Cirrhosis, Hepatic Encephalopathy
Conditions
Keywords
albumin, cirrhosis, inflammation, cognitive performance
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.
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.
Interventions
DRUGAlbumin Infusion
Intravenous human serum albumin to be given at 1.5g/kg ideal body weight
Sponsors
Hunter Holmes Mcguire Veteran Affairs Medical Center
Grifols Biologicals, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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), higher is good |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EncephalApp Stroop change in Placebo phase vs Albumin phase | 4 weeks each | cognitive improvement (Stroop OffTime+OnTime in seconds will be evaluated); higher is worse |
| Critical Flicker Frequency change in Placebo phase vs Albumin phase | 4 weeks each | cognitive improvement (Hz at which CFF is reached will be evaluated), higher is good |
| 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; higher is worse |
| Change in endotoxin binding protein Placebo phase vs Albumin phase | 4 weeks each | Change in endotoxin binding protein will be recorded in the serum; higher is worse |
| Change in oxidized albumin Placebo phase vs Albumin phase | 4 weeks each | Change in oxidized albumin will be recorded in the serum ; higher is worse |
| 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 |
Countries
United States
Outcome results
None listed