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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a special amino acid supplement can help individuals with liver cirrhosis gain muscle mass. Liver cirrhosis often leads to muscle loss, causing serious health issues. Participants will receive either a leucine-enriched essential amino acid supplement (EEA/LEU) or a regular balanced amino acid supplement (BAA) to determine which is more effective. Individuals with liver cirrhosis who have abstained from alcohol or drugs for at least six months and meet specific medical criteria related to liver health may qualify for this trial. As an unphased trial, this study provides a unique opportunity for participants to contribute to important research that could enhance muscle health in liver cirrhosis patients.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that leucine-enriched essential amino acid (EAA/LEU) supplements are generally safe for people with liver cirrhosis. One study found that taking 12 grams daily did not cause allergic reactions or other negative effects. The body seems to handle the supplement well, and it can help improve some muscle problems caused by liver disease.

For balanced amino acid supplements, studies suggest they can improve nutrition and assist with liver issues, though some side effects might still occur. These supplements can also help reduce certain complications related to cirrhosis.

Both types of supplements appear safe, especially for people with liver problems. However, individual experiences can vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard treatments for liver cirrhosis, which typically involve managing symptoms with medications like diuretics and beta-blockers, the leucine enriched essential amino acid (EEA/LEU) supplement targets the nutritional deficiencies often seen in cirrhosis patients. Researchers are excited about this treatment because leucine, a key amino acid, plays a crucial role in muscle protein synthesis and may help improve muscle mass and strength in these patients. By directly addressing the loss of muscle mass, known as sarcopenia, this supplement offers a novel approach that could enhance patients' quality of life and overall health outcomes.

What evidence suggests that leucine enriched essential amino acid could be an effective treatment for cirrhosis?

Research has shown that leucine, a type of amino acid, can aid muscle growth. In people with liver cirrhosis, studies have found that amino acid supplements can improve muscle strength and reduce symptoms like fluid buildup. This trial will provide participants with either a balanced amino acid (BAA) supplement or a leucine-enriched essential amino acid (EEA/LEU) supplement. Leucine may help by activating a process in the body crucial for building muscle, potentially increasing muscle mass and strength. Although more research is needed, early studies offer promise for those experiencing muscle loss due to cirrhosis. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

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.

My liver function score is between 5 to 9.

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

Exclusion Criteria

I do not have sepsis or brain dysfunction.

I have diabetes.

My liver cancer does not meet the Milan criteria.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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]

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 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]

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]

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]

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 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]

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]

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]

Citations

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New Evidence of Oral Branched-Chain Amino Acid... Theoretically, the beneficial effects of BCAA supplementation during chronic liver disease include improvements in body composition and nitrogen balance, liver ...

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Side Effects of Amino Acid Supplements - PMC In the article is shown that enhanced intake of most amino acid supplements may not be risk-free and can cause a number of detrimental side effects.

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