<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03281083</url>
  </required_header>
  <id_info>
    <org_study_id>MRN-01-NAFLD-01</org_study_id>
    <nct_id>NCT03281083</nct_id>
  </id_info>
  <brief_title>Levothyroxine for Non-Alcoholic Fatty Liver Disease (NAFLD)</brief_title>
  <official_title>Effects of 4-month Therapy of Levothyroxine on Non-Alcoholic Fatty Liver Disease (NAFLD) and Diabetes Control in Diabetic Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke-NUS Graduate Medical School</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Singapore Clinical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Singapore Institute for Clinical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Bioengineering and Bioimaging (IBB)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tan Tock Seng Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Singapore General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ng Teng Fong General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Changi General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Khoo Teck Puat Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National University Health System, Singapore</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke-NUS Graduate Medical School</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders&#xD;
      characterized by lipid accumulation in hepatocytes. Evidence shows that thyroid hormone might&#xD;
      be beneficial for this condition.&#xD;
&#xD;
      Objective: To determine whether low dose levothyroxine (LT4) therapy may be a potential&#xD;
      treatment for diabetic patients with NAFLD in a single arm study.&#xD;
&#xD;
      Primary: To ascertain whether administration of LT4 for 16 weeks by titrating the serum&#xD;
      thyroid stimulating hormone (TSH) to 0.34 mIU/L - 1.7 mIU /L reduces liver fat content by at&#xD;
      least 3% among patients with type II diabetes as measured by functional MRI.&#xD;
&#xD;
      Secondary: To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH&#xD;
      to 0.34 mIU/L - 1.7 mIU /L can improve glycemic control as measured by reduction in&#xD;
      glycosylated hemoglobin (HbA1c), improve serum lipid profile in Type II diabetic patients&#xD;
      with NAFLD as measured by total serum cholesterol, high-density lipoprotein (HDL),&#xD;
      low-density lipoprotein (LDL) and total triglycerides (TG) and reduce the proportion of liver&#xD;
      fat over body fat, which is reflected by fat in abdominal subcutaneous and visceral tissues,&#xD;
      as measured by functional MRI on abdomen.&#xD;
&#xD;
      Subjects and Centres: A total of 50 eligible adult diabetic men with NAFLD will be recruited&#xD;
      from 6 centres in Singapore - Changi General Hospital (CGH), Singapore General Hospital&#xD;
      (SGH), Tan Tock Seng Hospital (TTSH), National University Health System (NUHS), Khoo Teck&#xD;
      Puat Hospital (KTPH), Jurong Health (JH)&#xD;
&#xD;
      Eligible patients: Males between 21 to 60 years of age diagnosed with stable Type II diabetes&#xD;
      mellitus (DM) with a baseline alanine aminotransferase (ALT) &lt; 3 times upper limit of normal&#xD;
      as per the institution's specified reference range, with a liver ultrasound (US) showing&#xD;
      presence of fatty liver and baseline Thyroid stimulating hormone (TSH) levels between 1 - 10&#xD;
      mIU/L.&#xD;
&#xD;
      Treatment: Low dose levothyroxine (LT4) for 16 weeks, not including the 12 weeks of pre-study&#xD;
      titration of LT4 in order to attain target TSH level of 0.34-1.70 mIU/L.&#xD;
&#xD;
      Statistical Analysis: The absolute change in liver fat content from baseline (primary&#xD;
      endpoint) will be analyzed using one-sample two-sided t-test at a 5% significance level. The&#xD;
      same test will be applied to secondary endpoints. Mean, standard deviation and 95% confidence&#xD;
      interval will be calculated for primary endpoint and secondary endpoints.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders&#xD;
      characterized by lipid accumulation in hepatocytes. These conditions range from fat&#xD;
      accumulation in the liver (hepatosteatosis) to non-alcoholic steatohepatitis (NASH), which in&#xD;
      turn, increases the risk for cirrhosis and hepatocellular cancer. NAFLD occurs in 25-35 % of&#xD;
      the general United States population, and its prevalence is estimated to be 60 %-80 % for&#xD;
      patients with type II diabetes mellitus (DM). Its co-occurrence with type II DM significantly&#xD;
      increases the risks for renal and cardiovascular disease. The prevalence of NAFLD in&#xD;
      Singapore is not known. However, given that the estimated percentage of adults with type II&#xD;
      DM or obesity are approaching 10 % and rapidly rising, a significant proportion of the&#xD;
      Singaporean population is likely at risk for NAFLD. Although there are drug therapies for&#xD;
      diabetes; currently, there is no effective treatment for NAFLD.&#xD;
&#xD;
      Although NAFLD may cause inflammation, lipotoxicity, and scarring within the liver, it also&#xD;
      can have profound metabolic effects as it induces hepatic insulin resistance. Defects in&#xD;
      β-oxidation of fatty acids are thought to play an important role in the pathogenesis of&#xD;
      NAFLD, which then leads to further insulin resistance and worsened glycemic control in&#xD;
      diabetic patients. Since thyroid hormones (THs: T3, T4) promote the oxidation of fatty acids&#xD;
      within the liver, it is possible that ineffective TH action in the liver may contribute to&#xD;
      NAFLD.&#xD;
&#xD;
      It has been shown recently that the incidence of hypothyroidism is doubled in patients with&#xD;
      NAFLD as approximately 15% patients are affected. Additionally, several TH and TH analogues&#xD;
      are able to ameliorate NAFLD in rodents fed with high fat chow diets. At the genomic level,&#xD;
      many of the genes that have altered expression in NAFLD are regulated by TH further&#xD;
      supporting the notion that defects in TH signalling may promote hepatosteatosis and hepatic&#xD;
      damage. Two recent studies also have shown thyroid hypo-function in both young and elderly&#xD;
      adults with NAFLD.&#xD;
&#xD;
      In this study, we seek to examine whether short-term low dose levothyroxine can decrease&#xD;
      hepatic fat deposition and improve glucose control in diabetic patients with NAFLD.&#xD;
&#xD;
      Accordingly, we plan to treat 50 male patients with stable Type II DM and NAFLD with low dose&#xD;
      LT4, and assess fat content in the liver by MRI and glucose control by measuring serum&#xD;
      fasting glucose, HbA1c, and degree of insulin resistance as determined by the homeostatic&#xD;
      model assessment (HOMA-IR). The potential benefit for the patient will be reduction of&#xD;
      hepatic fat content and/or improvement in glucose control. The potential major side effects&#xD;
      are atrial arrhythmias and osteoporosis. The risk for the latter side effects will be&#xD;
      minimized by treating subjects that do not have any known heart disease or osteoporosis with&#xD;
      low dose levothyroxine. It is expected that thyroid hormone levels will be in the high normal&#xD;
      range. Patient will undergo hepatic MRI at beginning of study and at 16 weeks and phlebotomy&#xD;
      at beginning of study, at 8 weeks, and at 16 weeks. The study will be conducted in compliance&#xD;
      with the protocol, Singapore Guideline for Good Clinical Practice (SGGCP), site's respective&#xD;
      Institutional Review Board (IRB), and Health Science Authority (HSA) requirements.&#xD;
&#xD;
      Preliminary Studies:To investigate the potential etiological role of TH in hepatosteatosis,&#xD;
      we initiated studies in which human liver HepG2 cells over-expressing TH receptors (TRs) were&#xD;
      treated with palmitate in the absence or presence of T3. In this cell culture model of NAFLD,&#xD;
      the uptake of palmitate and the intracellular accumulation of fatty acids caused apoptosis in&#xD;
      the absence of hormone. Surprisingly, T3 treatment blocked the palmitate-induced apoptosis.&#xD;
      Additionally, our studies suggest that part of this protective effect by T3 is due to&#xD;
      induction of &quot;lipophagy&quot;, a type of autophagy in which cells consume and digest fatty acids&#xD;
      before delivery to mitochondria. Concomitantly, we have observed induction of cpt1a mRNA, a&#xD;
      protein which transports fatty acids to mitochondria. Our findings suggest that T3 may&#xD;
      facilitate both the consumption and β oxidation of fatty acids within the hepatocyte. If this&#xD;
      is the case, and when taken together with previous findings, our data would suggest the liver&#xD;
      may be particularly susceptible to lipid accumulation and damage in hypothyroidism.&#xD;
      Additionally, NAFLD itself may engender a &quot;relative hypothyroid&quot; state within the liver -&#xD;
      resulting in impaired responsiveness of key metabolic target genes to TH. Thus, it is&#xD;
      possible that TH, or TH analogues may be useful in the treatment and prevention of NAFLD.&#xD;
&#xD;
      Our cell culture and in vivo data, in combination with previous studies in rodents showing&#xD;
      that T3 and its analogues may be able to decrease hepatosteatosis and evidence that TH action&#xD;
      may be decreased in human liver in obese patients undergoing gastric bypass and in patients&#xD;
      with NAFLD, provide the experimental rationale to examine whether short-term levothyroxine&#xD;
      therapy can decrease hepatosteatosis in Type II diabetic patients and improve glycemic&#xD;
      control in Type II diabetic patients with NAFLD.&#xD;
&#xD;
      Objective: To determine whether low dose levothyroxine (LT4) therapy may be a potential&#xD;
      treatment for diabetic patients with NAFLD.&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
      - To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to 0.34&#xD;
      mIU/L - 1.7 mIU /L reduces liver fat content by at least 3% among patients with type II DM as&#xD;
      measured by functional MRI.&#xD;
&#xD;
      Secondary Objective:&#xD;
&#xD;
        -  To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to&#xD;
           0.34 mIU/L - 1.7 mIU /L can improve glycemic control in Type II diabetic patients with&#xD;
           NAFLD as measured by reduction in glycosylated hemoglobin (HbA1c).&#xD;
&#xD;
        -  To ascertain whether administration of LT4 for 16 weeks by titrating the serum TSH to&#xD;
           0.34 mIU/L - 1.7 mIU /L can improve serum lipid profile in Type II diabetic patients&#xD;
           with NAFLD as measured by total serum cholesterol, high-density lipoprotein (HDL),&#xD;
           low-density lipoprotein (LDL) and total triglycerides (TG).&#xD;
&#xD;
        -  To ascertain whether administration of LT4 for 16 weeks by titrating the serum thyroid&#xD;
           stimulating hormone (TSH) to 0.34 mIU/L - 1.7 mIU /L reduces the proportion of liver fat&#xD;
           over body fat, which is reflected by fat in abdominal subcutaneous and visceral tissues,&#xD;
           among patients with type II diabetes as measured by functional MRI on abdomen.&#xD;
&#xD;
