Leucine Enriched Amino Acids for Liver Cirrhosis

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Must not be taking: Anabolic steroids, Corticosteroids

Disqualifiers: Diabetes, Renal failure, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

32 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those taking medications like anabolic steroids or corticosteroids that affect muscle mass.

What data supports the effectiveness of the treatment Leucine Enriched Amino Acids for Liver Cirrhosis?

Research suggests that branched-chain amino acids (BCAAs), which include leucine, may help improve protein metabolism and nutritional status in patients with liver cirrhosis. Some studies indicate that BCAA supplements can enhance protein synthesis and improve nutritional parameters, potentially benefiting patients with cirrhosis. ^{1 2 3 4 5}

Is leucine-enriched amino acid supplementation safe for humans?

Research indicates that branched-chain amino acid (BCAA) supplements, which include leucine, are generally safe for humans with liver cirrhosis, as they did not induce adverse events in studies and improved certain health markers without affecting survival. ^{1 6 7 8 9}

How is the treatment with leucine enriched amino acids different from other treatments for liver cirrhosis?

This treatment is unique because it uses leucine, a branched-chain amino acid, to help improve protein metabolism and nutritional status in patients with liver cirrhosis, which is not typically addressed by standard treatments. Leucine activates specific signals in the body that promote protein synthesis and improve glucose metabolism, offering a novel approach to managing the condition. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for individuals with liver cirrhosis, confirmed by biopsy or other methods, who have a moderate level of disease severity (Child's Pugh score 5-9) and have not consumed alcohol or recreational drugs for at least six months. People with severe cirrhosis, swelling in the legs, other serious illnesses, diabetes, recent bleeding from the gut, brain issues due to liver disease, kidney failure or certain cancers can't join.

Inclusion Criteria

I have been diagnosed with cirrhosis through a biopsy or tests.

Abstinence from alcohol and/or other recreational drugs for at least 6 months

My liver function score is between 5 to 9.

Exclusion Criteria

I do not have sepsis or brain dysfunction.

I have diabetes.

My liver cancer does not meet the Milan criteria.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Acute Treatment

Participants receive acute administration of leucine enriched essential amino acid (EAA/LEU) or balanced amino acid (BAA) supplement

1 week

1 visit (in-person)

Long-term Treatment

Participants receive long-term administration of leucine enriched essential amino acid (EAA/LEU) or balanced amino acid (BAA) supplement

12 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Balanced amino acid supplement (BAA)
• Leucine enriched essential amino acid (EEA/LEU)

Trial Overview The study is testing whether a special mix of amino acids including leucine (EAA/LEU), which may help build muscle protein and mass, works better than a balanced amino acid supplement (BAA) that doesn't stimulate muscle growth. The effects will be measured over three months using blood markers and muscle biopsies.

Participant Groups

Group I: Balanced amino acid supplement Active Control 1 Intervention

Patients with cirrhosis that are given a balanced amino acid (BAA) supplement.

Group II: Leucine enriched essential amino acid Active Control 1 Intervention

Patients with cirrhosis that are given a leucine enriched essential amino acid (EEA/LEU) supplement.

Leucine enriched essential amino acid (EEA/LEU) is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Leucine for:

• Nutritional supplement
• Flavor enhancer

Approved in United States as Leucine for:

• Dietary supplement
• Food additive

Approved in Canada as Leucine for:

• Nutritional supplement

Approved in Japan as Leucine for:

• Food additive

Approved in China as Leucine for:

• Nutritional supplement

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

In patients with compensated cirrhosis, the infusion of branched chain-enriched, aromatic-deficient amino acids with insulin led to normal net protein deposition, despite a reduced response in protein synthesis compared to healthy controls.

While the rates of phenylalanine and leucine disposal were nearly normalized after treatment, the underlying issue of excessive endogenous phenylalanine production was not fully corrected, indicating a need for further intervention in cirrhotic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of phenylalanine and leucine kinetics to branched chain-enriched amino acids and insulin in patients with cirrhosis. Tessari, P., Zanetti, M., Barazzoni, R., et al.[2019]

In a study of 40 cirrhotic patients with low albumin levels, adding a BCAA-enriched nutrient mixture improved serum albumin levels after 6 months, despite prior treatment with BCAA granules.

Specifically, in patients without complications like hepatocellular carcinoma or gastrointestinal bleeding, serum albumin levels significantly increased from 2.93 g/dL to 3.15 g/dL, indicating the efficacy of the additional BCAA therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Additional BCAA-enriched nutrient mixture improves the nutritional condition in cirrhotic patients with hypoalbuminemia despite treatment with regular BCAA granules: A pilot study. Fukui, A., Kawabe, N., Hashimoto, S., et al.[2015]

Patients with advanced cirrhosis often require a higher-than-normal intake of dietary proteins to maintain nitrogen balance, and most can tolerate increased protein intake without risking hepatic encephalopathy.

In cases of severe malnutrition, amino acid supplements may be beneficial, and for patients who struggle with protein intake, branched-chain amino acid (BCAA) supplements can provide necessary nutrients without negatively affecting mental health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. Marchesini, G., Bianchi, G., Rossi, B., et al.[2005]

In a study of 37 patients with cirrhosis, solutions containing 35% and 53% branched chain amino acids significantly improved protein synthesis without causing excessive protein breakdown.

Using a 100% branched chain amino acid solution led to increased protein breakdown that negated the benefits of protein synthesis, indicating it is not advisable for clinical use in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of branched chain amino acid infusions on body protein metabolism in cirrhosis of liver. Wright, PD., Holdsworth, JD., Dionigi, P., et al.[2019]

In a study of 174 patients with advanced cirrhosis, oral supplementation with branched-chain amino acids (BCAA) significantly reduced the rates of combined adverse events (like death and hospital admissions) compared to lactoalbumin, suggesting a protective effect against liver failure.

