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

Not Applicable

Recruiting

• Conditions: Cirrhosis, Liver
• Interventions: Dietary Supplement: Leucine enriched essential amino acid (EEA/LEU); Dietary Supplement: Balanced amino acid supplement (BAA)

• Registration Number: NCT03208868
• Lead Sponsor: The Cleveland Clinic

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-08-05
• Study First Submitted: 2017-04-12
• Study First Submitted QC: 2017-07-03
• Study First Posted: 2017-07-06
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-18
• Last Update Posted: 2024-12-20
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 32

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
• Does not meet inclusion criteria

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Leucine enriched essential amino acid	Leucine enriched essential amino acid (EEA/LEU)	Patients with cirrhosis that are given a leucine enriched essential amino acid (EEA/LEU) supplement.
Balanced amino acid supplement	Balanced amino acid supplement (BAA)	Patients with cirrhosis that are given a balanced amino acid (BAA) supplement.

Primary Outcome Measures

Name	Time	Method
Compare Fractional Synthesis Rate	Baseline to 90 days	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.

Trial Locations

Locations (1)

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States