Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement

Study Overview
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Brief Summary
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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

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

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

Conditions
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Cirrhosis, Hepatic Encephalopathy

Intervention / Treatment
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* Drug: Albumin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Saline | Drug: Albumin<br>* Intravenous human serum albumin<br>* Other names: Albutein;|
| Active Comparator: Albumin<br>IV Albumin | Drug: Albumin<br>* Intravenous human serum albumin<br>* Other names: Albutein;|

What is the study measuring?
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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) | 4 weeks each | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EncephalApp Stroop change in Placebo phase vs Albumin phase | cognitive improvement (Stroop OffTime+OnTime in seconds will be evaluated) | 4 weeks each | 
| Critical Flicker Frequency change in Placebo phase vs Albumin phase | cognitive improvement (Hz at which CFF is reached will be evaluated) | 4 weeks each | 
| 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 MELD-Na score Placebo phase vs Albumin phase | Liver disease severity change using MELD-Na | 4 weeks each | 
| Change in endotoxin binding protein Placebo phase vs Albumin phase | Change in endotoxin binding protein will be recorded in the serum | 4 weeks each | 
| Change in oxidized albumin Placebo phase vs Albumin phase | Change in oxidized albumin will be recorded in the serum | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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albumin, cirrhosis, inflammation, cognitive performance