Decompensated Cirrhosis and Ascites
Conditions
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.
Interventions
DRUGAlbutein 20%
Injectable solution
OTHERSMT
Participants received SMT according to institution standards for the management of decompensated cirrhosis.
Sponsors
Instituto Grifols, S.A.
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants ≥18 years of age. * Participants with diagnosis of liver cirrhosis (based on clinical, laboratory, endoscopic, and ultrasonographic features or on histology). * Participants 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. * In participants with cirrhosis due to hepatitis B virus, decompensation must occur in the setting of continuous (no less than 3 months) appropriate antiviral therapy. * In participants with cirrhosis due to hepatitis C virus, only decompensated participants who will not receive antiviral therapy during the study period will be included (Participants receiving antiviral therapy within 14 days prior to enrollment cannot be included in the study). * In participants with cirrhosis due to autoimmune hepatitis, decompensation must occur in the setting of continuous immunosuppressive therapy. * Participants 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 participant in accordance with local law and institutional policy. * Chronic liver failure-consortium acute decompensation (CLIF-C AD) score \> 50 points at screening.
Exclusion criteria
* Participants with ACLF at Screening * Participants with type 1 hepatorenal syndrome (HRS) currently on treatment with vasoconstrictors or hemodialysis. * Participants with transjugular intrahepatic portosystemic shunt (TIPS) or other surgical porto-caval shunts. * Participants with refractory ascites as defined by the International Club of Ascites (ICA) criteria without any other event of acute decompensation. * Participants receiving dual anti-platelet therapy or anti-coagulant therapy (exception: deep vein thrombosis (DVT) prophylaxis). * Participants with ongoing endoscopic eradication of esophageal varices with ≤ 2 endoscopic sessions completed before screening. * Participants with evidence of current locally advanced or metastatic malignancy. * Participants with acute or chronic heart failure (New York Heart Association \[NYHA\]). * Participants with severe (grade III or IV) pulmonary disease (Global Obstructive Lung Disease \[GOLD\]). * Participants with nephropathy with renal failure with serum creatinine \>2 milligrams/deciliters (mg/dL) or systemic hypertension. * Participants with severe psychiatric disorders. * Participants with a known infection with human immunodeficiency virus (HIV) or have clinical signs and symptoms consistent with current HIV infection. * Females who are pregnant, breastfeeding, or if of childbearing potential, unwilling to practice effective methods of contraception * Participants with previous liver transplantation. * Participants with known or suspected hypersensitivity to albumin. * Participants participating in another clinical study within 3 months prior to screening. * Participants with active drug addiction (exceptions: active alcoholism or marijuana). * In the opinion of the investigator, the participants may have compliance problems with the protocol and the procedures of the protocol. * Participants with ongoing or recent variceal bleeding (participants can be included 2 weeks after hemorrhagic episode). * Participants with septic shock at screening. * Participants with ongoing spontaneous bacterial peritonitis (SBP) infection (participants can be included upon resolution). * Participants with current infection of coronavirus disease of 2019 (COVID19), those who are less than 14 days post recovery, or those who have clinical signs and symptoms consistent with COVID19 infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Liver Transplantation or Death Through 1 Year After Randomization: Percentage of Participants With an Event | Up to Day 361 | Time to one-year transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 361 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 361, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 361) / (number of participants in the ITT group)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Liver Transplantation or Death Through 6 Months After Randomization: Percentage of Participants With an Event | Up to Day 181 | Time to 6-months transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 181 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 181, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 181) / (number of participants in the ITT group)\]. |
| Time to Death Through 3 Months After Randomization: Percentage of Participants With an Event | Up to Day 91 | Time to 3-months survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 91 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 91 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 91) / (number of participants in the ITT group)\]. |
| Time to Death Through 6 Months After Randomization: Percentage of Participants With an Event | Up to Day 181 | Time to 6-months survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 181 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 181 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 181) / (number of participants in the ITT group)\]. |
| Time to Liver Transplantation or Death Through 3 Months After Randomization: Percentage of Participants With an Event | Up to Day 91 | Time to 3-months transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 91 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 91, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 91) / (number of participants in the ITT group)\]. |
| Total Number of Paracenteses Through 1 Year After Randomization | Up to Day 361 | Paracenteses is a medical procedure used to remove excess fluid from the abdominal cavity. For each participant, the total number of reported paracenteses on treatment was calculated. Number of paracenteses per participant while on treatment was reported. |
| Number of Participants With Refractory Ascites According to the International Club of Ascites (ICA) Through 1 Year After Randomization | Up to Day 361 | Refractory Ascites was defined as 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, or the development of diuretic-induced complications that preclude the use of an effective diuretic dosage treatment. Incidence of refractory ascites occurring on treatment was defined as any incidence that occurred with a start date/time on or after the participants date/time of randomization (for SMT Alone group) or commencement of Albutein (SMT+ Albutein 20% group) treatment. |
| Time to Death Through 1 Year After Randomization: Percentage of Participants With an Event | Up to Day 361 | Time to 1 year survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 361 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 361 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 361) / (number of participants in the ITT group)\]. |
Countries
Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Denmark, France, Germany, Hungary, Italy, Poland, Serbia, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 410 participants took part in the study at 40 investigative sites across 14 countries in Europe and the United States from 24 July 2018 to 21 May 2024.
