HMB-Enriched Supplement for Alcoholic Liver Disease and COVID-19

Overseen By Alina Tuladhar, MPH

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Must not be taking: Anticoagulants, Antiplatelets, Muscle metabolism

Disqualifiers: Ventilator support, Pregnancy, Advanced organ diseases, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

48 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with COVID-19 and comorbidities including alcohol associated liver disease (ALD) are at risk for severe illness and abrupt or sudden clinical deterioration with ventilatory failure. â-hydroxy â-methyl butyrate (HMB), a non-nitrogenous leucine metabolite with anabolic properties, increases muscle mass and contractile function and enhances immune function. We aim to study the natural course of COVID-19 in patients with ALD and test whether HMB can affect ventilatory deterioration and improve short and long-term morbidity, mortality, and recovery from critical illness in symptomatic COVID-19 patients with ALD.

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 on anticoagulant therapy and medications that alter muscle protein metabolism, except for systemic corticosteroids. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the HMB-enriched supplement treatment for alcoholic liver disease?

Research shows that an essential amino acid supplement can reduce liver fat in people with alcohol use disorder, which suggests that similar supplements, like the HMB-enriched one, might also help with liver health in these patients. ^{1 2 3 4 5}

Is HMB-enriched supplementation safe for humans?

HMB-enriched supplements have been studied in humans with liver cirrhosis, and no significant safety concerns were reported in these trials. However, in animal studies, HMB showed detrimental effects in rats with liver cirrhosis, suggesting that more research is needed to fully understand its safety in humans with liver conditions. ^{6 7 8 9 10}

How is the HMB-enriched supplement treatment different from other treatments for alcoholic liver disease and COVID-19?

The HMB-enriched supplement is unique because it combines β-hydroxy β-methyl butyrate (HMB) with amino acids, which may help improve muscle health and reduce liver fat. Unlike other treatments that focus on gut health or probiotics, this supplement targets protein synthesis and liver fat reduction, offering a novel approach to managing liver disease. ^{3 4 5 11 12}

Research Team

Srinivasan Dasarathy, MD

Principal Investigator

Staff

Eligibility Criteria

This trial is for adults over 21 with alcoholic liver disease (ALD) and COVID-19 pneumonia, who have a moderate level of liver impairment but not severe kidney issues or advanced organ diseases. They shouldn't be on certain muscle-affecting meds or blood thinners if in the biopsy group, need ventilator support, be pregnant, or have had recent gastrointestinal bleeding.

Inclusion Criteria

I have ALD and COVID-19 pneumonia with moderate liver disease.

I am over 21 and do not have alcoholic liver disease but have COVID-19 pneumonia.

I am over 21 and have ALD with COVID-19 pneumonia.

Exclusion Criteria

I am not on medication that changes muscle protein, except for corticosteroids.

I am currently taking blood thinners.

You need help breathing with a ventilator.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either HMB enriched amino acid or balanced amino acid supplementation for 90 days

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Balanced amino acid
• β-hydroxy β-methyl butyrate (HMB) enriched amino acid

Trial Overview The study tests whether an HMB-enriched amino acid supplement can help prevent severe illness and improve recovery in patients with ALD affected by COVID-19. It looks at how this condition progresses naturally and if HMB affects breathing problems and overall health outcomes.

Participant Groups

Group I: HMB enriched amino acid arm Active Control 1 Intervention

The patients randomized to the HMB enriched amino acid (HMB/EAA) arm will be given HMB/EAA for 90 days.

Group II: Balanced amino acid arm Placebo Group 1 Intervention

The patients randomized to the Balanced amino acid (BAA) arm will be given BAA for 90 days.

