HEAL-LAST: Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement

Sponsor

Hunter Holmes Mcguire Veteran Affairs Medical Center (U.S. Fed)

Overall Status

Not yet recruiting

CT.gov ID

NCT06052176

Collaborator

Grifols Biologicals, LLC (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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	Phase 2

Detailed Description

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

Our 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 life4. 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 unelucidated5. The mechanisms and length of time albumin's potential improvement for patients with MHE after treatment discontinuation also require continued study.

Study design:

We will change the order the albumin and placebo infusion and blind the infusions from the subjects and the assessors of the outcoemes.

Study Design

Study Type:

Interventional

Anticipated 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

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Saline	Drug: Albumin Intravenous human serum albumin Other Names: Albutein
Active Comparator: Albumin IV Albumin	Drug: Albumin Intravenous human serum albumin Other Names: Albutein

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Saline

Drug: Albumin

Intravenous human serum albumin

Other Names:

Albutein

Active Comparator: Albumin

IV Albumin

Drug: Albumin

Intravenous human serum albumin

Other Names:

Albutein

Outcome Measures

Primary Outcome Measures

Delta change in Psychometric Hepatic Encephalopathy Score (PHES) in Placebo phase vs Albumin phase [4 weeks each]
cognitive improvement (PHES score ranges from -15 to 5)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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