Levothyroxine for Non-Alcoholic Fatty Liver Disease (NAFLD)

NCT03281083 | Terminated Phase 2

• 1 other identifier: MRN-01-NAFLD-01
• Study Type: interventional
• Target: 29
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Non-Alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2

Keywords

Non-Alcoholic Fatty Liver Disease; Diabetes Mellitus, type 2; Thyroid hormone; Levothyroxine

Outcome Measures

Primary Outcomes (1)

• Liver fat content

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

  16 weeks

Secondary Outcomes (3)

• HbA1c

  16 weeks

• Lipid profile

  16 weeks

• Abdominal fat

  16 weeks

Study Arms (1)

Levothyroxine (LT4)

EXPERIMENTAL

Levothyroxine sodium (LT4) dose titrated at TSH 0.34 - 1.70mIU/L during maximum 12 weeks, followed by a maintenance phase of 16 weeks using the dose necessary for titration.

Drug: Levothyroxine Sodium

Interventions

Levothyroxine Sodium DRUG

Also known as: H03AA01

Levothyroxine (LT4)

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male between 21 to 60 years of age
• 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%.
• 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
• 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)
• The IHL content on the MRI/MRS should be more than 10% to allow enrollment in the trial.
• Baseline TSH levels between 1 - 10 mIU/L
• Baseline heart rate \<90 beats/min
• Ability to provide informed consent

You may not qualify if:

• 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
• Baseline estimated glomerular filtration rate (eGFR) \< 60 ml/min
• 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
• Consumption of ethanol greater than 30g/day (i.e. 3 drinks/day or 21 drinks/week, with about 10g of alcohol per drink)
• Has advanced liver disease with a baseline NAFLD fibrosis score of \>0.675 (stage 3 or 4 fibrosis)
• Has an implant or device in the body which is not safe for MRI scan
• Baseline ECG findings considered to be clinically significant (e.g., ischemic changes, arrhythmias) by the Investigator(s)
• Subject with history of claustrophobia
• 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.

Sponsors & Collaborators

• Duke-NUS Graduate Medical School: lead
• Singapore Clinical Research Institute: collaborator
• Institute for Human Development and Potential (IHDP), Singapore: collaborator
• Institute of Bioengineering and Bioimaging (IBB): collaborator
• Tan Tock Seng Hospital: collaborator
• Singapore General Hospital: collaborator
• Ng Teng Fong General Hospital: collaborator
• Changi General Hospital: collaborator
• Khoo Teck Puat Hospital: collaborator
• National University Health System, Singapore: collaborator

Related Publications (13)

• Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, Day CP, Trenell MI. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011 Sep;60(9):1278-83. doi: 10.1136/gut.2011.242073. Epub 2011 Jun 27.

  PMID: 21708823 BACKGROUND

• Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112. doi: 10.1002/hep.20973.

  PMID: 16447287 BACKGROUND

• Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, Zenari L, Falezza G. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005 Dec;54(12):3541-6. doi: 10.2337/diabetes.54.12.3541.

  PMID: 16306373 BACKGROUND

• Casoinic F, Sampelean D, Badau C, Pruna L. Nonalcoholic fatty liver disease--a risk factor for microalbuminuria in type 2 diabetic patients. Rom J Intern Med. 2009;47(1):55-9.

  PMID: 19886070 BACKGROUND

• Salgado AL, Carvalho Ld, Oliveira AC, Santos VN, Vieira JG, Parise ER. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. Arq Gastroenterol. 2010 Apr-Jun;47(2):165-9. doi: 10.1590/s0004-28032010000200009.

  PMID: 20721461 BACKGROUND

• Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol. 2003 Oct;37(4):340-3. doi: 10.1097/00004836-200310000-00014.

  PMID: 14506393 BACKGROUND

• Perra A, Simbula G, Simbula M, Pibiri M, Kowalik MA, Sulas P, Cocco MT, Ledda-Columbano GM, Columbano A. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 2008 Aug;22(8):2981-9. doi: 10.1096/fj.08-108464. Epub 2008 Apr 23.

  PMID: 18434432 BACKGROUND

• Cable EE, Finn PD, Stebbins JW, Hou J, Ito BR, van Poelje PD, Linemeyer DL, Erion MD. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology. 2009 Feb;49(2):407-17. doi: 10.1002/hep.22572.

  PMID: 19072834 BACKGROUND

• Pihlajamaki J, Boes T, Kim EY, Dearie F, Kim BW, Schroeder J, Mun E, Nasser I, Park PJ, Bianco AC, Goldfine AB, Patti ME. Thyroid hormone-related regulation of gene expression in human fatty liver. J Clin Endocrinol Metab. 2009 Sep;94(9):3521-9. doi: 10.1210/jc.2009-0212. Epub 2009 Jun 23.

  PMID: 19549744 BACKGROUND

• Xu C, Xu L, Yu C, Miao M, Li Y. Association between thyroid function and nonalcoholic fatty liver disease in euthyroid elderly Chinese. Clin Endocrinol (Oxf). 2011 Aug;75(2):240-6. doi: 10.1111/j.1365-2265.2011.04016.x.

  PMID: 21521285 BACKGROUND

• Carulli L, Ballestri S, Lonardo A, Lami F, Violi E, Losi L, Bonilauri L, Verrone AM, Odoardi MR, Scaglioni F, Bertolotti M, Loria P. Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels? Intern Emerg Med. 2013 Jun;8(4):297-305. doi: 10.1007/s11739-011-0609-4. Epub 2011 May 11.

  PMID: 21559749 BACKGROUND

• Sinha RA, You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012 Jul;122(7):2428-38. doi: 10.1172/JCI60580. Epub 2012 Jun 11.

  PMID: 22684107 BACKGROUND

• Bruinstroop E, Dalan R, Cao Y, Bee YM, Chandran K, Cho LW, Soh SB, Teo EK, Toh SA, Leow MKS, Sinha RA, Sadananthan SA, Michael N, Stapleton HM, Leung C, Angus PW, Patel SK, Burrell LM, Lim SC, Sum CF, Velan SS, Yen PM. Low-Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients With Type 2 Diabetes Mellitus and NAFLD. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2698-2706. doi: 10.1210/jc.2018-00475.

  PMID: 29718334 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2

Interventions

Thyroxine

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

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

• Paul M Yen, MD

  Duke-NUS Graduate Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Single arm study.

Study Record Dates

• First Submitted: September 11, 2017
• First Posted: September 13, 2017
• Study Start: March 28, 2014
• Primary Completion: July 28, 2016
• Study Completion: July 28, 2016
• Last Updated: September 14, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share