Pre-assignment details
476 participants with decompensated cirrhosis and ascites were screened of which 410 participants were randomized in a 1:1 ratio to receive either the Standard Medical Treatment (SMT) + Albutein 20% or the SMT alone.
Participants by arm
| Arm | Count |
|---|---|
| SMT + Albutein 20% Participants received Albutein 20%, at a dose of 1.5 g/kg, based on their body weight (maximum 100 grams per participant), as an IV infusion on Day 1, followed by the same dose of Albutein 20% every 10±2 days along with SMT administered as per institution standards for the management of decompensated cirrhosis up to 12 months. | 203 |
| SMT Alone Participants received SMT up to 12 months as per institution standards for the management of decompensated cirrhosis. | 207 |
| Total | 410 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Death | 44 | 59 |
| Overall Study | Lost to Follow-up | 4 | 12 |
| Overall Study | Non-compliance with Study Drug | 2 | 0 |
| Overall Study | Physician Decision | 4 | 3 |
| Overall Study | Transplantation | 18 | 12 |
| Overall Study | Withdrawal by Subject | 18 | 13 |
Baseline characteristics
| Characteristic | SMT Alone | Total | SMT + Albutein 20% |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 10.3 | 58.8 years STANDARD_DEVIATION 10.16 | 58.9 years STANDARD_DEVIATION 10.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 35 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 190 Participants | 375 Participants | 185 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 199 Participants | 396 Participants | 197 Participants |
| Sex: Female, Male Female | 55 Participants | 117 Participants | 62 Participants |
| Sex: Female, Male Male | 152 Participants | 293 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 53 / 203 | 67 / 207 |
| other Total, other adverse events | 51 / 203 | 47 / 207 |
| serious Total, serious adverse events | 52 / 203 | 70 / 207 |
Outcome results
Primary
Time to Liver Transplantation or Death Through 1 Year After Randomization: Percentage of Participants With an Event
Time to one-year transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 361 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 361, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 361) / (number of participants in the ITT group)\].
Time frame: Up to Day 361
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Liver Transplantation or Death Through 1 Year After Randomization: Percentage of Participants With an Event | 33.5 percentage of participants |
| SMT Alone | Time to Liver Transplantation or Death Through 1 Year After Randomization: Percentage of Participants With an Event | 38.6 percentage of participants |
Comparison: Stratification factors included were the region (Europe or North America) and history of hospitalization for acute decompensation of liver cirrhosis (yes or no).p-value: 0.1795% CI: [0.58, 1.1]Cox Proportional- Hazards (PH) model
Secondary
Number of Participants With Refractory Ascites According to the International Club of Ascites (ICA) Through 1 Year After Randomization
Refractory Ascites was defined as 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, or the development of diuretic-induced complications that preclude the use of an effective diuretic dosage treatment. Incidence of refractory ascites occurring on treatment was defined as any incidence that occurred with a start date/time on or after the participants date/time of randomization (for SMT Alone group) or commencement of Albutein (SMT+ Albutein 20% group) treatment.