      Subjects and Centres: A total of 50 eligible adult diabetic men with NAFLD will be recruited&#xD;
      from 6 centres in Singapore - Changi General Hospital (CGH), Singapore General Hospital&#xD;
      (SGH), Tan Tock Seng Hospital (TTSH), National University Health System (NUHS), Khoo Teck&#xD;
      Puat Hospital (KTPH), Jurong Health (JH)&#xD;
&#xD;
      Inclusion and exclusion criteria are mentioned in the eligibility section.&#xD;
&#xD;
      Randomization: This is an open-labeled, single arm study.&#xD;
&#xD;
      Study protocol: After giving informed consent the subjects will undergo screening laboratory,&#xD;
      abdominal imaging, ECG, review of medical history, medications for the past 6 months, and&#xD;
      physical examination to determine eligibility. Once enrolled into the study the subjects will&#xD;
      be treated with low dose LT4. There will be a titration phase of 12 weeks wherein the&#xD;
      levothyroxine will be titrated to attain a TSH level between 0.34-1.70 mIU/L. It is possible&#xD;
      that the desired TSH level may be achieved earlier than 12 weeks. It will not be considered&#xD;
      protocol deviation if the 12-week titration period is not completed due to achieving the&#xD;
      target TSH level earlier after following the defined titration method.&#xD;
&#xD;
      Subjects will undergo MRI/MRS at the beginning and end of study to assess changes in fatty&#xD;
      liver content and changes in abdominal subcutaneous and visceral adipose tissue volumes. All&#xD;
      study related liver MRI/MRS will be done at the Clinical Imaging Research Centre (CIRC) and&#xD;
      will be read by a single imaging expert to minimize inter-reader variability.&#xD;
&#xD;
      Fasting glucose, HbA1c, insulin resistance, and lipid profile will also be ascertained before&#xD;
      and after treatment. These tests will be done at respective institutions where the subject is&#xD;
      recruited. The degree of insulin resistance will be determined using HOMA-IR which can be&#xD;
      calculated easily online at www.hcvsociety.org/files/HOMACalc.html.&#xD;
&#xD;
      All subjects will still receive the standard care of treatment for NAFLD which is life style&#xD;
      modification such as weight loss through diet and regular exercise. At each follow-up visit&#xD;
      (visits 5 - 9), the investigator will solicit information from the subject on the latter's&#xD;
      dietary and exercise habits and will counsel the subject accordingly on life style&#xD;
      modification. BMI will be monitored during each follow-up visit. The random glucose and hbA1c&#xD;
      tests will be done during each follow-up visit (visits 5-8) to monitor diabetes status. The&#xD;
      subjects will also be encouraged to continue their diabetes follow-up.&#xD;
&#xD;
      Treatment: Titration of thyroxine is complicated and safety is paramount. Subjects will have&#xD;
      their LT4 dose adjusted and monitored by highly-trained board-certified endocrinologists&#xD;
      participating in this study. Investigators are provided with tables indicating the initial&#xD;
      dosing and titration based on measured TSH values and timelines for subsequent TSH&#xD;
      measurement. The investigators are authorized to exercise discretion to LT4 titration on case&#xD;
      by case basis.&#xD;
&#xD;
      Study Duration: Maximum of 28 weeks: 12 weeks of pre-study drug titration and 16 weeks on&#xD;
      low-dose LT4.&#xD;
&#xD;
      Statistical Analysis: Our primary endpoint is the absolute change in liver fat content from&#xD;
      baseline after 16-week administration of LT4. Secondary endpoints are changes in HbA1c, total&#xD;
      serum cholesterol, HDL, LDL and total triglycerides from baselines. The absolute change in&#xD;
      liver fat content from baseline will be analyzed using one-sample two-sided t-test at a 5 %&#xD;
      significance level. The same test will be applied to secondary endpoints.&#xD;
&#xD;
      For the primary endpoint and secondary endpoints, mean, standard deviation and 95 %&#xD;
      confidence interval will be provided. Demographic and baseline data will be summarized with&#xD;
      mean and standard deviation for continuous variables such as age, and count and proportion in&#xD;
      each category for categorical variables such as gender and race. Adverse events and serious&#xD;
      adverse events will be tabulated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Difficult recruitment and end of funding.&#xD;
  </why_stopped>
  <start_date type="Actual">March 28, 2014</start_date>
  <completion_date type="Actual">July 28, 2016</completion_date>
  <primary_completion_date type="Actual">July 28, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Single arm study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Liver fat content</measure>
    <time_frame>16 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>HbA1c</measure>
    <time_frame>16 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lipid profile</measure>
    <time_frame>16 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abdominal fat</measure>
    <time_frame>16 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <condition>Diabetes Mellitus, Type 2</condition>
  <arm_group>
    <arm_group_label>Levothyroxine (LT4)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levothyroxine Sodium</intervention_name>
    <arm_group_label>Levothyroxine (LT4)</arm_group_label>
    <other_name>H03AA01</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male between 21 to 60 years of age&#xD;
&#xD;
          2. Diagnosed with stable Type II diabetes mellitus (DM) with no changes in oral&#xD;
