Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5%
- Conditions
- Acute-On-Chronic Liver Failure
- Interventions
- Biological: SMT + PE-A 5%Other: Standard Medical Treatment
- Registration Number
- NCT03702920
- Lead Sponsor
- Grifols Therapeutics LLC
- 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.
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:
The Treatment Period will be 7 days for all subjects and will be prolonged depending on subject's ACLF evolution to up to 17 days.
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 275
- 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.
- Subjects without ACLF.
- Subjects with ACLF-1a or ACLF-3b (See Table 2-1 for ACLF grades) 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 (≤20×109/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 [Appendix 5]), 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 COVID19, those who are less than 14 days post recovery or those who have clinical signs and symptoms consistent with COVID19 infection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description SMT+ PE-A 5% SMT + PE-A 5% PE-A 5% will be performed using 5% albumin (Albutein 5%) as the main replacement fluid administered intravenously. Standard Medical Treatment (SMT) Standard Medical Treatment Standard medical treatment (SMT) will be administered according to institution standards.
- Primary Outcome Measures
Name Time Method Time to death through Day 90 Day 1 to Day 90 Time to death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone
- Secondary Outcome Measures
Name Time Method Time to transplant or death through Day 90 Day 1 to Day 90 Time to transplant or death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone
Time to death through Day 28 Day 1 to Day 28 Time to death through Day 28 after randomization of SMT+PE-A 5% versus SMT alone
Trial Locations
- Locations (40)
Centro Hospitalar Lisboa Norte
🇵🇹Lisboa, Portugal
Hospital General Gregorio Marañón
🇪🇸Madrid, Spain
Nottingham University Hospital
🇬🇧Nottingham, United Kingdom
University of Alabama at Birmingham (UAB) Hospital
🇺🇸Birmingham, Alabama, United States
Southern California Research Center
🇺🇸Coronado, California, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Mayo Clinic Phoenix
🇺🇸Phoenix, Arizona, United States
University of Kansas
🇺🇸Kansas City, Kansas, United States
Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Rigshospitalet
🇩🇰Copenhagen, Denmark
Universitätsklinikum Bonn
🇩🇪Bonn, Germany
ASST Papa Giovanni XXIII
🇮🇹Bergamo, Italy
Rutgers-New Jersey Medical School
🇺🇸Newark, New Jersey, United States
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Mayo Clinic Rochester
🇺🇸Rochester, New York, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
McGuire VA Medical Center
🇺🇸Richmond, Virginia, United States
Aurora Health Care, Inc.
🇺🇸Milwaukee, Wisconsin, United States
Medical University of Vienna
🇦🇹Vienna, Austria
Université libre de Bruxelles
🇧🇪Bruxelles, Belgium
UZ Leuven - Campus Gasthuisberg
🇧🇪Leuven, Belgium
Hôpital Beaujon
🇫🇷Clichy, France
Centre Hépato-Biliaire - Hôpital Universitaire Paul Brousse
🇫🇷Villejuif, France
Universitätsklinikum Frankfurt
🇩🇪Frankfurt, Germany
Hannover Medical School
🇩🇪Hannover, Germany
Universitaetsklinikum Leipzig
🇩🇪Leipzig, Germany
Klinikum der Universitaet Muenchen
🇩🇪München, Germany
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
Milano Hospital Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
🇮🇹Milan, Italy
Azienda Ospedaliera di Padova
🇮🇹Padova, Italy
Azienda Ospedaliero-Universitaria Policlinico Umberto I
🇮🇹Roma, Italy
Centro Hospitalar do Porto
🇵🇹Porto, Portugal
Hospital Universitario del Valle Hebron
🇪🇸Barcelona, Spain
Hospital Clínic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, Spain
Royal Free NHS Foundation Trust Hospital
🇬🇧London, United Kingdom
King's College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom