provide written informed consent on behalf of the 
subject in accordance with local law and institutional policy.
9v5.
CLIF-C score > 50 points at screening.
5.2
Exclusion Criteria
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study.
1v5.
Subjects with ACLF at Screening.
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2v5.
Subjects with type 1 HRS currently on treatment with vasoconstrictors or 
hemodialysis.
3.         Subjects with TIPS or other surgical porto-caval shunts.
4v5.
Subject with refractory ascites as defined by ICA criteria without any other event of 
acute decompensation (Appendix 2).
5v5.
This criterion has been removed from protocol Version 5.
6v5.
Subjects receiving dual anti-platelet therapy or anti-coagulant therapy (exception: 
DVT prophylaxis).
7v5.
Subjects with ongoing endoscopic eradication of esophageal varices with ≤2 
endoscopic sessions completed before screening.
8v5.
This criterion has been removed from protocol Version 5.
9.
Subjects with evidence of current locally advanced or metastatic malignancy.
Subjects with hepatocellular carcinoma within the Milan criteria [1 nodule ≤5 cm or 3 
nodules ≤3 cm] [Appendix 6], non-melanocytic skin cancer, or controlled breast or 
prostate cancer can be included.
10v4. Subjects with acute or chronic heart failure (New York Heart Association [NYHA] 
Appendix 7).
11.
Subjects with severe (grade III or IV) pulmonary disease (Global Obstructive Lung 
Disease [GOLD] Appendix 8).
12v5. Subjects with  nephropathy with renal failure with a serum creatinine >2 mg/dL or 
systemic hypertension.
13v5. This criterion has been removed from protocol Version 5. 
14.
Subjects with severe psychiatric disorders.
15.
Subjects with a known infection with human immunodeficiency virus (HIV) or have
clinical signs and symptoms consistent with current HIV infection.
16.
Females who are pregnant, breastfeeding, or, if of childbearing potential, unwilling to 
practice effective methods of contraception (oral, injectable, or implanted hormonal 
methods of contraception, placement of an intrauterine device (IUD) or intrauterine 
system, condom, or occlusive cap with spermicidal foam/gel/cream/suppository, 
male sterilization, or true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods], declaration of abstinence for the duration of the clinical study, 
and withdrawal are not acceptable methods of contraception).
17.
Subjects with previous liver transplantation.
18.
Subjects with known or suspected hypersensitivity to albumin.
19.
Subjects participating in another clinical study within 3 months prior to screening.
20v4. Subjects with active drug addiction (exceptions: active alcoholism or marijuana)
21.
In the opinion of the investigator, the subject may have compliance problems with the 
protocol and the procedures of the protocol.
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22.
Subjects with ongoing or recent variceal bleeding. (subjects can be included 2 weeks 
after hemorrhagic episode).
23.
Subjects with septic shock at screening.  
24.
Subjects with ongoing SBP infection (subjects can be included upon resolution).
25.
Subjects with current infection of COVID19, those who are less than 14 days post 
recovery, or those who have clinical signs and symptoms consistent with COVID19
infection.
5.3
Subject Withdrawal Criteria
5.3.1
Screen Failures 
Screening evaluations will be used to determine the eligibility of each subject for enrollment
into this study. Subjects who fail to meet eligibility criteria during screening evaluations will 
be considered screen failures and will not participate in the study.
5.3.2
Discontinuation of Subjects from Treatment
If a subject receives a liver transplant, study treatment and all treatment-related assessments 
will be discontinued upon transplant. The criteria to determine when a subject becomes a 
candidate for liver transplantation is described in Section 5.3.2.1. The subject will continue to 
have subsequent planned visit assessment procedures performed.
Discontinuation of the treatment in subjects who receive a TIPS insertion will be at the 
discretion of the investigators. In case it is decided to discontinue the subject’s treatment 
early, study treatment will be stopped and the subject will continue to have subsequent 
planned visit assessment procedures performed.
Adverse events that will determine temporary subject’s discontinuation from study treatment 
include the following:
•
Subjects developing severe bleeding, Albutein 20% infusions will be temporarily stopped 
until the bleeding episode is resolved. For subjects with variceal bleeding, Albutein 20% 
infusions will be temporarily stopped until the subject has received at least 2 banding 
sessions. Albutein 20% infusions will be resumed after the bleeding episode is resolved 
or after the subject has received at least 2 banding sessions, respectively.
Adverse events that will determine permanent subject’s discontinuation from study treatment 
include the following:
•
Anaphylactic shock or transfusion-related acute lung injury 
•
Severe AEs (ie, acute myocardial infarction, cerebral hemorrhage, cardiac failure, 
pulmonary edema, or intestinal necrosis) that precludes the continuation of the subject in 
the clinical study
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Subjects with any one of these severe AEs will be discontinued from study treatment and all 
treatment-related assessments, and should continue to have subsequent planned visit 
assessment procedures performed.
5.3.2.1
Liver Transplantation Criteria
To confirm that a subject meets the criteria for a liver transplant, the MELD score and the 
Child Pugh score (Appendix 3) will be assessed. Priority status will be defined by the MELD 
score and should be considered once a subject with cirrhosis experiences an index 
complication such as ascites, HE, variceal hemorrhage, and/or hepatocellular dysfunction. 
Subjects with an index complication and a MELD score ≥15, a Child-Pugh score of ≥7,
worsening renal dysfunction, or other evidence of rapid hepatic decompensation should be 
promptly evaluated for a liver transplant.
Additional criteria for liver transplantation in subjects with hepatocellular carcinoma or 
worsening within the Milan criteria (Appendix 6) with no CONTRAINDICATIONS as 
determined by the Organ Procurement and Transplantation Network (OPTN) Dynamic 
Imaging criteria (31) are as follows:
•
Subject is not a candidate for total resection
•
The hepatocellular carcinoma meets the definition of a Stage T2 lesion(s) that includes 
any of the following:
-
One lesion ≥2 cm and ≤5 cm
-
Two or 3 lesions ≥1 cm and ≤3 cm
-
No macrovascular involvement
-
No identifiable extrahepatic spread of tumor to surrounding lymph nodes, lungs, 
abdominal organs, or bone
5.3.3
Removal of Subjects
Subjects may withdraw or be withdrawn from the study for the following reasons:
1. At their own request or at the request of their legally acceptable representative.
2. If, in the investigator's opinion, continuation in the study would be detrimental to the 
subject's well-being.
3. At the specific request of the sponsor*
* Subjects will only be removed at the request of the sponsor if a safety concern is 
identified that may potentially cause harm to a subject or if the risk of the specified 
treatment outweighs the benefit.
4. Post-consent decision due to inclusion error (determination of ineligibility based on 
safety or eligibility criteria).
5. Physician’s judgment following an AE after treatment.
6. Termination of the study by a regulatory authority.
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In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
records. 
5.3.4
Subject Replacement 
Subjects who are randomized and withdrawn from the study will not be replaced.
5.3.5
Follow-up of Subjects Withdrawn from Study
If possible, blood samples will be obtained to complete all pertinent tests at the time of 
subject withdrawal. In all cases, the reason for withdrawal must be recorded in the eCRF and 
in the subject’s records. No subject can be re-enrolled into the study after having been 
withdrawn from the study.
Subjects who receive any amount of IP and discontinue early from the study should have all 
Month 12/Early Discontinuation visit procedures performed at the time of withdrawal 
(preferably within 1 week of withdrawal).
All efforts should be made to collect the vital status of the subject (including data on liver 
transplantation, subject survival, and cause of death) at Months 3, 6, and 12.
6
TREATMENT OF SUBJECTS
See Section 4.4 for the treatment(s) to be administered, including the name(s) of all the 
product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration. 
6.1
Administration and Timing of Investigational Products for Each 
Subject
6.1.1
Albutein 20% Dosage, Procedures, and Treatment Regimen
Randomization must occur within 72 hours of screening, and it can occur while the subject is 
hospitalized or after discharge from the hospital. The first dose of Albutein 20% is 
administered on the same day as randomization at a dose of 1.5 g/kg body weight (maximum 
100 grams per subject). Thereafter, subjects will receive Albutein 20% infusions at the dose 
of 1.5 g/kg body weight (maximum 100 grams per subject) every 10 ± 2 days for the rest of 
the study (up to a maximum of 12 months). At each administration, the infusion rate should 
be 4 mL/min.
6.1.2
Standard Medical Treatment
Standard medical treatment will be administered within 3 days (72 hours) of screening, and 
following randomization, per institution standards. Several guidelines are published for the 
management of decompensated cirrhosis (2-5). Subjects will receive SMT (see 
Section 4.4.1.2) for the length of the study or as long as needed.
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6.2
Prior and Concomitant Therapy
Prior (within 30 days prior to screening) and concomitant medications must be recorded in 
the eCRF and subject’s source documents, including the trade or generic names of the 
medication, the dose, the route of administration, and the duration of the medication 
(frequency).
Any medication administered during the study (including any blood products) will be 
recorded on the eCRF and subject’s source documents with the exception of anesthesia 
related products, fluid replacement therapies, and electrolyte supplementation. In addition, 
products administered at different doses on the same day to manage and maintain vital 
functions (eg, insulin, furosemide) will only be recorded once on the eCRF and subject’s 
source documents with the dosage reported as pro re nata.
In the event that an AE or suspected adverse drug reaction (ADR) should occur, complete 
details of all concomitant medications administered will be reported to the sponsor.
Usual treatments in decompensated cirrhosis will be allowed.
Treatment with terlipressin and albumin will be allowed in both treatment groups only in 
subjects developing type-1 HRS according to the ICA criteria (Appendix 2).