             hypoglycaemic medications or dose for the last 2 months from the time of start LT4,&#xD;
             and if on insulin &lt; 10 units change in insulin dosage, documented by patient's medical&#xD;
             records. The most recent HbA1C for the last 6 months from the time of start LT4 should&#xD;
             be no more than 10%.&#xD;
&#xD;
          3. If the subject is on statin medication, there should be no change in the medication or&#xD;
             dose of statin for the last 2 months from the time of start LT4&#xD;
&#xD;
          4. Baseline ALT &lt;3 times upper limit of normal as per the institution's specified&#xD;
             reference range , with a liver ultrasound showing presence of fatty liver (liver&#xD;
             ultrasound will not be requested if a prior scan has been done within the past 6&#xD;
             months from the time of screening)&#xD;
&#xD;
          5. The IHL content on the MRI/MRS should be more than 10% to allow enrollment in the&#xD;
             trial.&#xD;
&#xD;
          6. Baseline TSH levels between 1 - 10 mIU/L&#xD;
&#xD;
          7. Baseline heart rate &lt;90 beats/min&#xD;
&#xD;
          8. Ability to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subject with history of viral hepatitis (except subject with history of viral A&#xD;
             hepatitis or history of viral E hepatitis that was diagnosed at least 1 year before),&#xD;
             hepatocellular carcinoma, liver cirrhosis, heart disease, osteoporosis,&#xD;
             hyper/hypothyroidism, anxiety disorder, Graves' disease, thyroid/liver surgery,&#xD;
             lactose intolerance, or malabsorption&#xD;
&#xD;
          2. Baseline estimated glomerular filtration rate (eGFR) &lt; 60 ml/min&#xD;
&#xD;
          3. Currently on or within 6 months from the time of screening on either thyroxine,&#xD;
             thiazolidinedione (TZD), oral T4/T3, anticoagulants (coumadin and warfarin),&#xD;
             anti-viral drugs such as the protease inhibitors (ritonavir, indinavir, lopinavir),&#xD;
             phenytoin, colestyramine, aluminium containing drugs (antacids, sucralfate),&#xD;
             salicylates (&gt; 100mg/day), dicumarol, furosemide, or sevelamer&#xD;
&#xD;
          4. Consumption of ethanol greater than 30g/day (i.e. 3 drinks/day or 21 drinks/week, with&#xD;
             about 10g of alcohol per drink)&#xD;
&#xD;
          5. Has advanced liver disease with a baseline NAFLD fibrosis score of &gt;0.675 (stage 3 or&#xD;
             4 fibrosis)&#xD;
&#xD;
          6. Has an implant or device in the body which is not safe for MRI scan&#xD;
&#xD;
          7. Baseline ECG findings considered to be clinically significant (e.g., ischemic changes,&#xD;
             arrhythmias) by the Investigator(s)&#xD;
&#xD;
          8. Subject with history of claustrophobia&#xD;
&#xD;
          9. Baseline free T4 of more than the institution's specified reference range If a sole&#xD;
             blood test result is deemed borderline according to the laboratory reference interval&#xD;
             and not clinically significant, the investigator is authorized to exercise discretion.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul M Yen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke-NUS Graduate Medical School</affiliation>
  </overall_official>
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    <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.</citation>
    <PMID>21708823</PMID>
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  <reference>
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  <reference>
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  <reference>
    <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. doi: 10.1590/s0004-28032010000200009.</citation>
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  <reference>
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    <PMID>21559749</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>22684107</PMID>
  </reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>September 12, 2017</last_update_submitted>
  <last_update_submitted_qc>September 12, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Duke-NUS Graduate Medical School</investigator_affiliation>
    <investigator_full_name>Paul M. Yen</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Non-Alcoholic Fatty Liver Disease</keyword>
  <keyword>Diabetes Mellitus, type 2</keyword>
  <keyword>Thyroid hormone</keyword>
  <keyword>Levothyroxine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03281083
org study id: MRN-01-NAFLD-01
nct id: NCT03281083
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
Background: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders
      characterized by lipid accumulation in hepatocytes. These conditions range from fat
      accumulation in the liver (hepatosteatosis) to non-alcoholic steatohepatitis (NASH), which in
      turn, increases the risk for cirrhosis and hepatocellular cancer. NAFLD occurs in 25-35 % of
      the general United States population, and its prevalence is estimated to be 60 %-80 % for
      patients with type II diabetes mellitus (DM). Its co-occurrence with type II DM significantly
      increases the risks for renal and cardiovascular disease. The prevalence of NAFLD in
      Singapore is not known. However, given that the estimated percentage of adults with type II
      DM or obesity are approaching 10 % and rapidly rising, a significant proportion of the
      Singaporean population is likely at risk for NAFLD. Although there are drug therapies for
      diabetes; currently, there is no effective treatment for NAFLD.

