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Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement (HEAL-LAST)

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ClinicalTrials.gov Identifier: NCT06052176
Recruitment Status : Recruiting
First Posted : September 25, 2023
Last Update Posted : January 3, 2024
Sponsor:
Collaborator:
Grifols Biologicals, LLC
Information provided by (Responsible Party):
Hunter Holmes Mcguire Veteran Affairs Medical Center

Study Description
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Brief Summary:

Hypothesis: Improvement in cognitive dysfunction with IV albumin in patients with cirrhosis with prior HE and MHE lasts for several weeks after albumin infusion has ended, and is due to persistent improvement in inflammatory markers, endothelial dysfunction, albumin function and gut microbial changes.

This will be a single-arm, single-blind sequential trial of IV 25% albumin and IV saline over 8 weeks with biological sampling and cognitive and health related quality of life (HRQOL) testing with each subject acting as their own control.


Condition or disease Intervention/treatment Phase
Cirrhosis Hepatic Encephalopathy Drug: Albumin Infusion Phase 2

Detailed Description:

In outpatients with cirrhosis with prior HE who have cognitive impairment despite adequate therapy, how long the impact of albumin lasts and through which potential mechanism(s) needs to be determined.

A prior recent HEAL trial showed that patients with prior HE and current minimal hepatic encephalopathy (MHE) randomized to albumin experienced significant improvement in cognitive dysfunction and psychosocial quality of life. Moreover, these improvements persisted a week after the last albumin infusion, which was not seen in the placebo group. This was accompanied by an improvement in endothelial dysfunction, ischemia-modified albumin levels and inflammatory markers that persisted one week even after albumin discontinuation. The reported half-life of IV albumin is 2 weeks, but the function and the length of time of albumin's action in decompensated cirrhosis is lower, and further details surrounding albumin pharmacokinetics in this population remain unelucidated. The mechanisms and length of time albumin's potential improvement for patients with MHE after treatment discontinuation also require continued study.

Study design:

This will be a single-arm, single-blind sequential trial of IV 25% albumin and IV saline over 8 weeks with biological sampling and cognitive and health related quality of life (HRQOL) testing with each subject acting as their own control.

Th order of the albumin and placebo infusion and blind the infusions from the subjects and the assessors of the outcomes will be changed.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Outcomes Assessor)
Masking Description: Subjects will be blinded to which infusions are albumin versus placebo. All infusion tubing and bag will be covered in foil and the subjects will not be aware of the timing of the saline vs albumin infusion to maintain blinding for the patient.
Primary Purpose: Prevention
Official Title: Randomized Clinical Trial in Hepatic Encephalopathy to Study Lasting Cognitive Improvement With Intravenous Albumin
Actual Study Start Date : November 2, 2023
Estimated Primary Completion Date : March 1, 2025
Estimated Study Completion Date : June 1, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Albumins

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
Saline given at the same volume as the albumin on visits the patients are assigned to it
 Drug: Albumin Infusion
Intravenous human serum albumin to be given at 1.5g/kg ideal body weight
Other Name: Albutein
Active Comparator: Albumin
IV Albumin at 1.5g/kg ideal body weight
 Drug: Albumin Infusion
Intravenous human serum albumin to be given at 1.5g/kg ideal body weight
Other Name: Albutein


Outcome Measures
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Primary Outcome Measures :
  1. Delta change in Psychometric Hepatic Encephalopathy Score (PHES) in Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    cognitive improvement (PHES score ranges from -15 to 5), higher is good


Secondary Outcome Measures :
  1. EncephalApp Stroop change in Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    cognitive improvement (Stroop OffTime+OnTime in seconds will be evaluated); higher is worse

  2. Critical Flicker Frequency change in Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    cognitive improvement (Hz at which CFF is reached will be evaluated), higher is good

  3. Change in Sickness Impact Profile Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Health-related quality of life change (SIP total, psychosocial and physical scores where a higher score indicates poor HRQOL willl be evaluated)

