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Trial record 30 of 390 for:    Recruiting, Not yet recruiting, Available Studies | Cirrhosis

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

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ClinicalTrials.gov Identifier: NCT03208868
Recruitment Status : Recruiting
First Posted : July 6, 2017
Last Update Posted : April 11, 2019
Sponsor:
Information provided by (Responsible Party):
Srinivasan Dasarathy, 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.

Condition or disease Intervention/treatment Phase
Cirrhosis, Liver Dietary Supplement: Leucine enriched essential amino acid (EEA/LEU) Dietary Supplement: Balanced amino acid supplement (BAA) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Leucine Enriched Essential Amino Acid Mixture to Reverse Muscle Loss in Cirrhosis
Actual Study Start Date : August 5, 2013
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Leucine enriched essential amino acid
Patients with cirrhosis that are given a leucine enriched essential amino acid (EEA/LEU) supplement.
Dietary Supplement: 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.

Active Comparator: Balanced amino acid supplement
Patients with cirrhosis that are given a balanced amino acid (BAA) supplement.
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.




Primary Outcome Measures :
  1. Compare Fractional Synthesis Rate [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
  • Does not meet inclusion criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03208868


Locations
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United States, Ohio
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Annette Bellar, BS    216-636-5247    bellara@ccf.org   
Contact: Revathi Penumatsa, MD    216-445-0688    penumar@ccf.org   
Principal Investigator: Srinivasan Dasarathy, MD         
Sponsors and Collaborators
The Cleveland Clinic

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Responsible Party: Srinivasan Dasarathy, Staff Physician, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT03208868     History of Changes
Other Study ID Numbers: 12-916
First Posted: July 6, 2017    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Fibrosis
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases