Diabetes Mellitus, Type 2 Clinical Trial
Official title:
Effects of 4-month Therapy of Levothyroxine on Non-Alcoholic Fatty Liver Disease (NAFLD) and Diabetes Control in Diabetic Patients
Verified date | September 2017 |
Source | Duke-NUS Graduate Medical School |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Terminated |
Enrollment | 29 |
Est. completion date | July 28, 2016 |
Est. primary completion date | July 28, 2016 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 21 Years to 60 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
n/a |
Lead Sponsor | Collaborator |
---|---|
Duke-NUS Graduate Medical School | Changi General Hospital, 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 |
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. — View Citation
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. — View Citation
Casoinic F, Sâmpelean 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. — View Citation
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112. Review. — View Citation
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. — View Citation
Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol. 2003 Oct;37(4):340-3. — View Citation
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. — View Citation
Pihlajamäki 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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
* Note: There are 12 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | HbA1c | To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to 0.34mIU/L - 1.7 mIU/L can improve glycemic control in Type II diabetic patients with NAFLD measured by reduction in HbA1c. | 16 weeks | |
Secondary | Lipid profile | To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to 0.34mIU/L - 1.7 mIU/L can improve serum lipid profile in Type II diabetic patients with NAFLD as measured by total serum cholesterol, HDL, LDL and total triglycerides. | 16 weeks | |
Secondary | Abdominal fat | 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 the proportion of liver fat over body fat, which is reflected by fat in abdominal subcutaneous and visceral tissues, among patients with type II diabetes as measured by functional MRI on abdomen. | 16 weeks |
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