  4. Change in PROMIS-29 Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Health-related quality of life change (Total PROMIS-29 score will be evaluated)

  5. Change in MELD-Na score Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Liver disease severity change using MELD-Na; higher is worse

  6. Change in endotoxin binding protein Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in endotoxin binding protein will be recorded in the serum; higher is worse

  7. Change in oxidized albumin Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in oxidized albumin will be recorded in the serum ; higher is worse

  8. Change in ischemia modified albumin Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in ischemia modified albumin will be recorded in the serum

  9. Change in stool bile acids Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in stool bile acids (total, primary, secondary, conjugated/deconjugated) will be recorded

  10. Change in serum bile acids Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in serum bile acids (total, primary, secondary, conjugated/deconjugated) will be recorded

  11. Change in serum Short-chain fatty acids Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in serum Short-chain fatty acids (acetate, propionate, butyrate will be recorded

  12. Change in stool Short-chain fatty acids Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in stool Short-chain fatty acids (acetate, propionate, butyrate will be recorded

  13. Change in stool bacterial alpha diversity Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in Shannon diversity of stool bacteria

  14. Change in serum inflammatory cytokines Placebo phase vs Albumin phase [ Time Frame: 4 weeks each ]
    Change in IL-6, TNF-α, IL-10, IL-1β in serum


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age >18 years
  • Cirrhosis diagnosed using either (a) liver biopsy, (b) transient wave elastography (>20 KPa) (c) radiological evidence consistent with cirrhosis, (d) in a patient with chronic liver disease endoscopic or radiological evidence of varices (e), in a patient with chronic liver disease, platelet count <150,000/mm3 and AST/ALT ratio >1.
  • Cognitive impairment defined by MHE on psychometric hepatic encephalopathy score (PHES), critical flicker frequency (CFF), or EncephalApp Stroop
  • Prior HE controlled by lactulose or rifaximin for at least one month
  • Serum albumin <4gm/dl

Exclusion Criteria:

  • Unclear diagnosis of cirrhosis
  • No prior overt HE
  • No cognitive impairment on the tests noted
  • Requiring regular albumin infusions within 3 months or anticipated during the study visit
  • Infection within a month
  • Allergies to albumin
  • Unlikely to be adherent to the study
  • Unable or unwilling to consent
  • West Haven Criteria>2
  • Alcohol abuse within 1 month
  • Serum albumin >4gm/dl
  • Congestive heart failure
Contacts and Locations
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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): NCT06052176


Contacts
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Contact: Jasmohan Bajaj, MD 8046755802 jasmohan.bajaj@vcuhealth.org

Locations
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United States, Virginia
Hunter Holmes McGuire VA Medical Center Recruiting
Richmond, Virginia, United States, 23249
Contact: Haley Obolewicz, RN    804-675-5000 ext 6733    haley.obolewicz@va.gov   
Contact: Travis Mousel, RN    804 675 5584    travis.mousel@va.gov   
Principal Investigator: Jasmohan S Bajaj, MD, MSc         
Sponsors and Collaborators
Hunter Holmes Mcguire Veteran Affairs Medical Center
Grifols Biologicals, LLC
More Information
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Responsible Party: Hunter Holmes Mcguire Veteran Affairs Medical Center
ClinicalTrials.gov Identifier: NCT06052176    
Other Study ID Numbers: BAJAJ0035
First Posted: September 25, 2023    Key Record Dates
Last Update Posted: January 3, 2024
Last Verified: December 2023
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
Keywords provided by Hunter Holmes Mcguire Veteran Affairs Medical Center:
albumin
cirrhosis
inflammation
cognitive performance
Additional relevant MeSH terms:
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Hepatic Encephalopathy
Brain Diseases
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
 Central Nervous System Diseases
Nervous System Diseases
Liver Failure
Hepatic Insufficiency
Brain Diseases, Metabolic
Metabolic Diseases