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| ID | Type | Description | Link |
|---|---|---|---|
| 2019-000676-42 | EudraCT Number |
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A 2-years prospective, randomized and multicentric study will be performed to assess the efficacy of metformin compared to sitagliptin on benign thyroid nodules size ≥ 2 cm, in newly diagnosed patients with type 2 diabetes.
Previous studies reported that prevalence of thyroid nodules (TN) is increased in patients with insulin resistance (IR) and type 2 diabetes mellitus (T2DM). However, there are no guidelines for the management of TN in this target population. In 2013, the French National Health Insurance reported that thyroid surgery procedures for benign nodules have increased unjustifiably. The impact of such surgery on the patients could be serious, with psychological repercussions and risks of surgical complications and the need of a substitutive lifetime hormonal treatment. The investigators hypothesize that metformin may reduce the need of TN surgery by decreasing benign TN size through a reduction of IR profile. A 2-years multicentric prospective study will be conducted to compare efficacy of metformin versus sitagliptin on benign thyroid nodules size in patients with initial benign thyroid nodules ≥ 2 cm. The percentage of thyroid surgery avoided, IR profile measured by Homeostasis Model Assessment of Insulin Resistance-Index (HOMA-IR-index) and adipokines concentrations will be also collected at inclusion ad at 2 years. The Primary outcome will be the percentage of patients in each group who had at least a 20% decrease in one or more nodules of more than 2 cm at 2 years. Several secondary outcomes will be registered: percentage of thyroid surgery observed in each group at 2 years, number of new TN (≥ 10mm) after 2 years of follow-up , percentage of metabolic syndrome before and after treatment, proportion of subjects with improvement of the HOMA-IR index and adipokine concentrations, plasmatic thyroid-stimulating hormone (TSH), T4 and T3 levels evolution, percentage of insulin like growth factor-1 (IGF-1) and adiponectin receptor expression in thyroid tissues after TN surgery.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metformin | Experimental | In arm 1, the subjects will receive metformin at the initial dose of 500mg x 2 / day, which will be increased weekly to 500mgx3 / day and then 1gx2 / day in order to obtain the minimum effective dose on glycemic control. |
|
| Sitagliptin | Placebo Comparator | In arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| METFORMIN | Drug | After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). A follow-up schedule will be given to the included patient for future visits. thyroid ultrasonography to analyze the TN evolution in the 2 groups. In arm 1, the subjects will receive metformin at the initial dose of 500mg x 2 / day, which will be increased weekly to 500mgx3 / day and then 1gx2 / day in order to obtain the minimum effective dose on glycemic control. In case of intolerance, the tolerated and effective dose will be taken back provided an effective glycemic control. A classic follow-up will be done every 3 months. Thyroid US and measure of HOMA-IR index will be done every 6 months for 2 years. If the goal of HbA1c will not achieved, a treatment with glicazide will be introduced. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of patients in each group who had at least a 20% decrease in one or more nodules of more than 2 cm at 2 years. | Size : The reduction of TN will be evaluated by thyroid ultrasonography. The operator will be the same throughout the follow-up and in each center, with an evaluation every 6 months. A measurement and precise analysis of the TN will be performed. If a TIRADS 4 or 5 classification is described , a new fine-needle aspiration cytology will be performed. A final thyroid ultrasonography evaluation will be performed at 2 years in order to allow the comparison of TN sizes from the pre-inclusion period to the final period. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of thyroid surgery observed in each group at 2 years. | Record the number of thyroid surgeries performed after inclusion for 2 years | 24 months after treatment initiation |
