Beta-Hydroxy-Beta-Methylbutyrate Supplementation and Physical Activity in Liver Cirrhosis: a Controlled Trial (HMB)

March 25, 2019 updated by: Manuela Merli, University of Roma La Sapienza

Sarcopenia is an independent predictor of morbidity and mortality in the cirrhotic patient. Beta-hydroxy-beta-methyl butyrate (HMB) is a leucine metabolite with potential efficacy in increasing protein synthesis, muscle mass, and its functionality.

The aim of this randomized controlled study is to evaluate the effect of nutritional supplementation with HMB and physical activity both on muscle mass and on muscle function in cirrhotic patients.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

  1. Introduction Changes in nutritional status are a frequent complication in cirrhotic patients. The prevalence of malnutrition is related to the severity of the disease and has been reported by 65-90% in advanced cirrhosis. The most significant component of malnutrition is a progressive and generalized loss of mass understood as sarcopenia.

    Several studies have reported that sarcopenia represents a negative prognostic factor for survival in patients with liver cirrhosis. Other studies have shown that sarcopenia is an independent predictor of complications of portal hypertension.

    For these reasons and being a modifiable condition, identifying and treating sarcopenia in patients is very important for their prognosis.

    Sarcopenia in liver cirrhosis occurs as a result of an increase in proteolysis or a reduction in protein synthesis, or a combination of the two mechanisms. The alterations in the molecular pathways that involve the regulation of these mechanisms are not entirely known. Recent research has led to the identification of increased expression of myostatin, member of the transforming growth factor ß superfamily, in skeletal muscle in animal models of hepatic injury and in the plasma of cirrhotic patients with consequent inhibition of protein synthesis. In addition, myostatin is able to examine the protein kinase 5' AMP-activated protein kinase (AMPK), an inhibitor of signaling of mammalian target of rapamycin (mTOR), a key regulator of protein synthesis.

    I populations of non-cirrhotic malnourished patients, the benefits of a therapy aimed at improving malnutrition are highlighted by reduced mortality, infections, systemic inflammatory responses and hospital stay. For cirrhotic patients, specific studies in this regard are limited by the size of the cohort and by the design of the study, and there are no effective therapies mainly due to the fact that the mechanisms of muscle loss in cirrhosis are not yet well understood. In addition, the end-points of these studies are heterogeneous (regain muscle strength, the disappearance of sarcopenia, mortality, complications of portal hypertension, etc.). In a study that used a nutritional enteral supplement, the authors observed a modest improvement in nutritional parameters but found no statistically significant differences in morbidity and mortality between the two patient groups. Better results have been reported in clinical trials that used nocturnal nutritional support, in most cases represented by branched-chain amino acids (BCAA) (leucine, isoleucine, and valine). This type of intervention has obtained an improvement in the use of energy substrates in the short term and an improvement of some nutritional parameters in the long term.

    Beta hydroxy-beta-methyl-butyrate (HMB) is a leucine metabolite with the potential to increase muscle performance and tropism. Studies conducted in experimental models of cachexia have reported increased phosphorylation and activation of mTOR secondary to the use of HMB. Experimental studies performed on cell cultures of myoblasts also showed an increased expression of insulin like growth factor-1 (IGF-1) secondary to treatment with HMB. These findings confirm the anabolic properties of HMB. A role of HMB on the suppression of proteolysis by inhibiting the ubiquitin-proteasome pathway in models of neoplastic cachexia and an effect on attenuating muscle atrophy secondary to steroid therapy has also been demonstrated. The association of anabolic properties targeting mTOR and anti-proteolytic make HMB a potential efficacy supplement for the treatment of sarcopenia in the cirrhotic patient. There are currently no data in the literature on the use of HMB in this category of patients.

  2. Aim of the study

    Primary endpoints:

    • evaluate the effect at 3 months (T12) of HMB supplementation for 12 weeks in patients with liver cirrhosis on the mass and muscle performance compared to a group of patients

    The secondary objectives are:

    • assessment of the impact of supplementation with HMB on the development of complications (minimal and manifest hepatic encephalopathy, bacterial infections, ascites, GI bleeding) compared to the control group;
    • evaluation of the impact of sarcopenia on the number of admissions and the days of hospitalization for these complications compared to the control group;
    • identification of surrogate markers of sarcopenia through the preparation of a serum;

    This controlled trial is not sponsored by a drug company.

  3. Patients Patients are enrolled in the study after been informed of the purpose and protocol of treatment and need to sign a written informed consent.

  4. Statistical analysis, sample size, and randomization:

    For categorical variables, the Person-Chi-square test or the Fischer test will be used. For continuous variables, the Mann-Whitney Test will be used. The ANOVA variance analysis will be applied followed by the "t-test" when significant differences will be highlighted. Values of p <0.05 will be considered statistically significant.

    Block randomization, consisting of 4 individuals per block, was executed in a 1:1ratio using random numbers generated by an independent statistician (SPSS version 16.0). Knowledge of the randomization code was limited to the physician.

    While there is no evidence of HMB supplementation in cirrhotic patients, based on previously described variations in muscle mass in the elderly population, we aim to conduct a pilot study in which will be enrolled 20 patients per group.

  5. Protocol of the study:

The registration will include the main clinical and biochemical data of patients.

Nutritional counseling will be provided to all patients to ensure similar caloric and daily protein intake in the two groups, according to the current guidelines (caloric intake of 20-25 kcal/kg/ die ± 10%, protein intake of 1.2 g /kg/day).

At the time of the enrollment and during the subsequent controls the following data will be recorded :

  • calorie intake in the week preceding the visit by a three days non-consecutive food diary;
  • height, weight, body mass index
  • body composition by bioelectrical impedance analysis bioimmunoassay (BIA)
  • muscular function evaluated by 6-minute walk test (6MWT), Timed Up and Go test-TUGT), e l'Hand grip Test (HG).
  • biochemical and metabolic parameters
  • pharmacological therapy During the study, clinical complications (hospital admissions, infectious events, the onset of comorbidity) will be recorded.

During the study, the tolerability of the supplement (analog-visual scale), adherence to absorption and any intolerance or secondary adverse effects will be detected.

Randomization: Patients are randomized to Group 1 - placebo (or control group) and Group 2 - supplementation (or treatment group)

The placebo will be 1gr mannitol twice daily. Supplementation will be HMB 1.5 g dissolved twice daily. Supplementation/placebo will be provided for 12 weeks.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00100
        • Recruiting
        • Gastroenterology Department, Sapienza University of Rome
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • all cirrhotics followed in outpatients' clinic 18-70 years

Exclusion Criteria:

  • hepatocellular carcinoma or other neoplastic diseases;
  • neuromuscular or skeletal diseases,
  • chronic renal failure II-III degree;
  • cardiac decompensation with New York Heart Association (NYHA) score ≥ III;
  • severe pulmonary dysfunction;
  • active alcohol intake in the last 6 months;
  • ascites grade moderate-severe

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: HMB GROUP
HMB Supplementation with 1.5 g of HMB taken twice daily. Supplementation will be provided for 12 weeks
Dietary supplement: BETA-HYDROXY-BETA-METHYLBUTYRATE (HMB)
1.5 g of HMB will be provided for 12 weeks twice daily
Placebo Comparator: PLACEBO GROUP
Mannitol 1.5 g twice daily. Supplementation will be provided for 12 weeks
Dietary supplement: Mannitol
1.5 g twice daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Fat Free Mass Index after 12 weeks of supplementation
Time Frame: 12 weeks after the enrollment
Increase of Fat Free Mass evaluated by BIA
12 weeks after the enrollment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Fat Free Mass Index after 24 weeks of supplementation
Time Frame: 24 weeks after the enrollment
Increase of Fat Free Mass evaluated by BIA
24 weeks after the enrollment
Changes in HG Test at 12 and 24 weeks after enrollment
Time Frame: 12 and 24 weeks after enrollment
Recovery of muscle mass function evaluated by Recovery of muscle mass function evaluated by Hand grip Test (HG)
12 and 24 weeks after enrollment
Changes in 6MWT Test at 12 and 24 weeks after enrollment
Time Frame: 12 and 24 weeks after enrollment
Recovery of muscle mass function evaluated by 6 minute walk test-6MWT
12 and 24 weeks after enrollment
Evaluation og Animal Naming and The Psychometric Hepatic Encephalopathy Score (PHES)
Time Frame: 12 and 24 weeks after enrollment
evaluation of minimal hepatic encephalopathy
12 and 24 weeks after enrollment
Evaluation of hospitalization and decompensation episodes
Time Frame: 12 and 24 weeks after enrollment
episodes of decompensation during th study
12 and 24 weeks after enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Roma La Sapienza

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2019

Primary Completion (Anticipated)

December 10, 2019

Study Completion (Anticipated)

September 10, 2020

Study Registration Dates

First Submitted

March 25, 2019

First Submitted That Met QC Criteria

March 25, 2019

First Posted (Actual)

March 27, 2019

Study Record Updates

Last Update Posted (Actual)

March 27, 2019

Last Update Submitted That Met QC Criteria

March 25, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 5038

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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