6.2.1
Prohibited Medications Prior to Study Participation
Subjects receiving dual anti-platelet therapy or anti-coagulant therapy prior to enrollment
(within 7 days prior to enrollment [exception: DVT prophylaxis]) cannot be included. In 
addition, subjects with HCV receiving antiviral therapy within 14 days prior to enrollment 
cannot be included.
6.2.2
Prohibited Concomitant Medications during the Study
Use of the following medications is prohibited during the study participation:
Albumin dialysis will not be allowed during the treatment period in the SMT + Albutein 20% 
treatment group. 
6.2.3
Restricted Concomitant Medications during the Study
This section describes medications that are restricted but not prohibited during the study 
participation:
Platelet transfusion will be made in cases of severe thrombocytopenia (<20,000/mm3), or in 
the case of bleeding complications when the platelet count is below 50,000/mm3.
6.2.4
Cardiac Overload/Pulmonary Edema Treatment
In subjects with the diagnosis of cardiac overload/pulmonary edema, standard protocols will 
be applied as per institution standards and may include fluid restriction, IV administration of 
furosemide, and Renal Replacement Therapy if clinically indicated (diuresis lower than
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0.5 mL/kg under high doses of furosemide). See Appendix 9 for an example of Algorithm for 
Cardiogenic Pulmonary Overload and Appendix 10 for guidelines on the management of 
pulmonary edema.
6.3
Treatment Compliance
Reasons for any deviation from the administration of less than 100% of the IP dose as 
prepared by the pharmacist or designee must be recorded in the eCRF and in the subject’s 
medical records.
7
ASSESSMENT OF EFFICACY
7.1
Efficacy Variables 
7.1.1
Primary Efficacy Variable
•
Time to liver transplantation or death through 1 year after randomization.
7.1.2
Secondary Efficacy Variables
•
Time to liver transplantation or death through 3 and 6 months after randomization, and 
time to death through 3 and 6 months after randomization
•
Time to death through 1 year after randomization
•
Total number of paracenteses and incidence of refractory ascites according the ICA 
criteria (Appendix 2)
7.1.3
Exploratory Variables
•
Incidence of ACLF (3, 6, and 12 months)
•
Organ function subscores (liver, renal, cerebral, coagulation, circulation, and respiration), 
according to the CLIF-C OF score and the total CLIF-C OF score (Appendix 3)
•
Number and length of hospital readmission for an acute complication of cirrhosis 
•
Number and length of ICU admission
•
Incidence of disease-related complications (see Section 8.3.10)
•
Serum albumin concentration and albumin functional capacity in serum (albumin binding 
capacity [Table 7-1])
•
Incidence of insertion of TIPS for refractory ascites
•
CLIF-C ACLF score ,CLIF-C AD score, MELD score, and Child Pugh score
•
Quality of life: EQ-5D-5L health questionnaire (Appendix 5)
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7.2
Methods and Timing for Assessing, Recording, and Analyzing 
Efficacy Parameters
7.2.1
Observations and Measurements
The following is a description of the procedures/assessments to take place at each study visit. 
See the Schedules of Study Procedures and Events in Appendix 1.
7.2.1.1
Screening Visit
Following signature of the informed consent form (ICF), subjects will be screened while 
hospitalized. Local laboratory testing will be used for screening to determine inclusion and 
exclusion criteria have been met, prior to initiating treatment. Local laboratory tests 
performed for screening purpose only will be kept in subjects’ source documents but will not 
be entered into the eCRF. In addition, Central Laboratory testing will be collected for the 
purpose of safety assessment and data analyses. 
If a subject is ineligible for participation, their demographic data and specific reason for 
ineligibility will be captured on the subject’s source documents and eCRF.
The screening assessments and activities will include:
•
Assign subject number
•
Add subject’s data into the Screening Log
•
Review of the inclusion and exclusion criteria which include local labs (see Sections 5.1
and 5.2, respectively) to determine subject’s eligibility
•
Documentation of demographics: date of birth, gender, race, and ethnic origin
•
Documentation of medical history, including etiology of cirrhosis, history, and significant 
concomitant disease conditions
•
Urine pregnancy test (human chorionic gonadotrophin [HCG]-based urine assay) for 
women of childbearing potential (to be performed locally at the investigative study 
center)
-
Women of child-bearing potential include any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation or bilateral oophorectomy) or is not postmenopausal (postmenopausal is 
defined as amenorrhea for more than 12 consecutive months or women on hormone 
replacement therapy with documented serum follicle stimulating hormone level 
<35 mIU/mL). Women who are using oral, implanted, or injectable contraceptive 
hormones or mechanical products such as an IUD or barrier methods to prevent 
pregnancy or practicing abstinence or where their sexual partner is sterile (eg, 
vasectomy) should be considered to be of child-bearing potential. 
•
Full physical examination (excluding breast and genitourinary examination)
•
Ascites assessment according to the ICA criteria (Appendix 2)
•
Hepatic encephalopathy evaluation (Appendix 4)
•
Hemodynamics assessment (mean arterial pressure [MAP])
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•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Blood sample collection for:
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score (Appendix 3).
•
Record endoscopic findings (if performed in the last 6 months)
•
Record abdominal ultrasound (if performed in the last 6 months)
•
Record ACLF grade (see Table 2-1)
•
Record prior (within the last 30 days) concomitant medications
•
Record AEs
7.2.1.2
Treatment Period (Day 1 through Month 12)
7.2.1.2.1
TREATMENT DAY 1
Randomization must occur within 72 hours of screening, and it can occur while the subject is 
hospitalized of after discharge from the hospital. The first dose of Albutein 20%  is 
administered on the same day as randomization. All assessments and activities will be 
performed prior to treatment. In the SMT + Albutein 20% treatment group, vital signs and 
serum albumin concentration will also be recorded after treatment. Study assessments and 
activities will include:
•
Randomization (after confirmation of subject eligibility, hospital discharge (if 
applicable), and prior to treatment)
•
Record vital signs (systolic and diastolic blood pressure [BP], heart rate [HR], respiratory 
rate [RR], temperature [T]) (measured immediately prior to and immediately after the end 
of the Albutein 20% administration in the SMT + Albutein 20% treatment group)
•
Ascites assessment according to the ICA criteria (Appendix 2)
•
Record weight
•
Blood sample collection for (see Table 7-1): 
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group)
-
Systemic inflammatory assessment 
-
Albumin functional capacity assessment (albumin binding capacity)
-
Blood biomarker retains (all clinical blood samples will need to be drawn first) 
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire [Appendix 5]) 
•
Record AEs
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
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7.2.1.2.2
TREATMENT DAY 11 AND MONTHLY VISITS (MONTH 1 THROUGH MONTH 11)
Subjects will have assessments on Day 11 (±2 days), Month 1 (±2 days), and then monthly 
(±2 days) for up to 11 months: Days 31, 61, 91, 121, 151, 181, 211, 241, 271, 301, 331. 
All assessments and activities will be performed prior to treatment. In the SMT + 
Albutein 20% treatment group, vital signs and serum albumin concentration will also be 
recorded after treatment. Study assessments and activities will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to 
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
•
Ascites assessment according to the ICA criteria (Appendix 2)
•
Hepatic encephalopathy evaluation (Appendix 4)
•
Hemodynamics assessment (MAP)
•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Assessment of TIPS insertion 
•
Record weight
•
Blood sample collection for (see Table 7-1):
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group
-
Systemic inflammatory assessment 
-
Albumin functional capacity assessment (albumin binding capacity [Day 11, Months 
1, 3, 6, and 9 only])
-
Blood biomarker retains (optional, all clinical blood samples will need to be drawn 
first) (Months 1, 3, 6, and 9 only) 
•
Record ACLF grade (see Table 2-1)
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score (Appendix 3).
•
Physical examination (Month 6 only)
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire [Appendix 5]) (Months 1, 3, 
6, and 9 only)
•
Record AEs 
•
Record data on liver transplantation, subject survival, and cause of death (Months 3 and 6 
only) 
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
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7.2.1.2.3
SMT + ALBUTEIN 20% TREATMENT DAYS 21, 41, 51, 71, 81, 101, 111, 131,
141, 161, 171, 191, 201, 221, 231, 251, 261, 281, 291, 311, 321, 341, 351
Subjects in the SMT + Albutein 20% treatment group will receive infusions every 10 (± 2) 
days for up to 12 months in the study. Study assessments and activities will include:
All treatment day assessments and activities will be performed prior to treatment in the 
SMT + Albutein 20% treatment group only. Vital signs will also be recorded in the 
SMT + Albutein 20% treatment group only after treatment. Study assessments and activities 
will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
•
Record weight
•
Record concomitant medications
•
Record AEs
•
Albutein 20% infusion (SMT + Albutein 20% treatment group only)
7.2.1.2.4
MONTH 12 VISIT/ EARLY DISCONTINUATION VISIT
All assessments and activities at the Month 12 (Day 361 ±2 days)/Early Discontinuation 
Visit will be performed prior to treatment. In the SMT + Albutein 20% treatment group, vital 
signs and serum albumin concentration will also be recorded after treatment. Study 
assessments and activities will include:
•
Record vital signs (systolic and diastolic BP, HR, RR, T) (measured immediately prior to
and immediately after the end of the Albutein 20% infusion in the SMT + Albutein 20% 
treatment group)
•
Ascites assessment according to the ICA criteria (Appendix 2)
•
Hepatic encephalopathy evaluation (Appendix 4)
•
Hemodynamics assessment (MAP)
•
Peripheral capillary oxygen saturation (SpO2) assessment
•
Assessment of TIPS insertion 
•
Record weight
•
Blood sample collection for (see Table 7-1):
-
Clinical laboratory assessments (eg, hematology, chemistry, coagulation)
-
Serum albumin concentration (measured immediately prior to and immediately after 
the end of the Albutein 20% administration in the SMT + Albutein 20% treatment 
group [Month 12 Visit only])
-
Systemic inflammatory assessment 
-
Albumin functional capacity assessment in serum (albumin binding capacity)
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-
Blood biomarker retains (optional, all clinical blood samples will need to be drawn 
first) 
•
Record ACLF grade (see Table 2-1)
•
Illness severity scores evaluation: CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF 
score, MELD score, and Child Pugh score (Appendix 3).
•
Physical examination 
•
Record concomitant medications
•
Quality of life assessment (EQ-5D-5L health questionnaire [Appendix 5])
•
Record AEs
•
Record data on liver transplantation, subject survival, and cause of death 
•
Albutein 20% infusion (SMT + Albutein 20% treatment group [Month 12 Visit only])
7.2.1.3
End of Study Visit for Subjects who Complete Study Treatment
Subjects will return to the study center within 1 week of study completion. End of study 
assessments in subjects who complete study treatment (up to 12 months) will include:
•
Record concomitant medications
•
Record AEs
7.2.1.4
Follow-Up for Early Discontinued Subjects (Months 3, 6, 12)
In subjects who discontinue from the study early, the following assessments will be 
performed at Months 3, 6, and 12:
•
Record data on liver transplantation, subject survival, and cause of death 
7.2.2
Description of Laboratory Tests and Procedures
Detailed descriptions of laboratory test procedures are located in the study Laboratory 
Manual. Table 7-1 provides a summary of the laboratory tests conducted for this study.
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Table 7-1 Name, Description, and Location of Laboratory Tests and Procedures
Test Panel
Description
Location
Hematologya
Hemoglobin, hematocrit, platelets, red blood cell count, white blood 
cell count with differential
Central
Chemistrya
Sodium, potassium, creatinine, blood urea nitrogen, calcium, 
magnesium, lactate dehydrogenase, AST, ALT, gamma-glutamyl 
transpeptidase, ALP, glucose, total bilirubin, direct and indirect 
bilirubin, C-reactive protein (CRP), lactate, serum albumin 
Central
Coagulationa
International normalized ratio (INR)a, fibrinogen, platelet count, 
prothrombin time
Central
Urine pregnancy test
Qualitative urine β-HCG will be performed at Screening
Local
Albumin functional 
capacity assessment
Albumin binding capacity
Central
Systemic inflammation 
assessment
Procalcitonin, WBC (hematology panel), CRP (chemistry panel)
Central
Biomarkers retainsb,c
Blood 
Central
Abbreviations: ALP - alkaline phosphatase; ALT - alanine aminotransferase; AST - aspartate aminotransferase; 
BUN – blood urea nitrogen; CRP – C-reactive protein; GGT – gamma-glutamyl transpeptidase; HCG - Human 
chorionic gonadotropin; INR – international normalized ratio; LDH – lactate dehydrogenase; WBC – white 
blood cells.
a
Laboratory tests required for determination of illness severity scores are presented in Appendix 3. A central 
laboratory will be used for all laboratory testing, including results required for illness severity scoring
(eg, creatinine, bilirubin, INR). At the Screening visit only, local laboratory tests will be performed in order 
to determine subject eligibility. Screening local laboratory test results will be kept in subjects’ source 
documents but will not be entered into the eCRF.
b
Biomarker retains will be drawn for potential analysis of cytokines (interleukin [IL] 6 (IL-6), IL-8, IL-10, 
and tumor necrosis factor alpha [TNFα]) found in the blood which are significantly correlated with disease 
activity. Blood samples will be stored for possible future analysis of other biomarkers that may be
identified throughout the length of the clinical study and beyond. These samples will be frozen and retained 
for 15 years at which time if no analysis is performed, the samples will be destroyed. All clinical blood 
samples will need to be drawn first.
c
For subjects in the SMT + Albutein 20% treatment group, biomarker retains should be collected prior to 
infusion.
7.2.3
Drug Concentration Measurements
As indicated, serum albumin concentration (clinical chemistry laboratory assessment) will be 
measured on Day 1 and throughout the treatment period (see Appendix 1). In the 
SMT + Albutein 20% treatment group, measurements will be collected prior to and after 
treatment administration.
8
ASSESSMENT OF SAFETY
8.1
Safety Variables
Safety of Albutein 20% will be evaluated in this study.
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•
The number of suspected ADRs, including ARs, and incidence rate of subjects with 
suspected ADRs during the treatment period and within 72 hours after Albutein 20% 
infusion completion (or after Albutein 20% infusion stops) will be considered as the main 
safety variables. The number and incidence rate of overall AEs and SAEs, as well as 
deaths and discontinuations due to AEs will be also collected and analyzed. 
•
Vital signs will be recorded at each scheduled visit and in particular before and after each 
Albutein 20% administration.
•
Clinical laboratory test parameters (blood cell counts, platelet count, INR, fibrinogen, 
etc.) will be assessed according to the study schedule.
•
Physical examinations will be assessed according to the study schedule.
•
According to the investigator’s assessment, all clinically relevant changes in vital 
function and laboratory testing parameters findings will be considered AEs.
8.2
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters
For timing of safety assessments, please see Section 7.2.1.
8.2.1
Adverse Events 
Adverse events (includes suspected ADRs) occurring at any time between signing of the 
subject’s ICF and the last day of the subject’s participation (End of Study or Early 
Discontinuation Visit) in the clinical study will be reported and recorded on the appropriate 
subject’s eCRF entry and subject’s source documents. 
It is the investigator’s responsibility to ensure that all AEs including suspected ADRs are 
appropriately recorded. 
8.2.2
Vital Signs
Vital signs will be measured by a medically certified individual or a nurse according to 
his/her standard clinical practice. 
The following vital signs will be assessed:
•
Temperature
•
Blood pressure (systolic and diastolic BP)
•
Heart rate
•
Respiratory rate
Vital signs will be routinely monitored by the study staff as detailed in Appendix 1. The 
investigator will be required to classify vital signs abnormalities as clinically significant or 
not according to his/her criteria. Results will be recorded in source documents and on the 
subject eCRF. Vital signs abnormalities judged by the investigator as clinically significant 
will be considered AEs.
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8.2.3
Clinical Laboratory Evaluations
Considering the medical history inherent in subjects with decompensated cirrhosis, certain 
laboratory abnormalities, while clinically significant, will be expected in this medical 
context, and would not indicate treatment-emergent worsening or a new AE (being instead an 
extension of medical history/underlying pre-existing conditions). Examples include: low 
platelet count, decreased albumin, prolonged prothrombin time/INR, elevated bilirubin, and 
abnormal transaminases. These conditions would be expected laboratory consequences of 
cirrhosis/decompensated liver diseases. These results would not be considered individual 
AEs as they most likely reflect manifestations of existing cirrhosis and hepatic 
decompensation, unless abnormalities worsen after initiation of study treatment and become 
accentuated to a medically significant degree in a treatment-emergent fashion.
Central clinical laboratory data for renal, hepatic, and hematological parameters will be listed 
for each clinical study subjects. 
The investigator will be required to classify laboratory results out of the normal range 
reported by the central laboratory as clinically significant or not according to his/her criteria. 
Laboratory results out of the normal range judged by the investigator as clinically significant 
will be considered AEs.
8.2.4
Physical Examinations
A medically certified individual will conduct a physical examination.
8.3
Procedures for Eliciting Reports of and for Recording and 
Reporting Adverse Event and Intercurrent Illnesses
The investigator is responsible for ensuring that all staff involved in the clinical study are 
familiar with the content of this section.
8.3.1
Warnings/Precautions
For complete information on Albutein 20% refer to the IB.
8.3.2
Adverse Event Monitoring
Subjects must be carefully monitored for AEs. This monitoring includes clinical and 
laboratory tests and physical signs. Adverse events should be assessed in terms of their 
seriousness, severity, and causal relationship to the IP. 
Adverse events will be elicited by spontaneous reporting by the study individual or by a non-
leading inquiry or direct observation by the study staff. 
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8.3.3
Adverse Event Definitions
8.3.3.1
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. This includes worsening of a pre-existing condition or 
increase in frequency of a pre-existing condition.
An AE is also defined as any occurrence that is new in onset, expected, or aggravated in 
severity or frequency from a baseline condition, or abnormal results or diagnostic procedures 
including laboratory test abnormalities.
In this clinical study, deterioration of the targeted disease and symptoms associated with the 
targeted disease will not be considered an AE as long as the deterioriation is anticipated and 
there is no evidence suggesting a causal relationship between the study drug and the AE. 
Anticipated disease progression includes, but not limited to: HE, GI bleeding, portal 
hypertension, ascites, SBP, hyponatremia and HRS (see Section 8.3.10).
8.3.3.2
Suspected Adverse Drug Reactions/Adverse Reactions
All noxious and unintended responses to a medicinal product or study treatment related to 
any dose should be considered suspected ADRs. The phrase “responses to a medicinal 
product” means that a causal relationship between a medicinal product or study treatment and 
an AE is at least a reasonable possibility. An AR is a subset of the suspected ADRs that are 
deemed as definitely related to the treatment. See below for additional details.
8.3.4
Assessment of Causality of Adverse Event
The investigator is required to provide a causality assessment for each AE reported to the 
sponsor. The sponsor will consider the investigator’s causality assessment and also provide 
its own assessment. Causal relationship to the study drug will be established according to 
medical judgment on whether there is a reasonable possibility of a causal relationship 
between the AE and the study drug.
The investigator must determine and classify the AE causality according to the following 
categories:
Unrelated/Not related: there is not a reasonable possibility of causal relationship between 
the AE and the study drug.