| Number of new TN (≥ 10mm) after 2 years of follow-up |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Valerie VS HAMONY SOTER | Contact | +590590934686 | valerie.soter@chu-guadeloupe.fr | |
| Mélanie MP PETAPERMAL | Contact | melanie.petapermal@chu-guadeloupe.fr |
| Name | Affiliation | Role |
|---|---|---|
| Fritz-Line FLV VELAYOUDOM, MD | CHU de la Guadeloupe | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Bordeaux | Bordeaux | 33000 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23395200 | Background | Anil C, Akkurt A, Ayturk S, Kut A, Gursoy A. Impaired glucose metabolism is a risk factor for increased thyroid volume and nodule prevalence in a mild-to-moderate iodine deficient area. Metabolism. 2013 Jul;62(7):970-5. doi: 10.1016/j.metabol.2013.01.009. Epub 2013 Feb 5. | |
| 19633072 | Background | Ayturk S, Gursoy A, Kut A, Anil C, Nar A, Tutuncu NB. Metabolic syndrome and its components are associated with increased thyroid volume and nodule prevalence in a mild-to-moderate iodine-deficient area. Eur J Endocrinol. 2009 Oct;161(4):599-605. doi: 10.1530/EJE-09-0410. Epub 2009 Jul 24. |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D016606 | Thyroid Nodule |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D014230 |
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Multicenter, prospective open-label study evaluating the efficacy of metformin compared to sitagliptin on benign TN growth in subjects with T2DM. After written approval, subjects with T2DM who meet the eligibility criteria will have a thyroid ultrasound. Subjects with TN of at least 2 cm and 2 benign cytology results after fine-needle aspiration, will be included after a run-in period of 1 month with a daily basal insulin therapy in order to reduce glucotoxicity. If the Hb1Ac levels remain above 8%, the subjects will not be included. After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). In both cases, the standard nutritional care and physical activity recommendations (150 minutes of physical activity per week) will be recalled. If HbA1c levels > 8% during the follow-up, treatment by gliclazide will be introduce (LP30mg). A follow-up schedule will be given to the included patient for future visits.
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|
| Sitagliptin | Drug | After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). A follow-up schedule will be given to the included patient for future visits. thyroid ultrasonography to analyze the TN evolution in the 2 groups. In arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months. Thyroid US and measure of HOMA-IR index will be done every 6 months for 2 years. If the goal of HbA1c will not achieved, a treatment with glicazide will be introduced. |
|
Detection of new TN (≥ 10mm) by thyroid ultrasonography. The operator will be the same throughout the follow-up and in each center
| Baseline and 24 months after treatment initiation |
| Change between percentage of metabolic syndrome before and after treatment according to the NCEP ATP III definition | Central or abdominal obesity (measured by waist circumference):
HDL cholesterol :
| Baseline, every 6 months after treatment initiation until 24 months |
| Proportion of subjects with improvement of the HOMA-IR index | The HOMA index will be measured after calculation the ratio between the [fasting plasma insulin (Mu / L) X Fasting plasma glucose (mmol / l)] / 22.5 | Baseline, every 6 months after treatment initiation until 24 months |
| Proportion of subjects with improvement of adipokine concentrations | Among the adipokines, we will measure the plasmatic Leptin, Adiponectin and Vifastin levels | Baseline and 24 months after treatment initiation |
| Plasmatic thyroid hormon levels | these dosages will allow us to evaluate the changes in the functioning of the nodular thyroid gland during follow-up under either treatment | Baseline, every 6 months after treatment initiation until 24 months |
| Percentage of IGF-1 receptor expression in thyroid tissues after TN surgery | The analysis of the tissue expression of IGF1 receptors will be performed on thyroid samples after surgery if performed. One sample will be frozen and another will be included in paraffin for further analysis. IGF1 receptors are involved in the insulin and glucose metabolism signaling pathways. Analysis of their expression could help us to understand the possible links between insulin resistance and thyroid nodule. | through study completion, an average of 1 year |
