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

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ClinicalTrials.gov Identifier: NCT03702920
Recruitment Status : Recruiting
First Posted : October 11, 2018
Last Update Posted : March 13, 2019
Sponsor:
Collaborator:
Instituto Grifols, S.A.
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Acute-On-Chronic Liver Failure Biological: SMT + PE-A 5% Other: Standard Medical Treatment Phase 3

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 (surrogate).

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 21, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


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 Name: 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 Name: SMT




Primary Outcome Measures :
  1. Time to death through Day 90 [ Time Frame: Day 1 to Day 90 ]
    Time to death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone


Secondary Outcome Measures :
  1. Time to transplant or death through Day 90 [ Time Frame: Day 1 to Day 90 ]
    Time to transplant or death through Day 90 after randomization of SMT+PE-A 5% versus SMT alone

  2. Time to death through Day 28 [ Time Frame: Day 1 to Day 28 ]
    Time to death through Day 28 after randomization of SMT+PE-A 5% versus SMT alone



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A subject must meet all the following inclusion criteria to be eligible for participation in this study:

    1. Male or female cirrhotic subjects between 18 and 79 years of age.
    2. 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]).
    3. 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.
    4. In case of HE, informed consent will be provided by a relative or a legally authorized representative (surrogate).

Exclusion Criteria:

  • A subject meeting any of the following exclusion criteria is NOT eligible for participation in the study:

    1. Subjects without ACLF.
    2. Subjects with ACLF-1a or ACLF-3b after the Screening Period.
    3. 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).
    4. Subjects with ACLF for more than 10 days prior to randomization.
    5. Subjects with acute or subacute liver failure without underlying cirrhosis.
    6. Subjects with septic shock lasting >1 hour that does not respond to fluid resuscitation-IV therapy or pharmacologic-pressors.
    7. Subjects with active bacterial or fungal infection with hemodynamic instability.
    8. Subjects with acute respiratory distress syndrome (ARDS) with peripheral oxygen saturation (SpO^2) ≤89.
    9. Subjects with active or recent bleeding (unless controlled for >48 hours).
    10. Subjects with severe thrombocytopenia (≤20×10^9/L) (based on local laboratory assessment).
    11. Subjects with chronic renal failure and currently receiving hemodialysis.
    12. 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).
    13. Subjects with severe chronic heart failure (New York Heart Association class III or IV).
    14. Subjects with severe pulmonary disease (Global Obstructive Lung Disease stage III or IV).
    15. Subjects with severe myopathy as defined clinically.
    16. Subjects with a known infection with human immunodeficiency virus (HIV) or have clinical signs and symptoms consistent with current HIV infection.
    17. Females who are pregnant, breastfeeding, or if of childbearing potential, unwilling to practice a highly effective method of contraception (oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom, or occlusive cap with spermicidal foam/gel/cream/suppository, male sterilization, or true abstinence*) throughout the study.

      • True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception).
    18. Subjects with previous liver transplantation.
    19. Subjects receiving anti-platelet or anti-coagulant therapy.
    20. Participation in another clinical study within at least 30 days prior to screening.
    21. Subjects with active drug addiction.
    22. Subjects with a do-not-resuscitate order.
    23. In the opinion of the investigator, the subject may have compliance problems with the protocol and the procedures of the protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03702920


Contacts
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Contact: Ed Corsi 919-316-6222 ed.corsi@grifols.com
Contact: Mireia Torres +34 93 5712273 mireia.torres@grifols.com

Locations
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United States, Ohio
Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: James Hanje, MD    614-293-6255    james.hanje@osumc.edu   
Sponsors and Collaborators
Grifols Therapeutics LLC
Instituto Grifols, S.A.

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Responsible Party: Grifols Therapeutics LLC
ClinicalTrials.gov Identifier: NCT03702920     History of Changes
Other Study ID Numbers: IG1407
First Posted: October 11, 2018    Key Record Dates
Last Update Posted: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Failure
Hepatic Insufficiency
End Stage Liver Disease
Acute-On-Chronic Liver Failure
Liver Diseases
Digestive System Diseases
Liver Failure, Acute