β-hydroxy β-methyl butyrate (HMB) enriched amino acid is already approved in United States, European Union for the following indications:

Approved in United States as β-hydroxy β-methyl butyrate for:

• Nutritional supplement for malnourished cirrhotic patients
• Muscle wasting prevention

Approved in European Union as HMB for:

• Nutritional support for liver cirrhosis patients
• Prevention of muscle wasting

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

Fecal microbiota transplantation (FMT) shows promise as a treatment for severe alcoholic hepatitis (SAH), addressing the limitations of current steroid therapies, which only benefit a third of patients and have uncertain long-term effects.

Initial human trials indicate that FMT can improve disease severity and survival rates in SAH patients, suggesting it may become a new standard of care with fewer side effects compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation in alcohol related liver diseases. Shasthry, SM.[2021]

Severe alcoholic hepatitis (AH), identified by a Maddrey score of ≥ 32, has a poor prognosis and is traditionally treated with a 28-day course of prednisone, which has shown to reduce short-term mortality but not improve long-term survival.

New therapeutic approaches, such as N-acetyl-cysteine combined with steroids, and potential future treatments targeting liver regeneration and gut microbiota modulation, are being explored in clinical trials to improve outcomes for patients with AH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe alcoholic hepatitis: past, present and future. Lanthier, N., Stärkel, P.[2018]

In a pilot study involving 25 participants with mild to moderate alcohol use disorder, a high dose of essential amino acid supplement (EAAS) significantly reduced intrahepatic lipid (IHL) by 23% after 4 weeks, indicating potential benefits for liver health.

The low dose of EAAS did not show significant changes in IHL, suggesting that higher dosages may be necessary for efficacy in reducing liver fat in individuals with alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Essential Amino Acid Supplement Lowers Intrahepatic Lipid despite Excess Alcohol Consumption. Coker, MS., Ladd, KR., Kim, J., et al.[2022]

In a study of 46 individuals with alcohol use disorder and moderate alcohol-associated hepatitis, daily oral Lactobacillus rhamnosus GG (LGG) significantly reduced liver injury after just one month of treatment.

After six months of LGG treatment, participants showed a marked decrease in heavy drinking, reaching levels of social drinking or abstinence, indicating potential benefits for both liver health and alcohol consumption behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis. Vatsalya, V., Feng, W., Kong, M., et al.[2023]

In a study on mice, gut microbiota-derived propionate showed protective effects against alcohol-related liver disease (ALD) by improving gut-liver axis homeostasis and intestinal permeability.

Propionate supplementation not only prevented liver damage and fat accumulation but also reduced intestinal inflammation and restored gut barrier function, suggesting it could be a potential treatment for ALD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propionate Ameliorates Alcohol-Induced Liver Injury in Mice via the Gut-Liver Axis: Focus on the Improvement of Intestinal Permeability. Xu, Q., Zhang, R., Mu, Y., et al.[2022]

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 pilot study involving 24 patients with liver cirrhosis, 12 weeks of beta-hydroxy-beta-methylbutyrate (HMB) supplementation significantly improved muscle function and increased quadriceps muscle mass compared to a placebo.

HMB supplementation was well tolerated with no reported adverse events, and it also led to a reduction in the Liver Frailty Index, indicating potential benefits for frailty in cirrhotic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of 12-Week Beta-Hydroxy-Beta-Methylbutyrate Supplementation in Patients with Liver Cirrhosis: Results from a Randomized Controlled Single-Blind Pilot Study. Lattanzi, B., Bruni, A., Di Cola, S., et al.[2021]

In a study of 43 patients with liver cirrhosis and malnutrition, those receiving HMB supplementation showed trends towards improved handgrip strength and reduced minimal hepatic encephalopathy over 12 weeks, although fat-free mass did not change.