      Although NAFLD may cause inflammation, lipotoxicity, and scarring within the liver, it also
      can have profound metabolic effects as it induces hepatic insulin resistance. Defects in
      β-oxidation of fatty acids are thought to play an important role in the pathogenesis of
      NAFLD, which then leads to further insulin resistance and worsened glycemic control in
      diabetic patients. Since thyroid hormones (THs: T3, T4) promote the oxidation of fatty acids
      within the liver, it is possible that ineffective TH action in the liver may contribute to
      NAFLD.

      It has been shown recently that the incidence of hypothyroidism is doubled in patients with
      NAFLD as approximately 15% patients are affected. Additionally, several TH and TH analogues
      are able to ameliorate NAFLD in rodents fed with high fat chow diets. At the genomic level,
      many of the genes that have altered expression in NAFLD are regulated by TH further
      supporting the notion that defects in TH signalling may promote hepatosteatosis and hepatic
      damage. Two recent studies also have shown thyroid hypo-function in both young and elderly
      adults with NAFLD.

      In this study, we seek to examine whether short-term low dose levothyroxine can decrease
      hepatic fat deposition and improve glucose control in diabetic patients with NAFLD.

      Accordingly, we plan to treat 50 male patients with stable Type II DM and NAFLD with low dose
      LT4, and assess fat content in the liver by MRI and glucose control by measuring serum
      fasting glucose, HbA1c, and degree of insulin resistance as determined by the homeostatic
      model assessment (HOMA-IR). The potential benefit for the patient will be reduction of
      hepatic fat content and/or improvement in glucose control. The potential major side effects
      are atrial arrhythmias and osteoporosis. The risk for the latter side effects will be
      minimized by treating subjects that do not have any known heart disease or osteoporosis with
      low dose levothyroxine. It is expected that thyroid hormone levels will be in the high normal
      range. Patient will undergo hepatic MRI at beginning of study and at 16 weeks and phlebotomy
      at beginning of study, at 8 weeks, and at 16 weeks. The study will be conducted in compliance
      with the protocol, Singapore Guideline for Good Clinical Practice (SGGCP), site's respective
      Institutional Review Board (IRB), and Health Science Authority (HSA) requirements.