| Percentage of adiponectin receptor expression in thyroid tissues after TN surgery | The analysis of the tissue expression of adiponectin receptor will be performed on thyroid samples after surgery if performed. One sample will be frozen and another will be included in paraffin for further analysis. Adiponectin receptor are involved in the insulin and glucose metabolism signaling pathways. Analysis of their expression could help us to understand the possible links between insulin resistance and thyroid nodule. | through study completion, an average of 1 year |
| CHU Limoges | Limoges | 87042 | France |
|
| University Hospital Center of Guadeloupe | Pointe-Ã -Pitre | 97159 | Guadeloupe |
|
| CHU de la Réunion | Saint-Pierre | 97400 | Reunion |
|
| 20578900 | Background | Barbesino G. Drugs affecting thyroid function. Thyroid. 2010 Jul;20(7):763-70. doi: 10.1089/thy.2010.1635. |
| 27987248 | Background | Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab. 2017 Apr;19(4):473-481. doi: 10.1111/dom.12854. Epub 2017 Feb 22. |
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| 2480830 | Background | Clemmons DR. Structural and functional analysis of insulin-like growth factors. Br Med Bull. 1989 Apr;45(2):465-80. doi: 10.1093/oxfordjournals.bmb.a072335. |
| 19860577 | Background | American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer; Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19(11):1167-214. doi: 10.1089/thy.2009.0110. |
| 25734734 | Background | Durante C, Costante G, Lucisano G, Bruno R, Meringolo D, Paciaroni A, Puxeddu E, Torlontano M, Tumino S, Attard M, Lamartina L, Nicolucci A, Filetti S. The natural history of benign thyroid nodules. JAMA. 2015 Mar 3;313(9):926-35. doi: 10.1001/jama.2015.0956. |
| 26154837 | Background | Hazel-Fernandez L, Xu Y, Moretz C, Meah Y, Baltz J, Lian J, Kimball E, Bouchard J. Historical cohort analysis of treatment patterns for patients with type 2 diabetes initiating metformin monotherapy. Curr Med Res Opin. 2015;31(9):1703-16. doi: 10.1185/03007995.2015.1067194. Epub 2015 Aug 27. |
| 16950706 | Background | Junik R, Kozinski M, Debska-Kozinska K. Thyroid ultrasound in diabetic patients without overt thyroid disease. Acta Radiol. 2006 Sep;47(7):687-91. doi: 10.1080/02841850600806308. |
| 9839117 | Background | Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care. 1998 Dec;21(12):2191-2. doi: 10.2337/diacare.21.12.2191. No abstract available. |
| 29858981 | Background | Liu MZ, He HY, Luo JQ, He FZ, Chen ZR, Liu YP, Xiang DX, Zhou HH, Zhang W. Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives. Arch Pharm Res. 2018 Jul;41(7):725-736. doi: 10.1007/s12272-018-1039-x. Epub 2018 Jun 1. |
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| 12525244 | Background | Menendez C, Baldelli R, Camina JP, Escudero B, Peino R, Dieguez C, Casanueva FF. TSH stimulates leptin secretion by a direct effect on adipocytes. J Endocrinol. 2003 Jan;176(1):7-12. doi: 10.1677/joe.0.1760007. |
| 28196954 | Background | Meng X, Xu S, Chen G, Derwahl M, Liu C. Metformin and thyroid disease. J Endocrinol. 2017 Apr;233(1):R43-R51. doi: 10.1530/JOE-16-0450. Epub 2017 Feb 14. |
| 15562188 | Background | Pladevall M, Williams LK, Potts LA, Divine G, Xi H, Lafata JE. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care. 2004 Dec;27(12):2800-5. doi: 10.2337/diacare.27.12.2800. |
| 19320560 | Background | Rezzonico JN, Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H. Increased prevalence of insulin resistance in patients with differentiated thyroid carcinoma. Metab Syndr Relat Disord. 2009 Aug;7(4):375-80. doi: 10.1089/met.2008.0062. |
| 18346005 | Background | Rezzonico J, Rezzonico M, Pusiol E, Pitoia F, Niepomniszcze H. Introducing the thyroid gland as another victim of the insulin resistance syndrome. Thyroid. 2008 Apr;18(4):461-4. doi: 10.1089/thy.2007.0223. |
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| D004700 | Endocrine System Diseases |
| D013964 | Thyroid Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D006258 | Head and Neck Neoplasms |
| D013959 | Thyroid Diseases |
| D006946 | Hyperinsulinism |
| Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |