Thyroid Hormone for Nonalcoholic Steatohepatitis

Recruiting in Palo Alto (17 mi)

Overseen by Jamal A Ibdah, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: VA Office of Research and Development

Must be taking: Antidiabetics, Vitamin E

Must not be taking: Antidepressants, Ketamine

Disqualifiers: Hepatitis, Cirrhosis, Hypertension, Heart failure, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Nonalcoholic steatohepatitis (NASH) is the aggressive form of nonalcoholic fatty liver disease, which is rapidly becoming a worldwide public health problem. It is more common in the military and Veteran population compared to the general US population. NASH may progress to end-stage liver disease and primary liver cancer, and hence there is critical need for effective treatment. The goal of this clinical trial is to test whether low dose thyroid hormone administered to Veterans diagnosed with NASH can be an effective therapy mediated by improvement in breaking down fat in the mitochondria. The study will be conducted in two stages, the first stage is for proof of concept to be followed by interim analysis. If the interim analysis supports the merit for continuing the study, the clinical trial will proceed to stage 2 for continuation. This study will provide new information and strategies for treatment of NASH using low dose thyroid hormone that will be highly relevant and impactful to the health of the Veteran population.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are on tricyclic or tetracyclic antidepressants or ketamine, you must stop them before joining. If you are on digitalis or amiodarone, you can continue them with your cardiologist's guidance.

What data supports the effectiveness of the drug for treating nonalcoholic steatohepatitis?

Research shows that thyroid hormone treatments, like triiodothyronine (T3) and levothyroxine (LT4), can help reduce liver fat and improve liver health in certain conditions. In animal studies, T3 prevented and reversed fatty liver, while LT4 reduced liver fat in patients with subclinical hypothyroidism. ^{1 2 3 4 5}

Is levothyroxine generally safe for humans?

Levothyroxine is generally well tolerated, but there are rare cases of liver injury associated with its use. Some people may experience liver problems, especially if the dose is increased too quickly, but these issues usually resolve after stopping the medication. ^{3 5 6 7 8}

How does the drug Synthroid (Levothyroxine) differ from other treatments for nonalcoholic steatohepatitis (NASH)?

Synthroid (Levothyroxine) is unique because it targets thyroid hormone receptors, specifically TRβ, which are mainly expressed in the liver, potentially reducing liver fat without causing heart-related side effects. This approach is different from other treatments as it focuses on enhancing liver metabolism through thyroid hormone pathways, which is not a standard treatment for NASH. ^{1 3 8 9 10}

Research Team

Jamal A Ibdah, MD PhD

Principal Investigator

Harry S. Truman Memorial, Columbia, MO

Eligibility Criteria

Veterans with nonalcoholic steatohepatitis (NASH) who are overweight or obese, may have type 2 diabetes on stable medication, and exhibit features of metabolic syndrome. They must not drink more than a small amount of alcohol daily and agree to use effective birth control if applicable. Those with certain heart conditions, uncontrolled blood pressure, recent severe cardiovascular events, other liver diseases or cirrhosis are excluded.

Inclusion Criteria

My BMI is 25.9 or higher, indicating I am overweight or obese.

I am scheduled for a liver biopsy for diagnosis.

I am not pregnant, breastfeeding, or planning to become pregnant and will use birth control, or I cannot become pregnant.

Exclusion Criteria

Evidence of Portal hypertension

I have had dangerously high blood pressure.

I have a serious heart block without a pacemaker.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Stage 1

Proof-of-concept stage where 32 Veterans with biopsy-proven NASH are randomized to receive either low dose thyroid hormone or placebo for 52 weeks

52 weeks

Baseline and end of treatment liver biopsies

Interim Analysis

Interim analysis to determine the probability of achieving statistically significant findings in the primary outcome

End of year 2

Treatment Stage 2

Continuation of the study with additional recruitment for a full 6-year clinical trial if interim analysis supports continuation

6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo (Other)
• Synthroid (Hormone Therapy)

Trial Overview The trial is testing low dose thyroid hormone (Synthroid) against a placebo to see if it helps break down fat in the liver for Veterans with NASH. The study has two stages: an initial proof of concept followed by interim analysis which will determine whether the trial continues into stage two.

Participant Groups

Group I: Study group Active Control 1 Intervention

Study group will receive Synthroid (Levothyroxine) 25, 50, or 75 mcg daily

Group II: Placebo group Placebo Group 1 Intervention

Placebo group will receive placebo tablets

Synthroid is already approved in Canada for the following indications:

Approved in Canada as Eltroxin for:

• Hypothyroidism
• Goiter
• Thyroid nodules
• Thyroid cancer

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

Findings from Research

The thyroid hormone triiodothyronine (T3) can completely prevent and even reverse fatty liver and steatohepatitis in rats induced by a choline-methionine deficient diet, highlighting its potential as a therapeutic approach for nonalcoholic fatty liver disease.

The TRbeta agonist GC-1 also effectively prevented and reversed fat accumulation in the liver without significant side effects, suggesting that targeting thyroid hormone receptors could be a promising strategy for treating liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. Perra, A., Simbula, G., Simbula, M., et al.[2013]

In significant subclinical hypothyroidism (SCH) patients, levothyroxine (LT4) therapy significantly reduced the prevalence of nonalcoholic fatty liver disease (NAFLD) from 48.5% to 24.2% after 15 months, indicating its efficacy in this group.