Possibly related: there is evidence to suggest a causal relationship between the study drug 
and the AE.
Definitively related: there is a reason to conclude that the study drug caused the AE.
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Criteria to assess the causal relationship should take into account of the following conditions:
•
A plausible temporal sequence from the study drug administration to the AE onset
•
Whether the event follows a known response pattern to the suspected treatment
•
Whether the AE could be reasonably explained by the subject’s clinical state, 
comorbidities, or concomitant medications
•
The occurrence of improvement on stopping/reducing the treatment (positive 
dechallenge) and/or reappearance of the event on repeated exposure (positive 
rechallenge)
For expedited safety reporting purposes, AEs assessed as either “definitively related” or 
“possibly related” will be considered POTENTIALLY RELATED or just RELATED.
8.3.5
Severity of Adverse Event or Suspected Adverse Drug Reaction
AEs including suspected ADRs will be classified according to severity, depending on the
intensity of the event, as follows:
Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise and 
without affecting activities of daily living (ADL).
Moderate: an AE that interferes with ADL.
Severe: an AE that prevents ADL.
Severity gradation of AEs including suspected ADRs must be distinguished from their 
seriousness gradation, which is defined according to event consequence. For example, 
headache can be mild, moderate or severe but not necessarily serious in all these cases. See 
Section 8.3.7 for Seriousness of AEs.
The investigator will be responsible for assessing the severity of AEs including suspected 
ADRs during the clinical study.
8.3.6
Expectedness of Adverse Event or Suspected Adverse Drug Reaction
An AE or suspected ADR is considered “unexpected” if the nature, seriousness, severity or 
outcome of the reaction(s) is not consistent with the reference information. The expectedness 
shall be determined by the sponsor according to the reference document (ie, IB or Summary 
of Product Characteristics) for any serious ADRs (potentially related serious adverse events 
[SAEs]) for expedited safety reporting purposes. 
8.3.7
Seriousness of Adverse Event or Suspected Adverse Drug Reaction  
Adverse Events including suspected ADRs are considered “serious” if, in the view of either 
the investigator or sponsor, they result in any of the following outcomes: 
•
Death
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•
Life-threatening AE (life-threatening in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe)
•
In-patient hospitalization or prolongation of existing hospitalization*
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
•
A congenital anomaly/birth defect
•
An important medical event (important medical event in the definition of “serious” refers 
to those events which may not be immediately life-threatening, or result in death, or 
hospitalization, but from medical and scientific judgment may jeopardize the subject 
or/and may require medical or surgical intervention to prevent one of the other outcomes 
listed above)
* After the initial hospital discharge, any hospitalization is to be considered only hospital 
stay for equal or more than 24 hours. The following hospitalizations should not be 
reported as SAEs:
-
Hospitalization or prolongation of hospitalization as part of a routine procedure 
followed by the center or clinical practice (according to the investigator’s criteria) for 
the treatment of decompensated cirrhosis
-
Hospitalization for a survey visit, annual physicals, or social reasons
-
Elective or pre-planned hospitalizations for a pre-existing condition that had not 
worsened from Baseline (eg, elective or scheduled surgery arranged prior to start of 
the study)
-
Admissions not associated with an AE (e.g. social hospitalization for purposes of 
respite care)
This definition permits either the sponsor or the investigator to decide whether an event is 
“serious.” If either the sponsor or the investigator believes that the event is serious, the event 
must be considered “serious” and evaluated by the sponsor for expedited reporting. 
8.3.8
Adverse Event Documentation
All AEs and SAEs occurring after the subject has signed the ICF through the Final Visit 
(ie, End of Study or Early Discontinuation Visit) must be fully recorded in the subject’s 
eCRF and SAE form (if serious) as well as in the medical record. If no AE has occurred 
during the study period, this should also be indicated in the eCRF.
It is the responsibility of the investigator to ensure that AEs are appropriately recorded.
At each visit, AEs will be elicited by asking the individual a non-leading question such as 
“Do you feel different in any way since the last visit?” Moreover, AEs will also be collected 
through directly observed events or spontaneously volunteered by the subject. Clearly related 
signs, symptoms, and abnormal diagnostic procedures should preferably be grouped together 
and recorded as a single diagnosis or syndrome wherever possible.
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The following variables must be recorded in the AE eCRF:
•
The verbatim term (a diagnosis is preferred)
•
Date/time of onset
•
Date/time of resolution
•
Severity (mild, moderate, severe)
•
Causality (unrelated/not related, possibly related, definitely related)*
•
Seriousness (yes, no)
•
Action taken (with regard to IP)
•
Other action (to treat the event)
•
Outcome and sequel (follow-up on AE)
* An AE occurring before subject’s exposure to treatment will be labeled as “unrelated/not 
related”.
If it is a preexisting AE that gets worse regarding intensity or frequency, it should be 
indicated.
For AEs that occur during infusions, the infusion rate in effect at the time of onset of the AE 
(if applicable), the time of onset of the AE and the time of AE change materially in intensity 
and/or resolve will be captured in the eCRF.
In addition to the investigator’s own description of the AEs, each AE will be encoded 
according to the Medical Dictionary for Regulatory Activities (MedDRA).
For example, a laboratory test abnormality considered clinically significant, eg, causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged clinically significant in the context of the subject’s medical history 
by the investigator, should be reported as an AE. Each event must be described in detail 
along with start and stop dates, severity, relationship to treatment, action taken, and outcome. 
Each event must be adequately supported by documentation as it appears in the subject’s 
medical or case file.
8.3.9
Event of Special Interest
There are no events of special interest related to Albutein 20%.
8.3.10
Disease Progression
In this clinical study, disease progression is defined as the worsening of a subject’s condition 
attributable to the disease for which the IP is being studied. It may be an increase in the 
severity of the targeted disease and/or increases in the symptoms of the targeted disease. 
Anticipated disease progression includes, but not limited to: HE, GI bleeding, portal 
hypertension, ascites, SBP, hyponatremia and HRS.  
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The development of sequelae of decompensated cirrhosis during the clinical study should be 
considered as disease progression and not an AE, unless there is evidence suggesting a causal 
relationship between the study drug and the AE. Manifestations of decompensated cirrhosis 
will be treated as disease progression and will be documented in the eCRF and subject’s 
medical records, but not immediately reported to the sponsor.
Hospitalization due to disease progression and/or the signs and symptoms of disease 
progression should not be reported as an SAE during the study.
8.3.11
Reporting of Serious Adverse Events, Deaths, and Pregnancy
8.3.11.1
Reporting of Serious Adverse Events
Any SAE (see Section 8.3.7) that occurs after signing the study ICF through the Final 
Visit (ie, End of Study or Early Discontinuation Visit) must be expeditiously reported 
whether or not considered attributable to the study drug. Each SAE must be fully recorded in 
the subject’s eCRF and SAE Report Form. In addition, any SAE that occurs after the end of
study/early discontinuation should be reported if the investigator feels that the event is 
related to the use of IP.
SAEs will be reported using the designated SAE Report Form. When the investigator 
becomes aware of an SAE, she/he must submit a completed, signed, and dated SAE Report 
Form (in English) within 24 hours to the sponsor by email/fax. The date of this SAE 
discovery by the study center staff should be documented in the source documents (ie, 
medical records). 
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow-up, and for the outcome, must also be supplied to the 
sponsor in a timely manner (within 3 days from its identification or within 24 hours for 
relevant new information) by means of the SAE Report Form. In addition, the sponsor or 
contract research organization may request additional information and/or reports.
All SAE Report Forms must be reported to:
Grifols Global Pharmacovigilance
Email:
FAX (back-up only):
(USA)
(International)
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities. Copies of the investigator’s reports must be sent to the 
sponsor.
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8.3.11.2
Reporting of Deaths
The following considerations should be made for all deaths occurring during the clinical 
study:
•
Any death that is unequivocally due to disease progression should not be reported as an 
SAE, but should be documented in the eCRF as well as in the subject’s medical record.
•
Any death that is not unequivocally due to disease progression should be immediately 
reported as an SAE (see Section 8.3.11.1) as well as documented in the subject’s medical 
record. Every effort should be made to establish a cause of death. Reporting of the SAE 
should include a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign a single primary cause of death (AE) together with any 
contributing causes.
8.3.11.3
Reporting Pregnancy
While pregnancy itself is not a true “AE,” pregnancy occurring in a clinical study must be 
followed to collect information regarding the experiences of gestation and pregnancy. The 
investigator must report any pregnancy that occurs in a study subject or partner of a male 
subject from the first treatment exposure until 28 days after the last dose of treatment. A 
pregnancy will not be considered an AE unless a relation to the treatment is suspected. A 
Pregnancy Report Form must be completed and sent as soon as possible to the sponsor. A 
copy of the form should be filed at the study center for pregnancy follow-up until delivery or 
to the end of pregnancy. Any anomalies, complications, abnormal outcomes, or birth defect 
observed in the child must be reported as an SAE within 24 hours of the investigator or study 
personnel’s first knowledge. 
Please use the email address or fax numbers (back up only) in Section 8.3.11.1 for reporting 
pregnancy.
8.4
Type and Duration of the Follow-Up of Subjects after Adverse 
Events 
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved. If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known, or the event 
has been stabilized and no further change is expected and the investigator decides that no 
further follow-up is necessary.
9
STATISTICS
9.1
Statistical Methods 
Unless otherwise specified, descriptive statistics will include the number of non-missing 
observations, mean, standard deviation (SD), median, minimum and maximum values for the 
continuous/quantitative data or absolute and relative frequency counts and percentages for 
categorical/qualitative data.
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Data handling and evaluation procedures will be described in the Statistical Analysis Plan 
(SAP).
