Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5% (APACHE)
Primary Purpose
Acute-On-Chronic Liver Failure
Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
SMT + PE-A 5%
Standard Medical Treatment
Sponsored by
About this trial
This is an interventional treatment trial for Acute-On-Chronic Liver Failure
Eligibility Criteria
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 (surrogate).
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.
Sites / Locations
- University of Alabama at Birmingham (UAB) HospitalRecruiting
- Mayo Clinic Phoenix
- Southern California Research Center
- Cedars-Sinai Medical CenterRecruiting
- Emory UniversityRecruiting
- University of Kansas
- Rutgers-New Jersey Medical School
- University of New MexicoRecruiting
- Mayo Clinic Rochester
- Ohio State University Wexner Medical Center
- University of Pennsylvania
- University of Pittsburgh Medical CenterRecruiting
- McGuire VA Medical CenterRecruiting
- University of Washington Medical Center
- Aurora Health Care, Inc.Recruiting
- Medical University of ViennaRecruiting
- Université libre de BruxellesRecruiting
- UZ Leuven - Campus GasthuisbergRecruiting
- Rigshospitalet
- Hôpital BeaujonRecruiting
- Centre Hépato-Biliaire - Hôpital Universitaire Paul BrousseRecruiting
- Universitätsklinikum Bonn
- Universitätsklinikum FrankfurtRecruiting
- Hannover Medical SchoolRecruiting
- Universitaetsklinikum LeipzigRecruiting
- Klinikum der Universitaet Muenchen
- Klinikum der Universitaet MuenchenRecruiting
- ASST Papa Giovanni XXIII
- ASST Grande Ospedale Metropolitano NiguardaRecruiting
- Milano Hospital Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
- Azienda Ospedaliera di PadovaRecruiting
- Azienda Ospedaliero-Universitaria Policlinico Umberto IRecruiting
- Centro Hospitalar Lisboa Norte
- Centro Hospitalar do Porto
- Hospital Universitario del Valle HebronRecruiting
- Hospital Clínic de BarcelonaRecruiting
- Hospital General Gregorio Marañón
- Hospital Universitario Ramón y CajalRecruiting
- Royal Free NHS Foundation Trust HospitalRecruiting
- King's College Hospital NHS Foundation TrustRecruiting
- Nottingham University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
SMT+ PE-A 5%
Standard Medical Treatment (SMT)
Arm Description
PE-A 5% will be performed using 5% albumin (Albutein 5%) as the main replacement fluid administered intravenously.
Standard medical treatment (SMT) will be administered according to institution standards.
Outcomes
Primary Outcome Measures
Time to death through Day 90
Time to death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone
Secondary Outcome Measures
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
Time to death through Day 28
Time to death through Day 28 after randomization of SMT+PE-A 5% versus SMT alone
Full Information
NCT ID
NCT03702920
First Posted
October 9, 2018
Last Updated
October 18, 2023
Sponsor
Grifols Therapeutics LLC
Collaborators
Instituto Grifols, S.A.
1. Study Identification
Unique Protocol Identification Number
NCT03702920
Brief Title
Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5%
Acronym
APACHE
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 21, 2019 (Actual)
Primary Completion Date
October 2026 (Anticipated)
Study Completion Date
October 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grifols Therapeutics LLC
Collaborators
Instituto Grifols, S.A.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute-On-Chronic Liver Failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
380 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
SMT+ PE-A 5%
Arm Type
Experimental
Arm Description
PE-A 5% will be performed using 5% albumin (Albutein 5%) as the main replacement fluid administered intravenously.
Arm Title
Standard Medical Treatment (SMT)
Arm Type
Active Comparator
Arm Description
Standard medical treatment (SMT) will be administered according to institution standards.
Intervention Type
Biological
Intervention Name(s)
SMT + PE-A 5%
Other Intervention Name(s)
Albutein 5%
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Standard Medical Treatment
Other Intervention Name(s)
SMT
Intervention Description
Standard medical treatment according to the institution's standard practice
Primary Outcome Measure Information:
Title
Time to death through Day 90
Description
Time to death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone
Time Frame
Day 1 to Day 90
Secondary Outcome Measure Information:
Title
Time to transplant or death through Day 90
Description
Time to transplant or death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone
Time Frame
Day 1 to Day 90
Title
Time to death through Day 28
Description
Time to death through Day 28 after randomization of SMT+PE-A 5% versus SMT alone
Time Frame
Day 1 to Day 28
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mireia Torres
Phone
+34 93 5710500
Email
approach_apache@grifols.com
Facility Information:
Facility Name
University of Alabama at Birmingham (UAB) Hospital
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brendan McGuire
Facility Name
Mayo Clinic Phoenix
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Individual Site Status
Withdrawn
Facility Name
Southern California Research Center
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Individual Site Status
Completed
Facility Name
Cedars-Sinai Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexander Kuo
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ram Subramanian
Facility Name
University of Kansas
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66045
Country
United States
Individual Site Status
Withdrawn
Facility Name
Rutgers-New Jersey Medical School
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07101
Country
United States
Individual Site Status
Active, not recruiting
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jay Raval
Facility Name
Mayo Clinic Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Completed
Facility Name
Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Withdrawn
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Completed
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ali Al- Khafaji
Facility Name
McGuire VA Medical Center
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jasmohan Bajaj
Facility Name
University of Washington Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
Individual Site Status
Withdrawn
Facility Name
Aurora Health Care, Inc.
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Kramer
Facility Name
Medical University of Vienna
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas Reiberger
Facility Name
Université libre de Bruxelles
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thierry Gustot
Facility Name
UZ Leuven - Campus Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Wilmer
Facility Name
Rigshospitalet
City
Copenhagen
Country
Denmark
Individual Site Status
Withdrawn
Facility Name
Hôpital Beaujon
City
Clichy
ZIP/Postal Code
92110
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mikhael Giabicani
Facility Name
Centre Hépato-Biliaire - Hôpital Universitaire Paul Brousse
City
Villejuif
ZIP/Postal Code
94804
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Faouzi Saliba
Facility Name
Universitätsklinikum Bonn
City
Bonn
ZIP/Postal Code
53105
Country
Germany
Individual Site Status
Withdrawn
Facility Name
Universitätsklinikum Frankfurt
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anita Pathil-Warth
Facility Name
Hannover Medical School
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benjamin Maasoumy
Facility Name
Universitaetsklinikum Leipzig
City
Leipzig
ZIP/Postal Code
4103
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Thomas Berg
Facility Name
Klinikum der Universitaet Muenchen
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Individual Site Status
Withdrawn
Facility Name
Klinikum der Universitaet Muenchen
City
München
ZIP/Postal Code
81377
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christian Lange
Facility Name
ASST Papa Giovanni XXIII
City
Bergamo
ZIP/Postal Code
24127
Country
Italy
Individual Site Status
Withdrawn
Facility Name
ASST Grande Ospedale Metropolitano Niguarda
City
Milano
ZIP/Postal Code
20162
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giovanni Perricone
Facility Name
Milano Hospital Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
City
Milan
ZIP/Postal Code
20122
Country
Italy
Individual Site Status
Completed
Facility Name
Azienda Ospedaliera di Padova
City
Padova
ZIP/Postal Code
35128
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paolo Angeli
Facility Name
Azienda Ospedaliero-Universitaria Policlinico Umberto I
City
Roma
ZIP/Postal Code
161
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Manuela Merli
Facility Name
Centro Hospitalar Lisboa Norte
City
Lisboa
ZIP/Postal Code
1649-028
Country
Portugal
Individual Site Status
Withdrawn
Facility Name
Centro Hospitalar do Porto
City
Porto
Country
Portugal
Individual Site Status
Completed
Facility Name
Hospital Universitario del Valle Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Victor Vargas
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Fernández
Facility Name
Hospital General Gregorio Marañón
City
Madrid
ZIP/Postal Code
28007
Country
Spain
Individual Site Status
Withdrawn
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Agustin Albillos
Facility Name
Royal Free NHS Foundation Trust Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gautam Mehta
Facility Name
King's College Hospital NHS Foundation Trust
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
William Bernal
Facility Name
Nottingham University Hospital
City
Nottingham
ZIP/Postal Code
NG72UH
Country
United Kingdom
Individual Site Status
Withdrawn
12. IPD Sharing Statement
Plan to Share IPD
No
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Short-term Survival of Subjects With Acute-on-chronic Liver Failure After Plasma Exchange With Human Serum Albumin 5%
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