HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

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.

Study Overview

• Status: Recruiting
• Conditions: Cirrhosis, Liver
• Intervention / Treatment: Dietary supplement: Hydroxy Methyl Butyrate; Dietary supplement: Balanced Amino Acids

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Annette Bellar; Phone Number: 2164456268; Email: bellara@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Contact: Annette Bellar

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fractional Synthesis Rate of Skeletal Muscle	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.	Day 0 to Day 90

Collaborators and Investigators

• Sponsor: The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Estimated): November 25, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms; Liver Cirrhosis; beta-hydroxyisovaleric acid
• Other Study ID Numbers: 21-830

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No