Both HMB and non-HMB supplements led to increased fat mass and improved liver function scores, indicating that while HMB may have specific benefits, overall nutritional support is crucial for patients with cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Clinical Trial: Effects of β-Hydroxy-β-Methylbutyrate (HMB)-Enriched vs. HMB-Free Oral Nutritional Supplementation in Malnourished Cirrhotic Patients. Espina, S., Sanz-Paris, A., Gonzalez-Irazabal, Y., et al.[2022]

In a study of 47 patients on the liver transplantation waiting list, both β-hydroxy β-methylbutyrate (HMB) and a control supplement improved muscle mass (measured by arm circumference) and strength (measured by dynamometry) over 12 weeks, indicating potential benefits of HMB supplementation.

Both groups showed a decrease in the frailty index, suggesting improved functionality and quality of life, although the specific advantages of HMB over the control were not clearly established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of β-hydroxy β-methylbutyrate (HMB) with nutritional counselling on anthropometric muscle mass markers, strength, functionality, and quality of life in patients on the waiting list for liver transplantation: A double-blind study. Ferreira, SC., Souza, NP., Amado, LRN., et al.[2023]

In healthy rats, HMB supplementation improved muscle mitochondrial function and increased levels of branched-chain amino acids (BCAAs) in the blood, although it did not significantly affect muscle mass or protein content.

In rats with liver cirrhosis induced by carbon tetrachloride, HMB supplementation led to negative outcomes, including higher mortality and lower body weight, suggesting that HMB may have harmful effects in the context of liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of beta-hydroxy-beta-methylbutyrate supplementation on skeletal muscle in healthy and cirrhotic rats. Holeček, M., Vodeničarovová, M.[2021]

Sodium butyrate (NaB) effectively improved non-alcoholic fatty liver disease (NAFLD) in mice by restoring gut microbiota balance and increasing beneficial bacteria, which helped reduce liver inflammation and fat accumulation.

After 8 weeks of NaB treatment, significant improvements were observed in liver function and metabolic indices, indicating its potential as a therapeutic agent for NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. Zhou, D., Pan, Q., Xin, FZ., et al.[2022]

A study of 410 fecal samples from 212 Korean twins found that higher levels of the butyrate-producing bacteria Roseburia are linked to lower alcohol use disorder scores, suggesting a protective role against alcohol-related liver diseases (ALDs).

In murine models of ALD, administering Roseburia spp. improved liver conditions by enhancing gut barrier integrity and restoring gut microbiota, indicating that these bacteria could be a potential therapeutic target for preventing ALDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roseburia spp. Abundance Associates with Alcohol Consumption in Humans and Its Administration Ameliorates Alcoholic Fatty Liver in Mice. Seo, B., Jeon, K., Moon, S., et al.[2020]

References

1. Korea (South) pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation in alcohol related liver diseases. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Treatment of severe alcoholic hepatitis: past, present and future. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Essential Amino Acid Supplement Lowers Intrahepatic Lipid despite Excess Alcohol Consumption. [2022]

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

The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis. [2023]

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

Propionate Ameliorates Alcohol-Induced Liver Injury in Mice via the Gut-Liver Axis: Focus on the Improvement of Intestinal Permeability. [2022]

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. Switzerland pubmed.ncbi.nlm.nih.gov

The Effects of 12-Week Beta-Hydroxy-Beta-Methylbutyrate Supplementation in Patients with Liver Cirrhosis: Results from a Randomized Controlled Single-Blind Pilot Study. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Randomized Clinical Trial: Effects of β-Hydroxy-β-Methylbutyrate (HMB)-Enriched vs. HMB-Free Oral Nutritional Supplementation in Malnourished Cirrhotic Patients. [2022]

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

The effect of β-hydroxy β-methylbutyrate (HMB) with nutritional counselling on anthropometric muscle mass markers, strength, functionality, and quality of life in patients on the waiting list for liver transplantation: A double-blind study. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Effects of beta-hydroxy-beta-methylbutyrate supplementation on skeletal muscle in healthy and cirrhotic rats. [2021]

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

Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. [2022]

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

Roseburia spp. Abundance Associates with Alcohol Consumption in Humans and Its Administration Ameliorates Alcoholic Fatty Liver in Mice. [2020]