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

Randomized Clinical Trial in Hepatic Encephalopathy to Study Lasting Cognitive Improvement With Intravenous Albumin

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatic Encephalopathy; Cirrhosis
• Intervention / Treatment: Drug: Albumin Infusion

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 Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jasmohan Bajaj, MD; Phone Number: 8046755802; Email: jasmohan.bajaj@vcuhealth.org

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Recruiting
      • Hunter Holmes McGuire VA Medical Center
      • Principal Investigator: Jasmohan S Bajaj, MD, MSc
      • Contact: Travis Mousel, RN; Phone Number: 804 675 5584; Email: travis.mousel@va.gov
      • Contact: Haley Obolewicz, RN; Phone Number: 6733 804 675 5000; Email: haley.obolewicz@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Albutein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delta change in Psychometric Hepatic Encephalopathy Score (PHES) in Placebo phase vs Albumin phase	cognitive improvement (PHES score ranges from -15 to 5), higher is good	4 weeks each

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Sickness Impact Profile Placebo phase vs Albumin phase	Health-related quality of life change (SIP total, psychosocial and physical scores where a higher score indicates poor HRQOL willl be evaluated)	4 weeks each
Change in PROMIS-29 Placebo phase vs Albumin phase	Health-related quality of life change (Total PROMIS-29 score will be evaluated)	4 weeks each
Change in ischemia modified albumin Placebo phase vs Albumin phase	Change in ischemia modified albumin will be recorded in the serum	4 weeks each
Change in stool bile acids Placebo phase vs Albumin phase	Change in stool bile acids (total, primary, secondary, conjugated/deconjugated) will be recorded	4 weeks each
Change in serum bile acids Placebo phase vs Albumin phase	Change in serum bile acids (total, primary, secondary, conjugated/deconjugated) will be recorded	4 weeks each
Change in serum Short-chain fatty acids Placebo phase vs Albumin phase	Change in serum Short-chain fatty acids (acetate, propionate, butyrate will be recorded	4 weeks each
Change in stool Short-chain fatty acids Placebo phase vs Albumin phase	Change in stool Short-chain fatty acids (acetate, propionate, butyrate will be recorded	4 weeks each
Change in stool bacterial alpha diversity Placebo phase vs Albumin phase	Change in Shannon diversity of stool bacteria	4 weeks each
Change in serum inflammatory cytokines Placebo phase vs Albumin phase	Change in IL-6, TNF-α, IL-10, IL-1β in serum	4 weeks each
EncephalApp Stroop change in Placebo phase vs Albumin phase	cognitive improvement (Stroop OffTime+OnTime in seconds will be evaluated); higher is worse	4 weeks each
Critical Flicker Frequency change in Placebo phase vs Albumin phase	cognitive improvement (Hz at which CFF is reached will be evaluated), higher is good	4 weeks each
Change in MELD-Na score Placebo phase vs Albumin phase	Liver disease severity change using MELD-Na; higher is worse	4 weeks each
Change in endotoxin binding protein Placebo phase vs Albumin phase	Change in endotoxin binding protein will be recorded in the serum; higher is worse	4 weeks each
Change in oxidized albumin Placebo phase vs Albumin phase	Change in oxidized albumin will be recorded in the serum ; higher is worse	4 weeks each

Collaborators and Investigators

• Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Collaborators: Grifols Biologicals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 18, 2023
• First Submitted That Met QC Criteria: September 18, 2023
• First Posted (Actual): September 25, 2023

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: albumin; inflammation; cirrhosis; cognitive performance
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Inflammation; Fibrosis; Hepatic Encephalopathy; Amino Acids, Peptides, and Proteins; Proteins; Albumins
• Other Study ID Numbers: BAJAJ0035

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