HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

Sponsor

The Cleveland Clinic (Other)

Overall Status

Recruiting

CT.gov ID

NCT05166499

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Loss of skeletal muscle mass or sarcopenia is the most common and potentially reversible complication in cirrhosis that increases morbidity and mortality before, during and after liver transplantation. No proven treatments exist for the prevention or reversal of sarcopenia in cirrhosis, primarily because the mechanisms responsible for this are unknown. Based on compelling preliminary studies and those of the co investigator, investigators hypothesize that the mechanism of reduced skeletal muscle mass in cirrhosis is due to a myostatin mediated impaired mTOR (mechanistic target of rapamycin) signaling resulting in reduced protein synthesis and increased autophagy. Investigators further postulate that leucine, a direct stimulant of mTOR, will reverse the impaired mTOR phosphorylation in the skeletal muscle of cirrhotics. The consequent increase in protein synthesis reduced autophagy will result in an increase in skeletal muscle mass. Investigators will test these hypotheses by quantifying the response to acute and long term (3 month) administration of hydroxymethyl butyrate (HMB) enriched essential amino acid compared with an isonitrogenous isocaloric non-essential balanced amino acid mixture (does not stimulate protein synthesis) in cirrhotic patients. Fractional protein synthesis rate (FSR) in skeletal muscle, responses of the molecular regulatory pathways of skeletal muscle protein synthesis, and autophagy flux will be quantified in the acute and long term protocols. Tracer studies using L-[D5]-phenylalanine (Phe) as a primed constant infusion (prime 2µmol.kg-1.hr-1; constant 0.05 µmol.kg-1.hr-1) with and L [ring-D2] tyrosine, forearm plethysmography, and sequential skeletal muscle biopsies (total of 3 per study subject) will be used to quantify these outcomes. Anthropometric, clinical and body composition measures will be additional outcome measures for the long term intervention. Expression of regulatory signaling proteins, myostatin, IGF-1 (insulin like growth factor) , phospho-Akt, phospho-AMPK (activated protein kinase), phospho-mTOR and phospho-p70s6k will be quantified by Western immunoblots. Autophagy flux will be measured by quantifying expression of the autophagosome proteins.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis, Liver	Dietary Supplement: Hydroxy Methyl Butyrate Dietary Supplement: Balanced Amino Acids	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

Actual Study Start Date :

Nov 30, 2021

Anticipated Primary Completion Date :

Dec 30, 2025

Anticipated Study Completion Date :

Dec 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hydroxy Methyl Butyrate	Dietary Supplement: Hydroxy Methyl Butyrate Hydroxy Methyl Butyrate
Other: Balanced Amino Acid Mixture	Dietary Supplement: Balanced Amino Acids Balanced Amino Acids

Arm

Intervention/Treatment

Active Comparator: Hydroxy Methyl Butyrate

Dietary Supplement: Hydroxy Methyl Butyrate

Hydroxy Methyl Butyrate

Other: Balanced Amino Acid Mixture

Dietary Supplement: Balanced Amino Acids

Balanced Amino Acids

Outcome Measures

Primary Outcome Measures

Change in Fractional Synthesis Rate of Skeletal Muscle [Day 0 to Day 90]
To test whether fractional synthesis of skeletal muscle proteins changes from baseline to 90 days with the administration of BAA or EAA/LEU. Fractional synthesis rate (FSR) of mixed muscle proteins will be calculated from the incorporation rate of the L- [ring D5] phenylalanine into the proteins and the free tissue phenylalanine enrichments using precursor product model: FSR= (∆Ep/t)/(∆Ec) x60x100 and expressed as %/hour. ΔEp is the increment in myofibrillar protein-bound L- [ring D5] phenylalanine enrichment, t is the time between the muscle biopsies. ∆Ec is the L- [ring D5] phenylalanine enrichments in the free intracellular pool in the muscle biopsies.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of cirrhosis of the liver
Child-Pugh score of 5-8

Exclusion Criteria:

Recent gastrointestinal bleeding (<3m)
Active infection
Overt encephalopathy
Renal failure on dialysis
Pedal edema
Uncontrolled diabetes (HbA1C > 7.9mg/dL)
Advanced cardiac, lung, kidney disease
Metastatic cancer
Medications that alter muscle protein metabolism
Pregnancy
Recent bowel resection or gastric bypass surgery,
INR >1.7, platelets <60,000/ml, serum creatinine >2mg/dL
Medications that interfere with blood clotting

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

The Cleveland Clinic

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Srinivasan Dasarathy, Staff, The Cleveland Clinic

ClinicalTrials.gov Identifier:

NCT05166499

Other Study ID Numbers:

21-830

First Posted:

Dec 22, 2021

Last Update Posted:

Dec 22, 2021

Last Verified:

Dec 1, 2021

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Liver Cirrhosis

Fibrosis

Study Results

No Results Posted as of Dec 22, 2021