128 Participants Needed

Thyroid Hormone for Nonalcoholic Steatohepatitis

RL
AT
JA
Overseen ByJennifer A Atherton
Age: 18+
Sex: Any
Trial Phase: Phase 2
Sponsor: VA Office of Research and Development
Must be taking: Antidiabetics, Vitamin E
Prior Safety DataThis treatment has passed at least one previous human trial
Approved in 3 JurisdictionsThis treatment is already approved in other countries

Trial Summary

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.12345

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.35678

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.138910

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.

Research Team

JA

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.
See 8 more

Exclusion Criteria

Evidence of Portal hypertension
I have had dangerously high blood pressure.
I have a serious heart block without a pacemaker.
See 11 more

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
  • Synthroid
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
2Treatment groups
Active Control
Placebo Group
Group I: Study groupActive Control1 Intervention
Study group will receive Synthroid (Levothyroxine) 25, 50, or 75 mcg daily
Group II: Placebo groupPlacebo Group1 Intervention
Placebo group will receive placebo tablets

Synthroid is already approved in United States, Canada, European Union for the following indications:

🇺🇸
Approved in United States as Synthroid for:
  • Hypothyroidism
  • Goiter
  • Thyroid nodules
  • Thyroid cancer
🇨🇦
Approved in Canada as Eltroxin for:
  • Hypothyroidism
  • Goiter
  • Thyroid nodules
  • Thyroid cancer
🇪🇺
Approved in European Union as Evotrox for:
  • Hypothyroidism
  • Goiter
  • Thyroid nodules
  • Thyroid cancer

Find a Clinic Near You

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials
1,691
Recruited
3,759,000+

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

References

Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. [2013]
Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. [2022]
Liver Stiffness in Obese Hypothyroid Patients Taking Levothyroxine. [2023]
The relationship between liver histology and thyroid function tests in patients with non-alcoholic fatty liver disease (NAFLD). [2021]
Liver dysfunction induced by Levothyroxine Sodium Tablets (Euthyrox®) in a hypothyroid patient with Hashimoto's thyroiditis: case report and literature review. [2020]
Levothyroxine-induced liver injury followed by complete recovery upon cessation of the drug: a case report. [2020]
Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites. [2022]
Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges. [2023]
Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. [2023]
Mediating effect analysis of visceral adiposity index on free triiodothyronine to free thyroxine ratio and non-alcoholic fatty liver disease in euthyroid population. [2022]
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