9.1.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group. For 
quantitative variables, mean, SD, median, minimum, and maximum will be provided. For 
qualitative variables, the frequency and percentage will be provided.
9.1.2
Efficacy Analysis 
9.1.2.1
Primary Endpoint
This is a study to demonstrate superiority of SMT + Albutein 20% to SMT alone on 1-year 
transplant-free survival. The null hypothesis is that the hazard functions for liver 
transplantation or death are the same for the 2 treatment groups, or equivalently, the hazard 
ratio is equal to 1. The alternative hypothesis is that the hazard functions for liver 
transplantation or death are not the same for the 2 treatment groups, or equivalently, the 
hazard ratio is not equal to 1. The effect of SMT + Albutein 20% administration on the 
transplant-free survival at 1 year after randomization versus SMT alone will be summarized 
by means of Kaplan-Meier survival estimates and curves and compared between treatment 
groups by means of the Log-rank test stratified by region (Europe or NA) and history of 
hospitalization for acute decompensation of liver cirrhosis (yes or no). An un-stratified 
analysis will be performed as a sensitivity analysis.
In the event that clinically and statistically significant imbalances are observed between 
treatment groups in any of subjects’ baseline characteristics, sensitivity analyses will be 
performed in which treatment effects will be adjusted by those characteristics by fitting an 
appropriate Cox Proportional-Hazards (PH) model. In addition, subgroup analyses by age 
group, sex, race, region (Europe vs NA), and history of hospitalization for acute 
decompensation of liver cirrhosis (yes vs no) will be carried out for the primary endpoint.
The primary efficacy analysis will be carried out on the ITT population and repeated on the 
Per-Protocol (PP) population (see Section 9.7 for description of subject populations for 
analysis).
9.1.2.2
Secondary Endpoints
The analysis of the secondary endpoints will be performed using the ITT population.
The effects of SMT + Albutein 20% administration on the overall survival at 3, 6, and 12 
months and transplant-free survival at 3 and 6 months after randomization versus SMT alone
will be assessed by carrying out the same analyses for the primary efficacy variable described 
above.
Total number of paracenteses and incidence of refractory ascites will be listed for each 
subject, summarized by treatment group,  and compared between treatment groups by means 
of analysis of covariance (ANCOVA) or Student’s t test (for normally-distributed variables), 
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Poisson regression model (for count variables), and Fisher’s exact test or Chi-square test (for 
binomial variables).
The fixed-sequence testing method will be used to adjust for multiplicity in the analyses of 
the secondary efficacy endpoints. Specifically, the superiority of SMT + Albutein 20% 
versus SMT alone for the secondary efficacy endpoints will only be tested if the superiority 
for the primary efficacy endpoint is demonstrated at the 2-sided significance level of 5%. For 
the secondary efficacy endpoints, each subsequent hypothesis is tested only if the superiority 
for the previous comparison(s) has been demonstrated at a 2-sided significance level of 5%. 
The order in which the null hypotheses will be tested is predetermined for the secondary 
efficacy endpoints as follows:
1. Time to death through 1 year after randomization
2. Time to liver transplantation or death through 6 months after randomization
3. Time to death through 6 months after randomization
4. Time to liver transplantation or death through 3 months after randomization
5. Time to death through 3 months after randomization
6. Total number of paracenteses
7. Incidence of refractory ascites according the ICA criteria
9.1.2.3
Exploratory Endpoints
As appropriate to the data, the original values or changes from baseline (last measurement 
taken prior to the start of study treatment on Day 1) of the following exploratory endpoints 
will be listed for each subject, summarized by treatment group, and compared between 
treatment groups by means of ANCOVA or Student’s t tests (for normally-distributed 
variables), non-parametric Mann-Whitney U test (for non-parametric variables), Kaplan-
Meier estimates and Log-rank test (for time-to-event variables), Poisson regression model 
(for count variables), and Fisher’s exact test or Chi-square test (for binomial variables): 
Incidence of ACLF, CLIF-C OF score, CLIF-C ACLF score, CLIF-C AD score, MELD 
score, Child Pugh score, number and length of hospital readmission for an acute 
complication of cirrhosis, number and length of ICU admission, incidence of disease-related 
complications, serum albumin concentration, albumin functional capacity (albumin binding 
capacity), incidence of insertion of TIPS for refractory ascites, and the EQ-5D-5L health 
questionnaire.
For the normally-distributed variables, the ANCOVA model will include change from 
baseline as the dependent variable, treatment as a fixed factor, and baseline value as a 
covariate. If any potential confounders are identified among subjects’ baseline 
characteristics, they will be included as additional covariates in the ANCOVA models to 
adjust treatment effects. In addition, for the longitudinal measurements taken repeatedly over 
time, the treatment effects may be explored by using the mixed-effect model repeated 
measures analysis.
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9.1.3
Safety Analysis
The safety analyses will be addressed by listing and tabulation of AEs (including suspected 
ADRs), vital signs, physical assessments, and clinical laboratory tests. Data will be described 
using descriptive analyses and treatment comparisons will be based on review of descriptive 
statistics. The safety analyses will be based on the Safety population.
9.1.3.1
Adverse Events
Adverse events will be coded and classified using MedDRA® terms (system organ class and 
preferred terms). 
When a causal relationship of an AE is classified by the investigator as definitively or 
possibly related, the event will be defined as a suspected ADR. A suspected ADR with a 
causal relationship of “definitively related” will be defined as an AR. The sponsor will 
consider the investigator’s causality assessment and also provide its own assessment. If there 
is any disagreement in the causality assessment between the investigator and the sponsor, a 
separate summary of suspected ADRs/ARs will be provided.
For summary purpose, AEs will be classified as treatment-emergent AEs (TEAEs) or non-
TEAEs depending on the comparison of AE onset date/time with the start date/time of study 
treatment. A TEAE will be defined as an AE which occurs between the start of study 
treatment and the final visit of the clinical study. A non-TEAE will be defined as an AE 
which occurs prior to the start of study treatment. Non-TEAEs and TEAEs will be 
summarized separately.
In addition, TEAEs, including suspected ADRs, will be summarized by each treatment 
group, system organ class, preferred term, causal relationship, severity, and seriousness 
(serious versus non-serious) using descriptive statistics. At each level of summarization, a 
subject will only be counted once per system organ class or preferred term using the most 
severe AE or the AE with the strongest causal relationship to the treatment. 
AEs temporally associated with the infusion of the IP (ie, infusional AEs, including 
infusional suspected ADRs) will be summarized by presenting infusion/subject incidences 
and percentages and listed. 
Subjects with SAEs, AEs leading to death, or who withdraw from the study because of an AE 
will also be individually listed and summarized. 
9.1.3.2
Clinical Laboratory Values
All clinical laboratory data (Table 7-1) will be listed for each subject and summarized by 
treatment group. 
The investigator will be required to classify out of the normal range laboratory results 
reported by the laboratory as clinically significant or not according to his/her criteria. 
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Out of the normal range laboratory results judged by the investigator as clinically significant 
in the context of the subject’s medical history will be considered AEs. 
9.1.3.3
Vital Signs
Vital signs (T, RR, HR, systolic and diastolic BP) will be listed for each subject and 
summarized by treatment group. In case a subject presents a clinically significant 
abnormality of vital signs during an infusion, the event will be flagged and reported as an AE 
temporally associated with the infusion.
Clinically significant vital signs abnormalities will be presented as AEs. Clinical relevance 
will be based on the investigator’s criteria. 
9.1.3.4
Physical Assessment
Physical assessment findings (normal and abnormal) will be listed for each subject and 
summarized by treatment group. Any clinically significant abnormality, as determined by the 
investigator, experienced by a subject during the clinical study and not already present at 
baseline will be reported as AE. 
9.2
Determination of Sample Size
Based on the CANONIC study, the overall 1-year transplant-free mortality rate in the current 
study population is assumed to be about 46% (24,26). Assuming a potential drop-out rate of 
20% and 5% type-1 error for a 2-sided Chi-square test, a global sample size of 410 patients 
(205 per treatment group) will allow an 80% statistical power to detect an absolute reduction 
of 15% (15) for the 1-year mortality rate in subjects treated with SMT + Albutein 20%. 
Alternatively, the sample size was calculated based on the log-rank test as follows. Assuming 
the 1-year transplant or mortality rate is 46% for the control group, or equivalently, the 
transplant-free survival rate is 54%, which translates to a hazard rate of 0.0017 assuming an 
exponential distribution. Using a log-rank test at the 2-sided significant level of 5%, a total of 
125 events would provide at least 80% power to detect an absolute reduction of 15% in 
transplant or mortality rate (a 31% 1-year transplant or mortality rate, or equivalently, a 69% 
transplant-free survival rate) in subjects treated with SMT + Albutein 20%. This absolute 
difference in transplant or mortality rates translates to a hazard ratio of 0.6022, or an 
approximate 40% risk reduction. With all subjects followed for the entire 1-year duration of 
the study, a total of 322 subjects would be required to obtain 125 events. Assuming a dropout 
rate of 20%, a global sample size of 404 subjects (202 per treatment group) is required. This 
sample size calculation was performed using Proc Power with the Twosamplesurvival 
statement in SAS version 9.4.
Taking a conservative approach, the larger of the 2 sample sizes (ie, the one based on the 
Chi-square test) will be used to ensure the study has sufficient power.
9.3
Level of Significance to Be Used
All statistical tests will be 2-sided and the significance level will be fixed at 0.05. 
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More details including approaches for multiplicity adjustments (if needed) will be provided 
in the SAP.
9.4
Criteria for Termination of the Study 
The criteria for termination of the study are listed in Section 4.6.2. Stopping rules for the 
study will also be provided separately in the DSMB charter.
