HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

Cirrhosis, Liver Clinical Trial

Official title:

HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05166499
• Other study ID #: 21-830
• Status: Recruiting
• Phase: N/A
• Start date: November 30, 2021
• Est. completion date: December 30, 2025

Study information

• Verified date: October 2023
• Source: The Cleveland Clinic
• Contact: Annette Bellar
• Phone: 2164456268
• Email: bellara[@]ccf.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 30, 2025
• Est. primary completion date: December 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Cirrhosis, Liver
• Fibrosis
• Liver Cirrhosis

Intervention

Dietary Supplement:
• Hydroxy Methyl Butyrate
Hydroxy Methyl Butyrate
• Balanced Amino Acids
Balanced Amino Acids

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
The Cleveland Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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. ?Ep 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