BCAA-CLD: Effect of BCAA Supplementation on Muscle Mass, Muscle Quality and Molecular Markers of Muscle Regeneration in CLD Patients

Sponsor

Institute of Liver and Biliary Sciences, India (Other)

Overall Status

Recruiting

CT.gov ID

NCT04246918

Collaborator

(none)

Enrollment

Location

Arms

22.9

Anticipated Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Loss of muscle mass (sarcopenia) is a major complication in a patient with cirrhosis, impacting the disease outcome, quality of life and survival. Cirrhotics lose muscle mass (MM) while waiting for liver transplant (LT) and even after LT, impacting the outcome of LT. Moreover, LT is elusive for majority of patients in India. The pathophysiology of muscle loss is complicated, multifactorial, interlinked and primarily nutrition driven, which gives clues for targeted therapeutic modalities other than feeding alone. Experimental studies have instilled faith in BCAA in successfully counteracting the pathogenesis of muscle loss. But there is lack of convincing data from clinical studies with direct evidence on muscle growth per se.

Condition or Disease	Intervention/Treatment	Phase
Chronic Liver Disease	Dietary Supplement: Branched Chain Amino Acid Dietary Supplement: Whey Protein concentrate powder	N/A

Detailed Description

Reduction in muscle mass (sarcopenia) is well documented in patients with chronic liver disease (CLD)leading to increased morbidity, mortality and poor quality of life. An equilibrium is maintained between the synthesis and degradation of muscles to maintain the muscle mass. However, an imbalance between the synthesis and degradation leads to loss of muscle mass. Various factors like alteration in dietary intake, hyper-metabolism, changes in amino acid profile, decreased physical activity, endotoxemia, hyperammonemia, increased myostatin levels have been postulated in the pathogenesis of muscle loss in liver disease. Reduced dietary intake, altered amino acid profile, decreased physical activity down regulate the anabolic pathway while the others increase the catabolic pathway. Increased level of myostatin inhibits the mTOR signaling and increases catabolism. Various therapeutic strategies such as increased calorie and protein intake, branched chain amino acid (BCAA) supplementation, late evening snack (LES), increased physical activity are the well accepted therapies. Hormone therapy (testosterone/growth hormone) also has been tried to improve muscle mass and function, reduce muscle catabolism in patients with CLD, however these newer treatment modalities i.e. hormone replacement, immune-nutrition and anti-myostatin antibodies are not free from adverse side-effects. Branched chain amino acids, a group of three essential amino acids (leucine, isoleucine, valine) have been tried since years in the setting of chronic liver disease patients for the treatment of hepatic encephalopathy and improvement in nutritional status. However, the studies assessing the impact of nutrition and BCAA in CLD have not assessed the direct impact on the muscle per se. The nutritional status has been assessed using different subjective methods like mid arm muscle circumference, triceps skin fold, nitrogen balance. Nutritional management is the cornerstone of the overall management of patients with cirrhosis, wherein BCAA constitutes an important therapeutic modality in the realm of nutrition in liver disease.

In the present study all the eligible cirrhotic patients will be randomized to a control group (receiving the nutritional therapy as per the standard nutritional practices and guidelines) or the intervention group (receiving BCAA supplementation over and above the standard nutrition therapy as per the standard nutritional practices and guidelines). Branched chain amino acids (BCAA) have the potential to up-regulate the anabolic pathway of muscle synthesis leading to improvement in muscle mass. Muscle mass as assessed by DEXA, along with changes in muscle histology, markers of the pathways that regulate muscle growth, functional capacity, and quality of life will be assessed after 3 months of BCAA intervention.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open LabelOpen Label

Masking:

None (Open Label)

Masking Description:

As it is a nutritional intervention study masking either the participant or the investigator is not possible.

Primary Purpose:

Treatment

Official Title:

Effect of Branched Chain Amino Acids Supplementation on Muscle Mass, Muscle Quality and Molecular Markers of Muscle Regeneration in Patients With Chronic Liver Disease - A Randomized Controlled Trial.

Actual Study Start Date :

Jun 1, 2020

Anticipated Primary Completion Date :

Apr 30, 2022

Anticipated Study Completion Date :

Apr 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Standard Treatment Group The patients would receive customized diet charts providing 30-35Kcal/ideal body wt/day and 1.5 gm protein/ideal body wt/day) describing the food items along with the quantity and approximate household measurements. Diet would be so planned for each patient keeping in mind the individual food habits and choices. This group would not receive any supplement other than the prescribed diet. Whey protein will be included in this group.	Dietary Supplement: Whey Protein concentrate powder Whey protein will be given to the standard treatment arm including in the same amount of 1.5gm/kg/IBW.
Active Comparator: Intervention Arm The patients would receive customized diet charts providing 30-35Kcal/ideal body wt/day and 1.5 gm protein/ideal body wt/day) describing the food items along with the quantity and approximate household measurements. Diet would be so planned for each patient keeping in mind the individual food habits and choices. In addition to the normal diet this group would receive 16gm of branched chain amino acid (BCAA) supplement (Commercial oral BCAA granules) daily in 4 divided doses, keeping the protein levels within the same range of 1.5 gm/Kg/day.	Dietary Supplement: Branched Chain Amino Acid Branched chain amino acid is a group of three amino acids known for there role in muscle growth.