Study stopping rules for individual subjects is presented in Section 5.3.
9.5
Procedure for Accounting for Missing, Unused, and Spurious Data
The procedure for accounting for missing, unused, and spurious data will be detailed in the 
SAP.
9.6
Reporting Deviations from the Statistical Analysis Plan
The detailed statistical analysis methodologies will be documented in the SAP. If there are 
any deviations from the originally planned analyses in the SAP, they will be fully described 
and justified in the protocol amendment(s) and/or final clinical study report.
9.7
Subject Population for Analysis
There will be 3 analysis populations in this study; 2 populations for efficacy assessment and 
1 population for safety evaluation.
The ITT population is defined as all subjects who are randomized. The ITT population will 
be used for all efficacy analyses. Subjects will be grouped according to the treatment to 
which they are randomized in all efficacy analyses.
The PP population is defined as the subset of subjects included in the ITT population who do 
not present major protocol violations which might have an impact on the primary efficacy 
analysis, complete at least 80% of the scheduled treatments and are not excluded from the 
study for interrupting the Albutein 20% treatment for more than 4 consecutive weeks (SMT + 
Albutein 20% treatment group subjects). The primary efficacy analyses will be carried out 
using the PP population in order to confirm the results based on the ITT population.
The Safety population is defined as the subset of patients who receive at least one SMT plus 
Albutein 20% treatment or SMT. Safety analyses will be based on this population. Subjects 
will be grouped according to the treatment they actually received in all safety analyses.
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The data will be recorded and kept current in eCRFs by the study center personnel directly 
responsible for the information and reviewed for completeness by the monitor. Grifols 
personnel or designee can review the records.
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In accordance with ICH GCP guidelines, the monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency and to verify adherence to the protocol, and the completeness, consistency, and 
accuracy of data entered. “Source documentation” includes individual subject files, separate 
from the eCRFs, which should be maintained and include visit dates, laboratory results, 
concomitant treatment, vital signs, medical history, examinations, AEs, IP dispensing logs, 
and other notes as appropriate. The investigator agrees to cooperate with the monitor to 
ensure that any problems noted during the course of these monitoring visits are resolved.
11 QUALITY CONTROL AND QUALITY ASSURANCE
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, in order 
to comply with ICH GCP guidelines. Each center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, ICH GCP and legal aspects. The on-
site verification of the eCRF for completeness and clarity will include cross checking with 
source documents, and clarification of administrative matters. Query verification of data will 
be described in the Data Management Plan.
Representatives of regulatory authorities or of Grifols may conduct audits or inspections or 
audits of the investigator study center. If the investigator is notified of an audit or inspection 
by a regulatory authority, the investigator agrees to notify the Grifols representative (eg, 
Clinical Assessment Monitor, Program Leader, or Program Manager) immediately. The 
investigator agrees to provide to representatives of a regulatory agency or Grifols access to 
records, facilities, and personnel for the effective conduct of an audit or inspection.
12 ETHICS
12.1
Institutional Review Board/Ethics Committee  
Documented approval from appropriate IRBs/ECs will be obtained for all participating 
centers/countries prior to study start, according to ICH GCP guidelines, local laws, 
regulations and organizations. When necessary, an extension, amendment or renewal of the 
IRB’s/EC’s approval must be obtained and also forwarded to the sponsor. Copies of the 
investigator’s report to the IRBs/ECs must be sent to the sponsor. The IRBs/ECs must supply 
to the sponsor, upon request, a list of the IRB’s/EC’s members involved in the vote and a 
statement to confirm that the IRB’s/EC’s is organized and operates according to ICH GCP 
guidelines and applicable laws and regulations.
12.2
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
ICH GCP guidelines. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). This may include an audit by the sponsor representatives and/or an 
inspection by regulatory authority representatives at any time. The investigator must agree to 
the audit or inspection of study-related records by the sponsor representatives and/or 
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regulatory authority representatives, and must allow direct access to source documents to the 
sponsor and/or regulatory authority representatives.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/EC/sponsor. Any deviations from the protocol 
must be fully explained and documented by the investigator. Protocol deviations will be 
submitted to the IRB/EC according to the requirements of each institution.
No medical waivers for protocol inclusion/exclusion criteria will be allowed by the sponsor, 
and in case the need for a change to the protocol is identified, it will be submitted as a 
protocol amendment to the competent regulatory authority and/or ethics committee as 
applicable per regulations.
12.3
Regulatory Authority Approvals/Authorizations
Regulatory authority approvals/authorizations/ notifications, where required, must be in place 
and fully documented prior to study start. Study information including contact information 
for investigator study centers responsible for conducting the study will be posted on a 
publicly accessible clinical registry(ies) as required by local law.
12.4
Subject Information and Consent
Subject information and ICF will be provided to investigator study centers. Prior to the 
beginning of the study, the investigator must have the IRB/EC written approval/favorable 
opinion of the written ICF and any other written information to be provided to subjects. The 
written approval of the IRB/EC together with the approved subject information/ICF must be 
filed in the study files and a copy of the documents must also be provided to the sponsor by 
the investigator’s study center. 
Written informed consent must be obtained before any study-specific procedure takes place. 
Participation in the study and the date the informed consent was given by the subject should 
be documented appropriately in the subject’s files. A signed copy of the subject ICF will be 
provided to the subject or subject’s authorized representative.
12.5
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor. Only the subject code number will be 
recorded in the eCRF, and if the subject’s name appears on any other document (eg,
pathologist report), it must be redacted before a copy of the document is supplied to the 
sponsor. Study findings stored on a computer will be stored in accordance with local data 
protection laws. Subjects will be informed in writing that representatives of the sponsor, 
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IRB/EC, or regulatory authorities may inspect their medical records and personal health 
information to verify the information collected, and that all personal information made 
available for an audit or inspection will be handled in strictest confidence and in accordance 
with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects’ records to be identified.
13 DATA HANDLING AND RECORD KEEPING
13.1
Data Handling
The study data will be recorded and kept current in the eCRF by the study center study 
personnel directly responsible for the information. Entries made in the eCRF must be 
verifiable against source documents, or must have been directly entered into the eCRF, in 
which case the entry in the eCRF will be considered the source data. The data in the eCRF 
will be monitored at the study center by Grifols representatives at regular intervals and 
reviewed for completeness and compared with the source documents. Examples of 
acceptable source documents include individual subject medical records, prospective 
information gathered on source documentation worksheets, lab reports and other diagnostics 
pertinent to this study which are separate from the eCRFs. The listing of types of source 
documents which will be defined in the source data agreement will be filed in TMF.
All AEs and SAEs must be recorded. All SAEs must be recorded on the SAE form. The SAE 
form must be kept in study center records with a copy provided to the designated person as 
detailed in the study file.  
13.2
Record Retention
At study completion, all study data will be transferred to Grifols according to ICH GCP 
guidelines, local laws, regulations, and Grifols requirements. The study file and all source 
data should be retained until notification is given by the sponsor for destruction.
An investigator is required by ICH GCP guidelines to retain the study files. If an investigator 
moves, withdraws from an investigation or retires, the responsibility for maintaining the 
records may be transferred to another person (eg, other investigator). Grifols must be notified 
in writing of the person responsible for record retention and the notification will be retained 
in the sponsor study file and the investigator study center file.
14 FINANCING AND INSURANCE
In the event of subject injury as a direct result of either administration of treatment or any 
non-standard-of-care study procedure, sponsor will pay for the costs of treatment, provided 
the subject has followed the instructions given by the study doctor and the illness or injury is 
not due to the natural progression of any conditions existing before the subject participated in 
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the study. Financial compensation for such things as lost wages, disability, or discomfort due 
to any research-related injury is not available.
Sponsor shall maintain comprehensive general liability insurance or self-insurance in 
amounts adequate to cover any damage, demand, claim, loss or liability caused or incurred by
sponsor, or as otherwise required by applicable laws and/or regulations.
15 PUBLICATION POLICY
Institution and the investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multicenter publication of the study results from all 
appropriates study centers. If such a multicenter publication is not submitted within 
12 months after conclusion of the study at all study centers or after Grifols confirms there 
will be no joint, multicenter publication, then institution and/or investigator shall have the 
right, at their discretion, to publish, either in writing or orally, the results of the study 
performed under the protocol, subject to the conditions outlined below:
•
The results of the study will be reported in the publicly accessible registry(ies).
•
The institution and/or investigator shall furnish Grifols with a copy of any proposed 
publication at least 30 days in advance of the date of submission for publication.
•
Within said 30-day period, Grifols shall: 
-
Review such proposed publication for confidential information (other than study 
results) and for subject information subject to the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”) and other applicable privacy laws;
-
Review such proposed publication for the unauthorized use of the name, symbols 
and/or trademarks of Grifols;
-
By written notice to the investigator, identify with specificity the text or graphics in 
such proposed publication that Grifols contends contains confidential information, 
protected subject information, or the unauthorized use of Grifols’s name, symbols 
and/or trademarks so that the proposed publication may be edited appropriately to 
remove such text or graphics before publication; and 
-
By written request, Grifols may delay proposed publications up to 60 days to allow 
Grifols to protect its interests in Grifols inventions described in such publications.
•
Institution and/or investigator shall give Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or presentation.
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1. Albutein® 5%, 20%, and 25% Investigator’s Brochure. Instituto Grifols, S.A. May 
2017.
2. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury 
in patients with cirrhosis: revised consensus recommendations of the International 
Club of Ascites. Gut 2015;64:531-537.
3. Gluud LL, Christensen K, Christensen E, et al. Terlipressin for hepatorenal syndrome. 
Cochrane Database Syst Rev 2012. doi:10.1002/14651858.CD005162.pub3.
4. Runyon BA. Introduction to the revised American Association for the Study of Liver 
Diseases. Practice Guideline management of adult patients with ascites due to 
cirrhosis 2012. Hepatology 2013; 57: 1651-3
5. 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
6. Arroyo V, García-Martinez R, Salvatella X. Human serum albumin, systemic 
inflammation, and cirrhosis. J Hepatol 2014; 61: 396-407
7. García-Martinez R, Caraceni P, Bernardi M, et al. Albumin: Pathophysiological basis 
and its role in the treatment of cirrhosis and its complications. Hepatology 2013; 58: 
1836-46
8. Fanali G, di Masi A, Trezza V, et al. Human serum albumin: from bench to bedside. 
Mol Aspects Med 2012; 33: 209-90
9. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment 
and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J 
Med 1999; 341: 403-9.
10. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on 
the consensus conference of the International Ascites Club. Hepatology 
2003;38(1):258-66.
11. Blei AT, Córdoba J; Practice Parameters Committee of the American College of 
Gastroenterology. Hepatic Encephalopathy. Am J Gastroenterol 2001;96(7):1968-76.
12. Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the 
age of MELD. Hepatology 2003;37(2):233-43.
13. Gentilini P, Casini-Raggi V, Di Fiore G, et al. Albumin improves the response to 
diuretics in patients with cirrhosis and ascites: results of a randomized, controlled 
trial. J Hepatol 1999; 30: 639-45
14. Romanelli RG, La Villa G, Barletta G, et al. Long-term albumin infusion improves 
survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J 
Gastroenterol 2006; 12: 1403-1407
15. Bernardi M, Riggio O, Angeli P, et al. Long-Term Use of Human Albumin for the 
Treatment of Ascites in Patients With Hepatic Cirrhosis: The Interim Analysis of the 
ANSWER Study.
16. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of 
hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-1308.
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17. Luca A, García-Pagán JC, Bosch J, et al. Beneficial effects of intravenous albumin 
infusion on the hemodynamic and humoral changes after total paracentesis. 
Hepatology 1995;22:753-758.
18. Uriz J, Gines P, Cardenas A, et al. Terlipressin plus albumin infusion: an effective 
and safe therapy of hepatorenal syndrome. J Hepatol 2000;33:43-48.
19. Duvoux C, Zanditenas D, Hezode C, et al. Effects of noradrenalin and albumin in 
patients with type I hepatorenal syndrome: A pilot study. Hepatology 2002;36:374-
380.
20. Angeli P, Albino G, Carraro P, , et al. Cirrhosis and muscle cramps: evidence of a 
causal relationship. Hepatology 1996;23:264-273.
21. Moeller S, Henriksen JH. Cardiovascular complications of cirrhosis. Postgrad Med J 
2009; 85: 44-54.
22. Peters T Jr. All about albumin. Biochemistry, genetics and medical applications. 
Academic Press, San Diego, 1996: 188-249.
23. Clinical Study Protocol IG0802. Long-term effects of prolonged administration of 
albumin 20% on cardiocirculatory and renal function and hepatic hemodynamics in 
patients with advanced cirrhosis and ascites. Instituto Grifols, SA. 14 Jun 2012.
24. Murray J, Ezzati M, Flaxman A, et al. The global burden of disease study 2010: a 
multi-investigator collaboration for global comparative descriptive epidemiology. 
Lancet 2012;380: 2055-2058.
25. Moreau R, Ginès P, Jalan R, et al. Acute-on-chronic liver failure is a distinct 
syndrome developing in subjects with acute decompensation of cirrhosis. 
Gastroenterology 2013;144:1426-37.
26. Bernal W, Jalan R, Quaglia A, et al. Acute-on-chronic liver failure. Lancet 2015; 
386:1576–87.
27. Dirchwolf M and Ruf AE. Role of systemic inflammation in cirrhosis: From 
pathogenesis to prognosis. World J Hepatol 2015 August 8; 7(16): 1974-1981.
28. Garcia-Tsao G, Friedman S, Iredale J, et al. Now there are many (stages) where 
before there was one: In search of a pathophysiological classification of cirrhosis. 
Hepatology 2010; 51(4): 1445–1449.
29. Era S, Kuwata K, Imai H, et al. Age-related change in redox state of human serum 
albumin. Biochim Biophys Acta. 1995;1247(1):12-16. 
30. Oettl K and Marsche G. Redox state of human serum albumin in terms of cysteine-34 
in heath and disease. Methods Enzymol 2010;474:181-195.
31. Clària J, Stauber R, Coenraad M, Moreau R, Jalan R, Pavesi M, et al. Systemic 
inflammation in decompensated cirrhosis: Characterization and role in acute-on-
chronic liver failure. Hepatology. 2016;64(4):1249-1264. 
32. Wald C, Russo M, Heimbach J, Hussain H, Pomfret E, Bruix J. New OPTN/UNOS 
policy for liver transplant allocation: standardization of liver imaging, diagnosis, 
classification, and reporting of hepatocellular carcinoma. Radiology. 2013 Feb; 
266(2):376-382.
33. The EuroQol Group. EuroQol – A new facility for the measurement of health-related 
quality of life. Health Policy 1990;16:199-208.
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34. Longo D, Fauci A, Kasper D, et al. Harrison’s Principles of Internal Medicine, 18th
Edition: www.accessmedicine.com.
35. Purvey M, Allen G. Managing acute pulmonary oedema. Aust Prescr 2017;40:59-63. 
https://doi.org/10.18773/austprescr.2017.013
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17 APPENDICES
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Appendix 1
Schedule of Study Procedures and Events
Procedures and Evaluation
Study Period
Screening
Treatment Perioda
End of Study:
Completed 
Subjects
Follow-up: 
Discontinued 
Subjectsd
Study Visitsb
Treatment 
Daysc
Month 12/Early 
Discontinuation
Study Day
Day 1
Day 11
Months 1-11
Inclusion/exclusion criteria
X
X
Medical history & demographics
X
Abdominal ultrasound
Xk
Endoscopic procedures
Xl
Urine pregnancy test
X
Physical exam
Xm
Xn
X
Randomization
X
Vital signse
X
X
X
X
Ascites assessment
X
X
X
X
Hepatic encephalopathy evaluation
X
X
X
Hemodynamics assessment (MAP)
X
X
X
Peripheral capillary oxygen saturation (SpO2) assessment
X
X
X
Weight
X
X
X
X
Clinical laboratory assessmentsf
X
X
X
X
Serum albumin concentrationg
X
X
Xr
Record ACLF grade
X
X
X
Systemic inflammation assessmenth
X
X
X
Illness severity scores evaluationi
X
X
X
Quality of life assessment (EQ-5D-5L health 
questionnaire)
X
Xo
X
Prior and concomitant medications
X
X
X
X
X
X
Albumin infusion
Xc
Xc
Xc
Xr
Assess TIPS insertion
X
X
Albumin functional capacity assessment (albumin binding 
capacity)
X
Xp
X
Adverse events
X
X
X
X
X
X
Biomarker retainsj
X
Xo
X
Record liver transplantation, survival, cause of death data
Xq
X
X
Footnotes continued on next page
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a
The treatment period will be up to 12 months.
b
Subjects will have assessments on Day 11 (±2 days), Month 1 (±2 days), and then monthly (±2 days) for up to 12 months.
c
Within 72 hours (3 days) of Screening, subjects will be randomized on Day 1. Following randomization, subjects in the SMT + Albutein 20% treatment 
group will receive the first infusion on the same day at the dose of 1.5 g/kg body weight (maximum 100 grams per subject). Thereafter, subjects will 
receive Albutein 20% infusions at the dose of 1.5 g/kg body weight (maximum 100 grams per subject) every 10 ± 2 days for the rest of the study.
d
Subjects who discontinue from the study early will have follow-up vital status assessments performed at Months 3, 6, and 12.
e
Vital signs include systolic BP, diastolic BP, HR, T, and RR. Vital signs will be measured immediately prior to and immediately after the end of the 
Albutein 20% administration in the SMT + Albutein 20% treatment group.
f
Clinical laboratory assessments will include hematology, chemistry, and coagulation performed by the central lab. At the Screening visit only, local 
laboratory tests will be performed in order to determine subject eligibility. Screening local laboratory test results will be kept in subjects’ source documents 
but will not be entered into the eCRF (see Table 7-1).
g
Serum albumin concentration will be measured immediately prior to treatment. In the SMT + Albutein 20% treatment group, serum albumin concentration 
will also be measured immediately after the end of the Albutein 20% administration.
h
Systemic inflammation assessment includes testing for procalcitonin, WBC, and CRP (see Table 7-1).
i
Illness severity scores include CLIF-C OF score, CLIF-C AD score, CLIF-C ACLF score, MELD score, and Child Pugh score (see Appendix 3 for illness 
severity scores).
j
Biomarker retains will be drawn for potential analysis of cytokines (interleukin [IL] 6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha [TNFα]) found in 
the blood which are significantly correlated with disease activity (see Table 7-1). All clinical blood samples will need to be drawn first before biomarker 
retains are drawn.
k
Findings from abdominal ultrasounds performed in the last 6 months will be recorded.
l
Findings from endoscopic procedures performed in the last 6 months will be recorded.
m
Full physical examination (excluding breast and genitourinary examination).
n
Physical examination performed on Month 6 only.
o
EQ-5D-5L health questionnaire and optional collection for blood biomarker retains on Months 1, 3, 6, and 9. All clinical blood samples will need to be 
drawn first.
p
Assessed on Day 11 and Months 1, 3, 6, and 9.
q
Assessed on Months 3 and 6.
r
Month 12 Visit only.
