Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement

Cirrhosis Clinical Trial

— HEAL-LAST  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06052176
• Other study ID #: BAJAJ0035
• Status: Recruiting
• Phase: Phase 2
• Start date: November 2, 2023
• Est. completion date: June 1, 2025

Study information

• Verified date: December 2023
• Source: Hunter Holmes Mcguire Veteran Affairs Medical Center
• Contact: Jasmohan Bajaj, MD
• Phone: 8046755802
• Email: jasmohan.bajaj[@]vcuhealth.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: June 1, 2025
• Est. primary completion date: March 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Cirrhosis
• Fibrosis
• Hepatic Encephalopathy

Intervention

Drug:
• Albumin Infusion
Intravenous human serum albumin to be given at 1.5g/kg ideal body weight

Locations

Country	Name	City	State
United States	Hunter Holmes McGuire VA Medical Center	Richmond	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Hunter Holmes Mcguire Veteran Affairs Medical Center	Grifols Biologicals, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in MELD-Na score Placebo phase vs Albumin phase	Liver disease severity change using MELD-Na; higher is worse	4 weeks each
Secondary	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
Secondary	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
Secondary	Change in ischemia modified albumin Placebo phase vs Albumin phase	Change in ischemia modified albumin will be recorded in the serum	4 weeks each
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in stool bacterial alpha diversity Placebo phase vs Albumin phase	Change in Shannon diversity of stool bacteria	4 weeks each
Secondary	Change in serum inflammatory cytokines Placebo phase vs Albumin phase	Change in IL-6, TNF-a, IL-10, IL-1ß in serum	4 weeks each