Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5% (APACHE)

Effects of Plasma Exchange With Human Serum Albumin 5% (PE-A 5%) on Short-term Survival in Subjects With "Acute-On-Chronic Liver Failure" (ACLF) at High Risk of Hospital Mortality

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.

Study Overview

• Status: Recruiting
• Conditions: Acute-On-Chronic Liver Failure
• Intervention / Treatment: Biological: SMT + PE-A 5%; Other: Standard Medical Treatment

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.

• Study Type: Interventional
• Enrollment (Estimated): 380
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mireia Torres; Phone Number: +34 93 5710500; Email: approach_apache@grifols.com

Study Locations

• Austria
  • Vienna, Austria, A-1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Thomas Reiberger
• Belgium
  • Bruxelles, Belgium, 1070
    • Recruiting
    • Université Libre de Bruxelles
    • Contact: Thierry Gustot
  • Leuven, Belgium, 3000
    • Recruiting
    • UZ Leuven - Campus Gasthuisberg
    • Contact: Alex Wilmer
• Denmark
  • Copenhagen, Denmark
    • Withdrawn
    • Rigshospitalet
• France
  • Clichy, France, 92110
    • Recruiting
    • Hopital Beaujon
    • Contact: Mikhael Giabicani
  • Villejuif, France, 94804
    • Recruiting
    • Centre Hépato-Biliaire - Hôpital Universitaire Paul Brousse
    • Contact: Faouzi Saliba
• Germany
  • Bonn, Germany, 53105
    • Withdrawn
    • Universitätsklinikum Bonn
  • Frankfurt, Germany, 60590
    • Recruiting
    • Universitatsklinikum Frankfurt
    • Contact: Anita Pathil-Warth
  • Hannover, Germany, 30625
    • Recruiting
    • Hannover Medical School
    • Contact: Benjamin Maasoumy
  • Leipzig, Germany, 4103
    • Recruiting
    • Universitaetsklinikum Leipzig
    • Contact: Thomas Berg
  • Muenchen, Germany, 81377
    • Withdrawn
    • Klinikum der Universitaet Muenchen
  • München, Germany, 81377
    • Recruiting
    • Klinikum der Universitaet Muenchen
    • Contact: Christian Lange
• Italy
  • Bergamo, Italy, 24127
    • Withdrawn
    • ASST Papa Giovanni XXIII
  • Milan, Italy, 20122
    • Completed
    • Milano Hospital Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
  • Milano, Italy, 20162
    • Recruiting
    • ASST Grande Ospedale Metropolitano Niguarda
    • Contact: Giovanni Perricone
  • Padova, Italy, 35128
    • Recruiting
    • Azienda Ospedaliera di Padova
    • Contact: Paolo Angeli
  • Roma, Italy, 161
    • Recruiting
    • Azienda Ospedaliero-Universitaria Policlinico Umberto I
    • Contact: Manuela Merli
• Portugal
  • Lisboa, Portugal, 1649-028
    • Withdrawn
    • Centro Hospitalar Lisboa Norte
  • Porto, Portugal
    • Completed
    • Centro Hospitalar do Porto
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic de Barcelona
    • Contact: Javier Fernández
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitario del Valle Hebron
    • Contact: Victor Vargas
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
    • Contact: Agustin Albillos
  • Madrid, Spain, 28007
    • Withdrawn
    • Hospital General Gregorio Maranon
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital NHS Foundation Trust
    • Contact: William Bernal
  • London, United Kingdom, NW3 2QG
    • Recruiting
    • Royal Free NHS Foundation Trust Hospital
    • Contact: Gautam Mehta
  • Nottingham, United Kingdom, NG72UH
    • Withdrawn
    • Nottingham University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham (UAB) Hospital
      • Contact: Brendan McGuire
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Withdrawn
      • Mayo Clinic Phoenix
  • California
    • Coronado, California, United States, 92118
      • Completed
      • Southern California Research Center
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
      • Contact: Alexander Kuo
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Ram Subramanian
  • Kansas
    • Kansas City, Kansas, United States, 66045
      • Withdrawn
      • University of Kansas
  • New Jersey
    • Newark, New Jersey, United States, 07101
      • Active, not recruiting
      • Rutgers-New Jersey Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Recruiting
      • University of New Mexico
      • Contact: Jay Raval
  • New York
    • Rochester, New York, United States, 55905
      • Completed
      • Mayo Clinic Rochester
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Withdrawn
      • Ohio State University Wexner Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Completed
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Contact: Ali Al- Khafaji
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Recruiting
      • McGuire VA Medical Center
      • Contact: Jasmohan Bajaj
  • Washington
    • Seattle, Washington, United States, 98195
      • Withdrawn
      • University of Washington Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Recruiting
      • Aurora Health Care, Inc.
      • Contact: David Kramer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SMT+ PE-A 5%; PE-A 5% will be performed using 5% albumin (Albutein 5%) as the main replacement fluid administered intravenously.	Biological: SMT + 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.; Other Names: Albutein 5%
Active Comparator: Standard Medical Treatment (SMT); Standard medical treatment (SMT) will be administered according to institution standards.	Other: Standard Medical Treatment; Standard medical treatment according to the institution's standard practice; Other Names: SMT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death through Day 90	Time to death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone	Day 1 to Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to transplant or death through Day 90	Time to transplant or death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone	Day 1 to Day 90
Time to death through Day 28	Time to death through Day 28 after randomization of SMT+PE-A 5% versus SMT alone	Day 1 to Day 28

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Collaborators: Instituto Grifols, S.A.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2019
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: October 9, 2018
• First Submitted That Met QC Criteria: October 9, 2018
• First Posted (Actual): October 11, 2018

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure, Acute; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure
• Other Study ID Numbers: IG1407

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No