Acute-On-Chronic Liver Failure
Conditions
Brief summary
This is a Phase 3, multicenter, randomized, controlled, parallel-group, open-label study to evaluate the effects of plasma exchange using human serum albumin 5% (PE-A 5%) in acute-on-chronic liver failure (ACLF) subjects. The study will involve approximately 40 study centers in the United States, Canada, and Europe with expertise in the management of subjects with ACLF. Subjects with ACLF at a high risk of hospital mortality will be enrolled. The study will consist of a Screening Period during which subjects will be randomized (1:1) to receive either standard medical treatment (SMT) + PE-A 5% (treatment group) or SMT only (control group), followed by a Treatment Period, and a Follow-up Period. The Treatment Period for subjects in the SMT+ PE-A 5% treatment group will be between 7 and 17 days, depending on ACLF evolution. The Treatment Period for subjects in the SMT control group will be a minimum of 7 days for all subjects and up to 17 days depending on the ACLF evolution. Subjects in this group will receive SMT according to the institution's standards. The Follow-up Period for subjects in both groups will be 90 days.
Detailed description
Approximately 380 subjects with cirrhosis, ACLF, and high risk of hospital mortality (ACLF-1b, ACLF-2, or ACLF-3a) will be included in this study after obtaining written informed consent. In case of hepatic encephalopathy (HE), written informed consent will be obtained from a relative or a legally authorized representative if the subject is considered incompetent to consent. Randomization of subjects will be stratified by region (European Union \[EU\] or North America \[NA\]) and the 3 ACLF grades (ACLF-1b, ACLF-2, or ACLF-3a). Within each stratum (ie, each unique combination of region and ACLF grade), subjects will be randomized in a 1:1 ratio into 2 treatment groups below: * SMT+PE-A 5% (treatment group) * SMT (control group) SMT + PE-A 5% Treatment Group: PE-A 5% will be performed using 5% albumin (Albutein® 5%) as the main replacement fluid administered intravenously. Fresh frozen plasma (FFP) will be given after each PE-A 5% session to prevent coagulopathy. SMT in addition to PE-A 5% will be administered according to institution standard practice. The exact number of sessions will be determined by the pattern of response (achieving complete response or no improvement/deterioration of ACLF) to PE-A 5% therapy. IVIGs will be administered to prevent the development of hypogammaglobulinemia and infection. SMT Control Group: SMT will be administered according to institution standards practices. Subjects in both the SMT+ PE-A 5% treatment group and the SMT control group will be followed for 90 days after randomization. During the entire study, the safety of both groups will be monitored by a Data Safety Monitoring Board.
Interventions
BIOLOGICALSMT + PE-A 5%
Plasma exchange treatment (PE-A 5%) will be performed using 5% albumin solution (Albutein 5%). Fresh frozen plasma will be given to prevent coagulopathy. IVIGs will be administered intravenously to prevent the development of hypogammaglobulinemia and infection. SMT in addition to PE-A 5% according to the institution's standard practice.
OTHERStandard Medical Treatment
Standard medical treatment according to the institution's standard practice
Sponsors
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Male or female cirrhotic subjects between 18 and 79 years of age. * Subjects with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization (must be ACLF-1b, -2, or -3a within the Screening Period \[a maximum of 10 days\]). * 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. * In case of HE, informed consent will be provided by a relative or a legally authorized representative if the subject is considered incompetent to consent.
Exclusion criteria
* Subjects without ACLF. * Subjects with ACLF-1a or ACLF-3b after the Screening Period. * Subjects fulfilling inclusion criteria that improve to no ACLF or to ACLF-1a or worsen to ACLF-3b during the Screening Period (between initial evaluation and time of randomization). * Subjects with ACLF for more than 10 days prior to randomization. * Subjects with acute or subacute liver failure without underlying cirrhosis. * Subjects with septic shock requiring use of norepinephrine (\> 0.3 mcg/kg/min) or need for a second vasopressor (including terlipressin). * Subjects with active bacterial or fungal infection: who have received less than 24h of appropriate antibiotic treatment. * Subjects with severe respiratory failure with PaO2/FiO2 ≤200. * Subjects with active or recent bleeding (unless controlled for \>48 hours). * Subjects with severe thrombocytopenia (≤20×10\^9/L) (based on local laboratory assessment). * Subjects with chronic renal failure and currently receiving hemodialysis. * 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, and controlled breast or prostate cancer, can be included). * Subjects with severe chronic heart failure (New York Heart Association \[NYHA\] class III or IV). * Subjects with severe pulmonary disease (Global Obstructive Lung Disease \[GOLD\] stage III or IV). * Subjects with severe myopathy as defined clinically. * Subjects 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 a highly effective method of contraception. * Subjects with previous liver transplantation. * Subjects receiving anti-platelet or anti-coagulant therapy (LMWH for DVT prophylaxis is allowed). * Participation in another clinical study within at least 30 days prior to screening. * Subjects with active drug addiction (exceptions: active alcoholism or marijuana). * Subjects with a do-not-resuscitate order. * In the opinion of the investigator, the subject may have compliance problems with the protocol and the procedures of the protocol. * Subjects with current infection of COVID-19, those who are less than 14 days post recovery or those who have clinical signs and symptoms consistent with COVID-19 infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death Without a Prior Liver Transplant Through Day 90 After Randomization | Up to Day 90 | Time to 90-day overall survival was to be calculated as \[(date of death) - randomization date\] for those participants who died without having liver transplant on or prior to 90 days. Participants who did not die, or had a liver transplant before death were to have their time to event censored at the earlier of date of last contact, liver transplant date or cut-off date. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off day) / (number of participants in the ITT group)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Liver Transplant or Death Through Day 90 After Randomization | Day 1 to Day 90 | Time to 90-day liver transplant free survival was calculated as \[the earlier of the date of liver transplantation or date of death - randomization date for those participants who died or had a liver transplant on or prior to 90 days\]. Participants who neither died nor had a liver transplant, were had their time to event censored at the earlier of date of last contact or cut-off date. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off day) / (number of participants in the ITT group)\]. |
| Time to Death Without a Prior Liver Transplant Through Day 28 After Randomization | Day 1 to Day 28 | Time to 28-day overall survival was calculated as \[date of death - randomization date\] for those participants who died without having liver transplant on or prior to 28 days. Participants who did not die, or had a liver transplant before death were to have their time to event censored at the earlier of date of last contact, liver transplant date or cut-off date. The percentage of participants with events are presented. The percentage of participants was calculated as \[(participants with an event up to the analysis cut-off day) / (number of participants in the ITT group)\]. |
Countries
Austria, Belgium, France, Germany, Italy, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 274 participants took part in the study at 29 investigative sites across 8 countries in Europe and the United States from 17 June 2019 to 14 April 2025.
Pre-assignment details
318 participants with ACLF were screened of which 274 participants were randomized in a 1:1 ratio to receive either the Standard Medical Treatment (SMT) + PE-A 5% or the SMT Alone.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 50.7 years STANDARD_DEVIATION 11.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 121 Participants |
| Region of Enrollment Austria | 7 Participants |
| Region of Enrollment Belgium | 34 Participants |
| Region of Enrollment France | 5 Participants |
| Region of Enrollment Germany | 17 Participants |
| Region of Enrollment Italy | 16 Participants |
| Region of Enrollment Portugal | 2 Participants |
| Region of Enrollment Spain | 21 Participants |
| Region of Enrollment United Kingdom | 9 Participants |
| Region of Enrollment United States | 97 Participants |
| Sex: Female, Male Female | 46 Participants |
| Sex: Female, Male Male | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 51 / 135 | 70 / 139 |
| other Total, other adverse events | 79 / 128 | 58 / 139 |
| serious Total, serious adverse events | 37 / 128 | 28 / 139 |
Outcome results
None listed