Arm

Intervention/Treatment

Placebo Comparator: Standard Treatment Group

The patients would receive customized diet charts providing 30-35Kcal/ideal body wt/day and 1.5 gm protein/ideal body wt/day) describing the food items along with the quantity and approximate household measurements. Diet would be so planned for each patient keeping in mind the individual food habits and choices. This group would not receive any supplement other than the prescribed diet. Whey protein will be included in this group.

Dietary Supplement: Whey Protein concentrate powder

Whey protein will be given to the standard treatment arm including in the same amount of 1.5gm/kg/IBW.

Active Comparator: Intervention Arm

The patients would receive customized diet charts providing 30-35Kcal/ideal body wt/day and 1.5 gm protein/ideal body wt/day) describing the food items along with the quantity and approximate household measurements. Diet would be so planned for each patient keeping in mind the individual food habits and choices. In addition to the normal diet this group would receive 16gm of branched chain amino acid (BCAA) supplement (Commercial oral BCAA granules) daily in 4 divided doses, keeping the protein levels within the same range of 1.5 gm/Kg/day.

Dietary Supplement: Branched Chain Amino Acid

Branched chain amino acid is a group of three amino acids known for there role in muscle growth.

Outcome Measures

Primary Outcome Measures

Improvement in the muscle mass [3 months]
Muscle mass change as assessed by DEXA scan will be done.

Secondary Outcome Measures

Changes in the muscle fibre type composition [3 months]
Muscle fibre type will be assessed in muscle biopsy sample
Changes in cross sectional area of muscle [3 months]
Muscle fibre cross sectional area will be assessed in muscle biopsy sample
Assessment of necrosis in muscle fibre [3 Months]
Muscle fibre necrosis will be assessed in muscle biopsy sample
Assessment of intramuscular fat deposition [3 months]
Change in intramuscular fat deposition will be assessed in muscle biopsy sample.
Assessment of myoD [3 month]
Change in myoD will be assessed as marker of muscle regeneration in muscle biopsy sample
Assessment of myogenin [3 months]
Change in myogenin will be assessed as marker of muscle regeneration in muscle biopsy sample
Assessment of PCNA [3 months]
Change in PCNA as marker of satellite function will be assessed in muscle biopsy sample
Assessment of proteosome C3, C5, C9 [3 months]
Change in these proteosome will be assessed in muscle biopsy sample
Assessment of ubiquitin ligase E3 [3 months]
Change in Ubiquitin ligase E3 will be assessed in muscle biopsy sample.
Assessment of myostatin level [3 months]
Change in myostatin level will be assessed in blood sample using commercially available kit.
Assessment of ammonia level [3 months]
Change in ammonia level will be assessed in blood sample using commercially available kit
Assessment of Insulin resistance [3 Month]
Insulin resistance will be calculated using homeostasis model for insulin resistance.
Assessment of IGF 1 [3 Month]
IGF1 will be assessed using commercially available kit.
Assessment of Nutritional Status [3 Month]
Change Nutritional status will be assessed using bioelectrical impedance analysis
Assessment of Nitrogen balance [3 Month]
Change in nitrogen balance will be assessed using formula : Nitrogen Balance = Protein intake (gm) / 6.25 - (UUN + 4 gm)
Assessment of functional capacity [3 Months]
The Functional capacity of the patients would be assessed by Hand Grip Strength using the Handgrip Dynamometer .
Assessment of Clinical parameter- CTP [3 Months]
Clinical improvement will be assessed in terms of change in CTP score.
Assessment of Clinical parameter-MELD [3 Months]
Clinical improvement will be assessed in terms of change in MELD score.
Assessment of Health Related Quality of Life [3 Months]
The Health Related Quality of Life (HRQoL) of the patients would be assessed using the Chronic liver disease questionnaire(CLDQ)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with decompensated cirrhosis (CTP 7-9)
Adult patients Age 18-60 years
Patients with corrected BMI in the range <22.9
Those who give consent for muscle biopsy
INR <1.5 or 1.5-2.5 after correction with Vitamin K
Platelets > 80000
All etiologies

Exclusion Criteria:

Presence of overt hepatic encephalopathy
Patients with co-morbidities e.g. acquired immunodeficiency syndrome, HCC, Other cancer, Diabetes Mellitus, chronic kidney disease, congestive heart disease , chronic respiratory disease
Patients with alcohol intake in past 3 months
Patients with TIPS
Patients on steroids
INR >2.5
Refusal to participate in the trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institute of Liver and Biliary Sciences	New Delhi	Delhi	India	110070

Sponsors and Collaborators

Institute of Liver and Biliary Sciences, India

Investigators

Principal Investigator: Puja Bhatia, MSc, Institute of Liver and Biliary Sciences
Study Director: Jaya Benjamin, PhD, Institute of Liver and Biliary Sciences