Time frame: Up to Day 361
Population: ITT population included all participants who were randomized. Overall number of participants analyzed included participants with at least one refractory ascites assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SMT + Albutein 20% | Number of Participants With Refractory Ascites According to the International Club of Ascites (ICA) Through 1 Year After Randomization | 33 Participants |
| SMT Alone | Number of Participants With Refractory Ascites According to the International Club of Ascites (ICA) Through 1 Year After Randomization | 46 Participants |
Secondary
Time to Death Through 1 Year After Randomization: Percentage of Participants With an Event
Time to 1 year survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 361 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 361 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 361) / (number of participants in the ITT group)\].
Time frame: Up to Day 361
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Death Through 1 Year After Randomization: Percentage of Participants With an Event | 26.1 percentage of participants |
| SMT Alone | Time to Death Through 1 Year After Randomization: Percentage of Participants With an Event | 31.9 percentage of participants |
Secondary
Time to Death Through 3 Months After Randomization: Percentage of Participants With an Event
Time to 3-months survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 91 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 91 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 91) / (number of participants in the ITT group)\].
Time frame: Up to Day 91
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Death Through 3 Months After Randomization: Percentage of Participants With an Event | 9.4 percentage of participants |
| SMT Alone | Time to Death Through 3 Months After Randomization: Percentage of Participants With an Event | 14.0 percentage of participants |
Secondary
Time to Death Through 6 Months After Randomization: Percentage of Participants With an Event
Time to 6-months survival was calculated as the earlier of \[(date of death) - randomization date + 1\] for those participants who died within the analysis period of 181 days. Participants who did not die within the analysis period were censored at the earlier of the date of last contact or analysis cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on death, these events if reported before the analysis cut-off Day 181 of this endpoint, were considered. The percentage of participants with events (death) without censoring participants who underwent liver transplantation within the analysis period were reported. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 181) / (number of participants in the ITT group)\].
Time frame: Up to Day 181
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Death Through 6 Months After Randomization: Percentage of Participants With an Event | 16.7 percentage of participants |
| SMT Alone | Time to Death Through 6 Months After Randomization: Percentage of Participants With an Event | 23.2 percentage of participants |
Secondary
Time to Liver Transplantation or Death Through 3 Months After Randomization: Percentage of Participants With an Event
Time to 3-months transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 91 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 91, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 91) / (number of participants in the ITT group)\].
Time frame: Up to Day 91
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Liver Transplantation or Death Through 3 Months After Randomization: Percentage of Participants With an Event | 10.8 percentage of participants |
| SMT Alone | Time to Liver Transplantation or Death Through 3 Months After Randomization: Percentage of Participants With an Event | 17.9 percentage of participants |
Secondary
Time to Liver Transplantation or Death Through 6 Months After Randomization: Percentage of Participants With an Event
Time to 6-months transplant-free survival was calculated as earlier of \[(date of liver transplantation or date of death) - randomization date + 1\] for participants who died or had liver transplant within the analysis period of 181 days. Participants who neither died nor had liver transplant within analysis period had their time to event censored at earlier of date of last contact or cut-off date. Participants who terminated early for reasons other than death were followed up at months 3, 6, and 12 to collect information on liver transplantation and death, these events if reported by cut-off Day 181, were considered for the endpoint. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off Day 181) / (number of participants in the ITT group)\].
Time frame: Up to Day 181
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SMT + Albutein 20% | Time to Liver Transplantation or Death Through 6 Months After Randomization: Percentage of Participants With an Event | 22.7 percentage of participants |
| SMT Alone | Time to Liver Transplantation or Death Through 6 Months After Randomization: Percentage of Participants With an Event | 28.5 percentage of participants |
Secondary
Total Number of Paracenteses Through 1 Year After Randomization
Paracenteses is a medical procedure used to remove excess fluid from the abdominal cavity. For each participant, the total number of reported paracenteses on treatment was calculated. Number of paracenteses per participant while on treatment was reported.
Time frame: Up to Day 361
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SMT + Albutein 20% | Total Number of Paracenteses Through 1 Year After Randomization | 1.3 paracenteses per participant | Standard Deviation 3.58 |
| SMT Alone | Total Number of Paracenteses Through 1 Year After Randomization | 2.3 paracenteses per participant | Standard Deviation 5.07 |