BCAA supplementation also led to improvements in nutritional parameters, liver function tests, and quality of life, although long-term compliance with the treatment was poor, indicating a need for better formulations to encourage adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Marchesini, G., Bianchi, G., Merli, M., et al.[2019]

In a study of 43 malnourished cirrhotic patients, oral nutritional supplements enriched with ß-Hydroxy-ß-methylbutyrate (HMB) significantly increased plasma levels of branched chain amino acids (BCAA) compared to a high-protein control, suggesting a potential therapeutic benefit in managing hepatic encephalopathy.

The HMB-enriched supplements improved the amino acid profile without raising harmful levels of ammonia, indicating a safe approach to potentially prevent minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy. Espina, S., Gonzalez-Irazabal, Y., Sanz-Paris, A., et al.[2021]

In a feasibility study involving 7 cirrhotic patients, BCAA supplementation for 8 weeks significantly improved the ratio of oxidized to reduced albumin, indicating a better quality of serum albumin.

While total albumin levels showed a tendency to rise and lipid peroxide concentrations tended to decrease, these changes were not statistically significant, suggesting that BCAA supplementation primarily enhances the redox state of albumin in cirrhotic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral branched-chain amino acid supplementation improves the oxidized/reduced albumin ratio in patients with liver cirrhosis. Fukushima, H., Miwa, Y., Shiraki, M., et al.[2020]

Oral branched-chain amino acid (BCAA) supplements significantly improve symptoms of hepatic encephalopathy (HE) in patients with cirrhosis, with a risk ratio of 1.71, indicating that for every 5 patients treated, one will benefit from the treatment.

While BCAAs help alleviate HE symptoms, they do not affect mortality rates or nutritional status, and they are safe with no reported adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. Gluud, LL., Dam, G., Borre, M., et al.[2023]

In a study involving male Sprague-Dawley rats with liver cirrhosis, oral supplementation with branched-chain amino acids (BCAA) at a ratio of isoleucine:leucine:valine of 1:2:1.2 or 2:1:1 significantly improved protein-nutritional status compared to other ratios.

The optimal supplementation level of total BCAA in the diet was found to be 2.5%, which positively affected nitrogen balance and plasma protein concentrations, suggesting it as a beneficial dietary intervention for liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of supplementation with branched-chain amino acids on protein-nutritional status in rats treated by carbon tetrachloride]. Ohashi, H., Sukegawa, E., Takami, T., et al.[2020]

Branched-chain amino acids (BCAAs), particularly leucine, have been used in Japan to treat hypoalbuminemia in patients with decompensated liver cirrhosis, showing potential benefits in protein synthesis and glucose metabolism.

Leucine activates mTOR signaling, which promotes protein synthesis and improves glucose metabolism, suggesting that BCAAs could play a significant role in managing cirrhotic diseases by targeting specific tissue responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. Nishitani, S., Ijichi, C., Takehana, K., et al.[2021]

In a study of 14 patients with liver cirrhosis, a branched-chain amino acid-enriched diet did not significantly improve symptoms of portal-systemic encephalopathy or other clinical parameters over 3 months.

While the diet increased plasma levels of valine and leucine, it did not affect the overall clinical state or laboratory results, suggesting that branched-chain amino acids may not influence hepatic encephalopathy but can still provide necessary nitrogen for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial. Sieg, A., Walker, S., Czygan, P., et al.[2009]

The nutritional product SF-1008C, rich in branched chain amino acids (BCAA) and low in aromatic amino acids (AAA) and methionine, significantly improved protein metabolism in patients with advanced liver cirrhosis over a 2-week period, as evidenced by increased plasma BCAA levels and improved serum prealbumin levels.

SF-1008C was well tolerated and showed potential benefits in preventing hepatic encephalopathy in cirrhotic patients, indicating its efficacy as a dietary intervention for managing complications associated with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis. Watanabe, A., Shiota, T., Okita, M., et al.[2017]

Branched-chain amino acid (BCAA) treatment can help manage hepatic encephalopathy and protein-energy malnutrition in patients with liver cirrhosis, which is crucial for improving their nutritional status.

BCAA supplements, when combined with diet therapy, may enhance nutritional outcomes in liver cirrhosis patients, but their effectiveness varies based on the severity of liver damage, indicating a need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Branched-chain amino acid treatment in patients with liver cirrhosis. Suzuki, K., Kato, A., Iwai, M.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Response of phenylalanine and leucine kinetics to branched chain-enriched amino acids and insulin in patients with cirrhosis. [2019]

2. Turkey pubmed.ncbi.nlm.nih.gov

Additional BCAA-enriched nutrient mixture improves the nutritional condition in cirrhotic patients with hypoalbuminemia despite treatment with regular BCAA granules: A pilot study. [2015]

3. Japan pubmed.ncbi.nlm.nih.gov

Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. [2005]

4. England pubmed.ncbi.nlm.nih.gov

Effect of branched chain amino acid infusions on body protein metabolism in cirrhosis of liver. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Oral branched-chain amino acid supplementation improves the oxidized/reduced albumin ratio in patients with liver cirrhosis. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

[Effects of supplementation with branched-chain amino acids on protein-nutritional status in rats treated by carbon tetrachloride]. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial. [2009]

12. Japan pubmed.ncbi.nlm.nih.gov

Effect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis. [2017]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Branched-chain amino acid treatment in patients with liver cirrhosis. [2022]