Levothyroxine for Non-Alcoholic Fatty Liver Disease (NAFLD)

• Status: Terminated
• Trial end date: 2016-07-28
• Target enrollment: 0
• Participant gender: Male

Summary

Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by lipid accumulation in hepatocytes. Evidence shows that thyroid hormone might be beneficial for this condition.

Objective: To determine whether low dose levothyroxine (LT4) therapy may be a potential treatment for diabetic patients with NAFLD in a single arm study.

Primary: To ascertain whether administration of LT4 for 16 weeks by titrating the serum thyroid stimulating hormone (TSH) to 0.34 mIU/L - 1.7 mIU /L reduces liver fat content by at least 3% among patients with type II diabetes as measured by functional MRI.

Secondary: To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to 0.34 mIU/L - 1.7 mIU /L can improve glycemic control as measured by reduction in glycosylated hemoglobin (HbA1c), improve serum lipid profile in Type II diabetic patients with NAFLD as measured by total serum cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total triglycerides (TG) and reduce the proportion of liver fat over body fat, which is reflected by fat in abdominal subcutaneous and visceral tissues, as measured by functional MRI on abdomen.

Subjects and Centres: A total of 50 eligible adult diabetic men with NAFLD will be recruited from 6 centres in Singapore - Changi General Hospital (CGH), Singapore General Hospital (SGH), Tan Tock Seng Hospital (TTSH), National University Health System (NUHS), Khoo Teck Puat Hospital (KTPH), Jurong Health (JH)

Eligible patients: Males between 21 to 60 years of age diagnosed with stable Type II diabetes mellitus (DM) with a baseline alanine aminotransferase (ALT) < 3 times upper limit of normal as per the institution's specified reference range, with a liver ultrasound (US) showing presence of fatty liver and baseline Thyroid stimulating hormone (TSH) levels between 1 - 10 mIU/L.

Treatment: Low dose levothyroxine (LT4) for 16 weeks, not including the 12 weeks of pre-study titration of LT4 in order to attain target TSH level of 0.34-1.70 mIU/L.

Statistical Analysis: The absolute change in liver fat content from baseline (primary endpoint) will be analyzed using one-sample two-sided t-test at a 5% significance level. The same test will be applied to secondary endpoints. Mean, standard deviation and 95% confidence interval will be calculated for primary endpoint and secondary endpoints.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Duke-NUS Graduate Medical School
• Collaborators: Changi General Hospital; Institute of Bioengineering and Bioimaging (IBB); Khoo Teck Puat Hospital; National University Health System, Singapore; Ng Teng Fong General Hospital; Singapore Bioimaging Consortium; Singapore Clinical Research Institute; Singapore General Hospital; Singapore Institute for Clinical Sciences; Tan Tock Seng Hospital

Criteria

Inclusion Criteria:

1. Male between 21 to 60 years of age

2. Diagnosed with stable Type II diabetes mellitus (DM) with no changes in oral hypoglycaemic medications or dose for the last 2 months from the time of start LT4, and if on insulin < 10 units change in insulin dosage, documented by patient's medical records. The most recent HbA1C for the last 6 months from the time of start LT4 should be no more than 10%.

3. If the subject is on statin medication, there should be no change in the medication or dose of statin for the last 2 months from the time of start LT4

4. Baseline ALT <3 times upper limit of normal as per the institution's specified reference range , with a liver ultrasound showing presence of fatty liver (liver ultrasound will not be requested if a prior scan has been done within the past 6 months from the time of screening)

5. The IHL content on the MRI/MRS should be more than 10% to allow enrollment in the trial.

6. Baseline TSH levels between 1 - 10 mIU/L

7. Baseline heart rate <90 beats/min

8. Ability to provide informed consent

Exclusion Criteria:

1. Subject with history of viral hepatitis (except subject with history of viral A hepatitis or history of viral E hepatitis that was diagnosed at least 1 year before), hepatocellular carcinoma, liver cirrhosis, heart disease, osteoporosis, hyper/hypothyroidism, anxiety disorder, Graves' disease, thyroid/liver surgery, lactose intolerance, or malabsorption

2. Baseline estimated glomerular filtration rate (eGFR) < 60 ml/min

3. Currently on or within 6 months from the time of screening on either thyroxine, thiazolidinedione (TZD), oral T4/T3, anticoagulants (coumadin and warfarin), anti-viral drugs such as the protease inhibitors (ritonavir, indinavir, lopinavir), phenytoin, colestyramine, aluminium containing drugs (antacids, sucralfate), salicylates (> 100mg/day), dicumarol, furosemide, or sevelamer

4. Consumption of ethanol greater than 30g/day (i.e. 3 drinks/day or 21 drinks/week, with about 10g of alcohol per drink)

5. Has advanced liver disease with a baseline NAFLD fibrosis score of >0.675 (stage 3 or 4 fibrosis)

6. Has an implant or device in the body which is not safe for MRI scan

7. Baseline ECG findings considered to be clinically significant (e.g., ischemic changes, arrhythmias) by the Investigator(s)

8. Subject with history of claustrophobia

9. Baseline free T4 of more than the institution's specified reference range If a sole blood test result is deemed borderline according to the laboratory reference interval and not clinically significant, the investigator is authorized to exercise discretion.