For mild SCH patients with dyslipidemia, LT4 treatment also led to a decrease in NAFLD prevalence and serum ALT levels, while those not receiving treatment showed no significant changes, suggesting that LT4 can be beneficial for specific subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. Liu, L., Yu, Y., Zhao, M., et al.[2022]

In a study of 137 obese individuals, those taking Levothyroxine had a significantly higher prevalence of liver fibrosis (30.6%) compared to those not on the medication (2.3%), suggesting a potential link between Levothyroxine use and liver damage.

The study also found that liver stiffness values were higher in Levothyroxine users, indicating increased liver fibrosis, although no significant differences were observed in medication dosage or treatment duration among those with and without liver fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver Stiffness in Obese Hypothyroid Patients Taking Levothyroxine. Pujia, R., Mazza, E., Montalcini, T., et al.[2023]

In a study of 52 patients with non-alcoholic fatty liver disease (NAFLD), hypothyroidism was found to be common and associated with increased NAFLD activity scores, suggesting a potential link between thyroid dysfunction and the progression of liver disease.

However, hypothyroidism did not show a significant association with the severity of liver fibrosis or steatosis, indicating that while thyroid dysfunction may influence NAFLD activity, it may not directly impact the severity of liver damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relationship between liver histology and thyroid function tests in patients with non-alcoholic fatty liver disease (NAFLD). D'Ambrosio, R., Campi, I., Maggioni, M., et al.[2021]

A 49-year-old woman with hypothyroidism experienced liver dysfunction after increasing her levothyroxine dose, which was resolved after stopping the medication, indicating a case of levothyroxine-induced liver injury.

Switching to a different levothyroxine formulation (Letrox®) without lactose and gradually increasing the dose helped maintain normal liver enzyme levels, suggesting that careful dosing and formulation choice are important in preventing drug-induced liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver dysfunction induced by Levothyroxine Sodium Tablets (Euthyrox®) in a hypothyroid patient with Hashimoto's thyroiditis: case report and literature review. Yu, H., Zhang, W., Shen, C., et al.[2020]

Levothyroxine, a common treatment for hypothyroidism, can rarely cause liver injury, as demonstrated in a case involving a 34-year-old woman who experienced this adverse effect after starting the medication.

The liver injury was self-limiting and resolved completely after stopping levothyroxine, highlighting the importance of monitoring liver function in patients beginning treatment with this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levothyroxine-induced liver injury followed by complete recovery upon cessation of the drug: a case report. Hlaihel, AF., Al-Khairalla, MZH.[2020]

In a study of over 10,000 patients treated with levothyroxine (LT4), the use of statins increased significantly after starting LT4 therapy, indicating a potential link between thyroid hormone normalization and lipid management.

Patients on LT4 had higher rates of statin prescriptions compared to those not on LT4, with odds ratios indicating a strong association, suggesting that LT4 treatment may influence lipid metabolism and necessitate further investigation into this relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites. Idrees, T., Prieto, WH., Casula, S., et al.[2022]

Thyroxine, a hormone that regulates metabolism, has shown promise in reducing liver fat in animal models of nonalcoholic fatty liver disease (NAFLD), but its use is limited by cardiac side effects.

TRβ-specific agonists, which target a subtype of the thyroid hormone receptor primarily found in the liver, have demonstrated positive effects in treating NAFLD without the adverse cardiac effects associated with thyroxine, and some of these agonists are currently in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges. Li, L., Song, Y., Shi, Y., et al.[2023]

Non-alcoholic fatty liver disease (NAFLD) is rapidly increasing, and while thyroid hormone signaling has shown promise in improving metabolic symptoms and liver injury, no drugs are currently approved for treating NASH, a severe form of NAFLD.

To minimize side effects like cardiotoxicity from non-selective thyroid hormone treatments, researchers are focusing on developing TRβ-selective thyromimetics, which could provide safer and more effective options for treating NAFLD in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. Zhao, M., Xie, H., Shan, H., et al.[2023]

In a study of 7,946 euthyroid participants, both the FT3/FT4 ratio and visceral adiposity index (VAI) were identified as significant predictors of non-alcoholic fatty liver disease (NAFLD), with 35.36% of participants diagnosed with NAFLD.

The VAI was found to partially mediate the relationship between the FT3/FT4 ratio and NAFLD prevalence, accounting for 42.75% of the total effect, indicating that higher FT3/FT4 ratios may increase NAFLD risk through their association with increased visceral fat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mediating effect analysis of visceral adiposity index on free triiodothyronine to free thyroxine ratio and non-alcoholic fatty liver disease in euthyroid population. Liu, HX., Ren, YY., Meng, CQ., et al.[2022]

References

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

Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. [2013]

2. Egypt pubmed.ncbi.nlm.nih.gov

Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. [2022]

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

Liver Stiffness in Obese Hypothyroid Patients Taking Levothyroxine. [2023]

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

The relationship between liver histology and thyroid function tests in patients with non-alcoholic fatty liver disease (NAFLD). [2021]

5. Japan pubmed.ncbi.nlm.nih.gov

Liver dysfunction induced by Levothyroxine Sodium Tablets (Euthyrox®) in a hypothyroid patient with Hashimoto's thyroiditis: case report and literature review. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Levothyroxine-induced liver injury followed by complete recovery upon cessation of the drug: a case report. [2020]

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

Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites. [2022]

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

Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Mediating effect analysis of visceral adiposity index on free triiodothyronine to free thyroxine ratio and non-alcoholic fatty liver disease in euthyroid population. [2022]