      Preliminary Studies:To investigate the potential etiological role of TH in hepatosteatosis,
      we initiated studies in which human liver HepG2 cells over-expressing TH receptors (TRs) were
      treated with palmitate in the absence or presence of T3. In this cell culture model of NAFLD,
      the uptake of palmitate and the intracellular accumulation of fatty acids caused apoptosis in
      the absence of hormone. Surprisingly, T3 treatment blocked the palmitate-induced apoptosis.
      Additionally, our studies suggest that part of this protective effect by T3 is due to
      induction of "lipophagy", a type of autophagy in which cells consume and digest fatty acids
      before delivery to mitochondria. Concomitantly, we have observed induction of cpt1a mRNA, a
      protein which transports fatty acids to mitochondria. Our findings suggest that T3 may
      facilitate both the consumption and β oxidation of fatty acids within the hepatocyte. If this
      is the case, and when taken together with previous findings, our data would suggest the liver
      may be particularly susceptible to lipid accumulation and damage in hypothyroidism.
      Additionally, NAFLD itself may engender a "relative hypothyroid" state within the liver -
      resulting in impaired responsiveness of key metabolic target genes to TH. Thus, it is
      possible that TH, or TH analogues may be useful in the treatment and prevention of NAFLD.

      Our cell culture and in vivo data, in combination with previous studies in rodents showing
      that T3 and its analogues may be able to decrease hepatosteatosis and evidence that TH action
      may be decreased in human liver in obese patients undergoing gastric bypass and in patients
      with NAFLD, provide the experimental rationale to examine whether short-term levothyroxine
      therapy can decrease hepatosteatosis in Type II diabetic patients and improve glycemic
      control in Type II diabetic patients with NAFLD.

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

      Primary Objective:

      - 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.

      Secondary Objective:

        -  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 in Type II diabetic patients with
           NAFLD as measured by reduction in glycosylated hemoglobin (HbA1c).

        -  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 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).

        -  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.

      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)

      Inclusion and exclusion criteria are mentioned in the eligibility section.

      Randomization: This is an open-labeled, single arm study.

