Hepatic Encephalopathy and Albumin Lasting Cognitive Improvement

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.

Primary Outcome Measures

1. 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

Secondary Outcome Measures

1. EncephalApp Stroop change in Placebo phase vs Albumin phase
   cognitive improvement (Stroop OffTime+OnTime in seconds will be evaluated); higher is worse
2. Critical Flicker Frequency change in Placebo phase vs Albumin phase
   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
   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
   Health-related quality of life change (Total PROMIS-29 score will be evaluated)
5. Change in MELD-Na score Placebo phase vs Albumin phase
   Liver disease severity change using MELD-Na; higher is worse
6. Change in endotoxin binding protein Placebo phase vs Albumin phase
   Change in endotoxin binding protein will be recorded in the serum; higher is worse
7. Change in oxidized albumin Placebo phase vs Albumin phase
   Change in oxidized albumin will be recorded in the serum ; higher is worse
8. Change in ischemia modified albumin Placebo phase vs Albumin phase
   Change in ischemia modified albumin will be recorded in the serum
9. Change in stool bile acids Placebo phase vs Albumin phase
   Change in stool bile acids (total, primary, secondary, conjugated/deconjugated) will be recorded
10. Change in serum bile acids Placebo phase vs Albumin phase
    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
    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
    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
    Change in Shannon diversity of stool bacteria
14. Change in serum inflammatory cytokines Placebo phase vs Albumin phase
    Change in IL-6, TNF-α, IL-10, IL-1β in serum