Thyroid Hormone for Treatment of Nonalcoholic Steatohepatitis in Veterans

NCT05526144 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: ENDA-010-21FI01CX002436
• Study Type: interventional
• Target: 128
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Nonalcoholic Steatohepatitis; Liver Fibrosis

Keywords

Thyroid hormone; Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); Mitochondrial fatty acid oxidation

Outcome Measures

Primary Outcomes (1)

• Improvement in Nonalcoholic fatty liver disease activity score (NAS) by 2 points

  To examine the efficacy of daily low dose Synthroid, using a dose-titration strategy based on serum thyroid stimulating hormone (TSH), on the histological progression of nonalcoholic steatohepatitis (NASH) in Veterans with normal serum TSH levels and biopsy-proven NASH, and to compare the treated patients with Veterans on placebo. Liver biopsies will be obtained at baseline (Week 0) and at end of treatment (Week 52). Nonalcoholic fatty liver disease activity score (NAS) will be assessed in baseline and post treatment liver biopsies and improvement in NAS will be compared between study group on active treatment and placebo group.

  12 months

Secondary Outcomes (4)

• Proportion of subjects experiencing improvement in biopsy-determined fibrosis by at least one stage

  12 months

• Improvement in mitochondrial fatty acid oxidation

  12 months

• Improvement in mitochondrial biogenesis

  12 months

• Improvement in mitochondrial mitophagy

  12 months

Study Arms (2)

Placebo group

PLACEBO COMPARATOR

Placebo group will receive placebo tablets

Drug: Placebo

Study group

ACTIVE COMPARATOR

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

Drug: Synthroid

Interventions

Synthroid DRUG

Synthroid tablets 25 mcg. Subjects in the study group will receive Synthroid at a titrated dose of 25 mcg (one tablet), 50 mcg (two tablets), or maximum of 75 mcg (3 tablets) daily for one year duration that will maintain TSH at normal level.

Also known as: Levothyroxine, T4

Study group

Placebo DRUG

Placebo tablets 25 mcg daily. Subjects in the placebo group will receive placebo tablets at a dose of 25 mcg (one tablet), 50 mcg (two tablets), or maximum of 75 mcg (3 tablets) daily for a one year duration.

Placebo group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women (pre- and post-menopausal)
• Overweight/obese subjects with body mass index (BMI) at or above 25.9 kg/m2
• Alcohol intake \< 20 grams per day
• Patients with type 2 diabetes on stable doses of antidiabetic medication for at least 3 months before enrollment
• Patients who are treated with vitamin E or pioglitazone should be on stable doses for at least 6 months before enrollment
• Features of metabolic syndrome: 3 or more (central obesity, hypertension, low HDL, high triglycerides, high fasting glucose)
• Scheduled for a medically indicated, diagnostic liver biopsy
• Female patients are eligible if they are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use two highly effective birth control methods during the study OR if they are not of child-bearing potential (i.e., surgically \[bilateral oophorectomy, hysterectomy, or tubal ligation\] or naturally sterile \[\> 12 consecutive months without menses\])
• Highly effective birth control methods include condoms with spermicide, diaphragm with spermicide, hormonal and nonhormonal intrauterine device, hormonal contraception (estrogens stable for at least 3 months), a vasectomized male partner, or sexual abstinence (defined as refraining from heterosexual intercourse), from screening, throughout the study, and for at least 30 days after the last dose of study drug administration
• Reliance on abstinence from heterosexual intercourse is acceptable only if it is the patient's habitual practice
• If a patient is on digitalis and amiodarone, he/she is expected to use/continue these medications throughout the treatment period only after consultation with their cardiologist for monitoring and dose adjustments if necessary

You may not qualify if:

• Other causes of hepatitis including hepatitis B \& C, autoimmune hepatitis, hemochromatosis, celiac disease, Wilson's disease, alpha-1-antitrypsin deficiency, medication-induced hepatitis
• Alcohol consumption of 20 g/d or more
• Patients with cirrhosis, bilirubin of 1.3 mg/dL or more, and INR of 1.3 or more
• Evidence of Portal hypertension
• Pregnancy
• History of malignant hypertension
• Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure \> 160 mm Hg or a diastolic blood pressure \> 100 mm Hg at screening
• New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction \< 30%
• Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia's formula (QTcF) \> 450 msec for males and \> 470 msec for females at the screening electrocardiogram (ECG) assessment
• History of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within at least 3 months prior to randomization
• History of high degree AV block (Mobitz II or complete) in the absence of a pacemaker
• Patients with uncorrected adrenal insufficiency
• Patients who are on tricyclic or tetracyclic antidepressants or ketamine, if they are unwilling and/or unable to discontinue these medications to allow adequate washout prior to randomization
• Patients who are on Teduglutide or Midodrine

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

Harry S. Truman Memorial, Columbia, MO

Columbia, Missouri, 65201-5275, United States

RECRUITING

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Cirrhosis

Interventions

Thyroxine

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Jamal A Ibdah, MD PhD

  Harry S. Truman Memorial, Columbia, MO

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adam T Whaley-Connell, DO MSPH

CONTACT

(573) 814-6552; Adam.Whaley-Connell@va.gov

Jennifer A Atherton

CONTACT

(573) 814-6000; Jennifer.Atherton@va.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Study subjects will be blinded whether they will receive Synthroid or placebo. All subjects will be coded serially with no identifiers used. The study coordinator will be the only individual to have access to the key list of Synthroid and placebo groups. Only the study coordinator and safety officer will have access to the thyroid function tests. The safety officer will determine whether a dose needs to be titrated. The study coordinator will coordinate with the Investigational Pharmacy for dispensing the study drug to the subjects. All dosage changes will be done for both study subjects receiving Synthroid and matching control subjects receiving placebo. The investigators will be blinded to the randomization and to dose titration. At interim analysis and final analysis, the statistician will be unblinded and will be provided with the study subjects codes for those in the Synthroid and placebo groups for analysis of the results.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: Study subjects who are eligible for the study will be assigned by block randomization to either the study group arm receiving active treatment of a titrated dose of Synthroid (25, 50, or 75 mcg/day) or placebo (25, 50, or 75 mcg/day).

Study Record Dates

• First Submitted: August 23, 2022
• First Posted: September 2, 2022
• Study Start: April 1, 2023
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• Access Criteria: 1. Access to trial IPD can be requested by qualified researchers conducting independent scientific research 2. Access will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) 3. Access will be provided after execution of a Data Sharing Agreement (DSA)

Locations

US (1)