      Study protocol: After giving informed consent the subjects will undergo screening laboratory,
      abdominal imaging, ECG, review of medical history, medications for the past 6 months, and
      physical examination to determine eligibility. Once enrolled into the study the subjects will
      be treated with low dose LT4. There will be a titration phase of 12 weeks wherein the
      levothyroxine will be titrated to attain a TSH level between 0.34-1.70 mIU/L. It is possible
      that the desired TSH level may be achieved earlier than 12 weeks. It will not be considered
      protocol deviation if the 12-week titration period is not completed due to achieving the
      target TSH level earlier after following the defined titration method.

      Subjects will undergo MRI/MRS at the beginning and end of study to assess changes in fatty
      liver content and changes in abdominal subcutaneous and visceral adipose tissue volumes. All
      study related liver MRI/MRS will be done at the Clinical Imaging Research Centre (CIRC) and
      will be read by a single imaging expert to minimize inter-reader variability.

      Fasting glucose, HbA1c, insulin resistance, and lipid profile will also be ascertained before
      and after treatment. These tests will be done at respective institutions where the subject is
      recruited. The degree of insulin resistance will be determined using HOMA-IR which can be
      calculated easily online at www.hcvsociety.org/files/HOMACalc.html.

      All subjects will still receive the standard care of treatment for NAFLD which is life style
      modification such as weight loss through diet and regular exercise. At each follow-up visit
      (visits 5 - 9), the investigator will solicit information from the subject on the latter's
      dietary and exercise habits and will counsel the subject accordingly on life style
      modification. BMI will be monitored during each follow-up visit. The random glucose and hbA1c
      tests will be done during each follow-up visit (visits 5-8) to monitor diabetes status. The
      subjects will also be encouraged to continue their diabetes follow-up.

      Treatment: Titration of thyroxine is complicated and safety is paramount. Subjects will have
      their LT4 dose adjusted and monitored by highly-trained board-certified endocrinologists
      participating in this study. Investigators are provided with tables indicating the initial
      dosing and titration based on measured TSH values and timelines for subsequent TSH
      measurement. The investigators are authorized to exercise discretion to LT4 titration on case
      by case basis.

      Study Duration: Maximum of 28 weeks: 12 weeks of pre-study drug titration and 16 weeks on
      low-dose LT4.

      Statistical Analysis: Our primary endpoint is the absolute change in liver fat content from
      baseline after 16-week administration of LT4. Secondary endpoints are changes in HbA1c, total
      serum cholesterol, HDL, LDL and total triglycerides from baselines. The absolute change in
      liver fat content from baseline will be analyzed using one-sample two-sided t-test at a 5 %
      significance level. The same test will be applied to secondary endpoints.

      For the primary endpoint and secondary endpoints, mean, standard deviation and 95 %
      confidence interval will be provided. Demographic and baseline data will be summarized with
      mean and standard deviation for continuous variables such as age, and count and proportion in
      each category for categorical variables such as gender and race. Adverse events and serious
      adverse events will be tabulated.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single arm study.
primary purpose: Treatment
masking: None (Open Label)
measure: Liver fat content
time frame: 16 weeks
description: 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.
measure: HbA1c
time frame: 16 weeks
description: 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.
measure: Lipid profile
time frame: 16 weeks
description: 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.
measure: Abdominal fat
time frame: 16 weeks
description: 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.
arm group label: Levothyroxine (LT4)
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Levothyroxine Sodium
arm group label: Levothyroxine (LT4)
other name: H03AA01
criteria: 
gender: Male
minimum age: 21 Years
maximum age: 60 Years
healthy volunteers: No
last name: Paul M Yen, MD
role: Principal Investigator
affiliation: Duke-NUS Graduate Medical School
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.
PMID: 21708823
citation: 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
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. doi: 10.2337/diabetes.54.12.3541.
PMID: 16306373
citation: 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
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. doi: 10.1590/s0004-28032010000200009.
PMID: 20721461
citation: 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
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.
PMID: 18434432
citation: 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
citation: 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
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.
PMID: 21521285
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.
PMID: 21559749
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.
PMID: 22684107
responsible party type: Principal Investigator
investigator affiliation: Duke-NUS Graduate Medical School
investigator full name: Paul M. Yen
investigator title: Professor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
sharing ipd: No