Leucine Enriched Essential Amino Acid Mixture to Reverse Muscle Loss in Cirrhosis

NCT ID: NCT03208868

Last Updated: 2025-10-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-05
• Study Completion Date: 2026-12-31

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 leucine enriched essential amino acid (EAA/LEU) 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.

Conditions

Cirrhosis, Liver

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Leucine enriched essential amino acid

Patients with cirrhosis that are given a leucine enriched essential amino acid (EEA/LEU) supplement.

Group Type: ACTIVE_COMPARATOR

Leucine enriched essential amino acid (EEA/LEU)

Intervention Type: DIETARY_SUPPLEMENT

Patient with cirrhosis will be randomized to either take a Leucine enriched essential amino acid or a balanced amino acid supplement.

Balanced amino acid supplement

Patients with cirrhosis that are given a balanced amino acid (BAA) supplement.

Group Type: ACTIVE_COMPARATOR

Balanced amino acid supplement (BAA)

Intervention Type: DIETARY_SUPPLEMENT

Patient with cirrhosis will be randomized to either take a Leucine enriched essential amino acid or a balanced amino acid supplement.

Interventions

Leucine enriched essential amino acid (EEA/LEU)

Patient with cirrhosis will be randomized to either take a Leucine enriched essential amino acid or a balanced amino acid supplement.

Intervention Type: DIETARY_SUPPLEMENT

Balanced amino acid supplement (BAA)

Patient with cirrhosis will be randomized to either take a Leucine enriched essential amino acid or a balanced amino acid supplement.

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• Cirrhotic patients:
• Cirrhosis diagnosed by liver biopsy and/or clinical, biochemical and imaging evidence of cirrhosis.
• Abstinence from alcohol and/or other recreational drugs for at least 6 months
• Child's Pugh score 5-9 (inclusive).

Exclusion

• Cirrhotic patients:
• Child's score >9
• Pedal edema above the ankle
• Presence of concurrent illnesses (renal, cardiac, pulmonary, cerebrovascular, malignancy) or medication (anabolic steroids, corticosteroids) intake that affect skeletal muscle mass.
• Diabetes mellitus
• Active gastrointestinal bleeding
• Sepsis, encephalopathy
• Renal failure
• Hepatocellular carcinoma outside of Milan criteria
• Unwilling to sign informed consent or follow research procedures

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Srinivasan Dasarathy

Staff Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Site Status: RECRUITING

Countries

United States

Facility Contacts

Annette Bellar, BS

Role: primary

bellara@ccf.org

216-636-5247

Revathi Penumatsa, MD

Role: backup

penumar@ccf.org

216-445-0688

Other Identifiers

12-916

Identifier Type: -

Identifier Source: org_study_id