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Appendix 2
European Association for the Study of the Liver 
Clinical Practice Guidelines on the Management of 
Ascites/International Club of Ascites
Uncomplicated ascites: Ascites that is not infected and which is not associated with the 
development of the hepatorenal syndrome. Ascites can be graded as follows:
Grading of Ascites and Suggested Treatment
Grade of Ascites 
Definition 
Treatment
Grade 1 ascites 
Mild ascites only detectable by 
ultrasound 
No treatment
Grade 2 ascites 
Moderate ascites evident by 
moderate symmetrical distention 
of abdomen
Restriction of sodium intake and 
diuretics
Grade 3 ascites
Large or gross ascites with marked 
abdominal distension
Large-volume paracentesis 
followed by restriction of sodium 
intake and diuretics (unless
patients have refractory ascites)
Definition and Diagnostic Criteria for Refractory Ascites in Cirrhosis:
Diuretic-resistant ascites
Ascites that cannot be mobilized or the early recurrence of which cannot be 
prevented because of a lack of response to sodium restriction and diuretic 
treatment
Diuretic-intractable 
ascites
Ascites that cannot be mobilized or the early recurrence of which cannot be 
prevented because of the development of diuretic-induced complications that 
preclude the use of an effective diuretic dosage
Requisites
1. Treatment duration
Patients must be on intensive diuretic therapy (spironolactone 400 mg/day and 
furosemide 160 mg/day) for at least 1 week and on a salt-restricted diet of less 
than 90 mmol/day
2. Lack of response
Mean weight loss of <0.8 kg over 4 days and urinary sodium output less than the 
sodium intake
3. Early ascites recurrence Reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization
4. Diuretic-induced 
complications
Diuretic-induced HE is the development of encephalopathy in the absence of any 
other precipitating factor.
Diuretic-induced renal impairment is an increase of serum creatinine by >100% 
to a value >2 mg/dL (177 µmol/L) in patients with ascites responding to 
treatment.
Diuretic-induced hyponatremia is defined as a decrease of serum sodium by 
>10 mmol/L to a serum sodium of <125 mmol/L.
Diuretic-induced hypo- or hyperkalemia are defined as a change in serum 
potassium to <3 mmol/L or >6 mmol/L, respectively, despite appropriate 
measures
Source: (5)
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Diagnostic criteria of hepatorenal syndrome (HRS) type of acute kidney injury (AKI) in 
patients with cirrhosis
Source: (2)
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Appendix 3
Illness Severity Scores
Criteria to Define Organ Failure (CLIF-C OF Score) 
CLIF-Organ Failure score system. 
Organ / System
Sub-score = 1
Sub-score = 2
Sub-score = 3
Liver
Bilirubin <6 mg/dL
6 ≤ Bilirubin <12 mg/dL
Bilirubin ≥12 mg/dL
Kidney
Creatinine <2 mg/dL
2 ≤ Creatinine <3.5 mg/dL
Creatinine ≥3.5 mg/dL
or renal replacement
Brain
(West-Haven grade for HE*)
Grade 0
Grade 1-2
Grade 3-4
Coagulation
INR <2.0
2.0 ≤ INR <2.5
INR ≥2.5
Circulatory
MAP ≥70 mm/Hg
MAP <70 mm/Hg
Use of vasopressors
Respiratory 
PaO2/FiO2
or
SpO2/FiO2
>300
>357
≤300 - >200
>214- ≤357
≤200 (#)
≤214 (#)
The shaded area describes criteria for diagnosing organ failures; *HE: Hepatic Encephalopathy; # patients 
enrolled in the study with MV were considered as presenting respiratory failure (respiratory sub-score=3) 
except for patients intubated due to severe HE or to other reasons and not to a respiratory failure, in whom 
respiratory failure is defined according to the PaO2/FiO2 ratio.
CLIF-C ACLF Score
CLIF-C ACLFs = 10*[0.33*CLIF-C OFs + 0.04*Age {years} + 0.63*Ln(white cell count 
{109 cells/L}) - 2]
CLIF-C AD Score
CLIF-C ADs= 10[0.03*Age {years} +0.66*Ln(Creatinine {mg/dL}) 
+1.71*Ln(INR)+0.88*Ln(white cell count {109 cells/L}) - 0.05*Sodium {mmol/L}+8]
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MELD Score
MELD Score = 9.57 Ln(Creatinine {mg/dL}) + 3.78 Ln(Bilirubin {mg/dL}) + 
11.2 Ln(INR) + 6.43
Child Pugh Score
Child-Turcotte-Pugh Classification for Severity of Cirrhosis
Points*
1
2
3
Encephalopathy
None
Grade 1-2
(or precipitant induced)
Grade 3-4
(or chronic)
Ascites
None
Mild to moderate
(diuretic responsive)
Severe
(diuretic refractory)
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
INR
<1.7
1.7-2.3
>2.3
*Child-Turcotte-Pugh Class obtained by adding score for each parameter (total points)
Class A = 5 to 6 points (least severe liver disease)
Class B = 7 to 9 points (moderately severe liver disease)
Class C = 10 to 15 points (most severe liver disease)
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Appendix 4
West Haven Criteria for Hepatic Encephalopathy
WEST HAVEN CRITERIA OF ALTERED MENTAL STATUS IN HEPATIC ENCEPHALOPATHY
Stage
Consciousness
Intellect and Behavior
Neurologic Findings
0
Normal
Normal
Normal examination; impaired 
psychomotor testing
1
Mild lack of 
awareness
Shortened attention 
span; impaired addition 
or subtraction
Mild asterixis or
tremor
2
Lethargic
Disoriented; 
inappropriate behavior
Muscular rigidity and clonus; 
Hyperreflexia
3
Somnolent but 
arousable
Gross disorientation; 
bizarre behaviour
Muscular rigidity and clonus; 
Hyperreflexia
4
Coma
Coma
Decerebrate posturing
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Appendix 5
EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) 
Health Questionnaire
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

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The worst health 
you can imagine

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box 
below.
Source: (33)
The best health 
you can imagine
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
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Appendix 6
Milan Criteria
The Milan criteria are a generally accepted set of criteria used to assess suitability in patients 
for liver transplantation with cirrhosis and hepatocellular carcinoma.
In order to be suitable for a liver transplantation, one needs to have the following:
•
Single tumor with diameter ≤5 cm or up to 3 tumors each with diameter ≤3 cm
•
No extra-hepatic involvement
•
No major vessel involvement
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Appendix 7
NYHA Classification – The Stages of Heart Failure
In order to determine the best course of therapy, physicians often assess the stage of heart 
failure according to the NYHA functional classification system. This system relates 
symptoms to everyday activities and the patient's quality of life.
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.
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Appendix 8
GOLD Staging System for COPD Severity
The European Respiratory Society (ERS) diagnostic criteria for COPD include the following 
symptoms: coughing, sputum production and/or dyspnea, as well as a history of exposure to 
risk factors for COPD. The diagnosis is confirmed by a post-bronchodilator FEV1/FVC < 0.7 
by spirometry, as sign of the airflow limitation that is not fully reversible.
Stage
Description
Findings (based on postbronchodilator FEV1)
0
At risk
Risk factors and chronic symptoms but normal spirometry
I
Mild
FEV1/FVC ratio less than 70 percent
FEV1 at least 80 percent of predicted value
May have symptoms
II
Moderate
FEV1/FVC ratio less than 70 percent
FEV1 50 percent to less than 80 percent of predicted value
May have chronic symptoms
III
Severe
FEV1/FVC ratio less than 70 percent
FEV1 30 percent to less than 50 percent of predicted value
May have chronic symptoms
IV
Very severe
FEV1/FVC ratio less than 70 percent
FEV1 less than 30 percent of predicted value 
Or FEV1 less than 50 percent of predicted value plus severe chronic 
symptoms
GOLD = Global Initiative for Chronic Obstructive Lung Disease; COPD = chronic obstructive pulmonary 
disease; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity
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Appendix 9
Algorithm For Cardiogenic Pulmonary Overload
Source: (34)
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Appendix 10
Management of Acute Pulmonary Edema
Source: (35)
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Appendix 11
Summary of Changes for Amendment 5
(Note: Administrative changes including minor administrative corrections are not included in Protocol Summary of Changes.)
Sections
Change From:
(Version 5)
(Strikethrough is added to highlight deleted text.)
Change To:
(Version 6)
(Underline is added to highlight new text.)
Rationale:
Synopsis, 5.2
Note: no deleted text. 
25. Subjects with current infection of COVID19, 
those who are less than 14 days post recovery, or 
those who have clinical signs and symptoms 
consistent with COVID19 infection.
New exclusion criteria 
added regarding 
infection of
COVID19.
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SAP_001.pdf: 
Official Title: 
Prevention of Mortality With Long-Term Administration of Human
Albumin in Subjects With Decompensated Cirrhosis and Ascites
NCT Number:
NCT03451292
Document Date: 
Statistical Analysis Plan, Version 2: 09-Sep-2024


Signed by:  
Reason:  
Date / Time (UTC):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Completion of the signature block below signifies the review and approval of this document.  
09-Sep-2024 09:30:37
05-Sep-2024 14:27:23
Owner
05-Sep-2024 13:43:45
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STATISTICAL ANALYSIS PLAN (SAP)
IG1601
Study Title: 
Prevention of Mortality with Long-Term Administration of 
Human Albumin in Subjects with Decompensated Cirrhosis 
and Ascites
Development Phase: 3
SAP Version: 
Version 2.0
SAP Effective Date: The effective date of the document is the last date of approval 
of the document
Protocol Version: 
IG1601 Amendment 5/Version 6 Dated 24SEP2020
Author:                    
 Grifols
                                    
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