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Diabetes Mellitus, Type 2Phase 4METNODTHYRNCT04298684

Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules in Type 2 Diabetes

A Phase 4 study testing METFORMIN and Sitagliptin in people with Diabetes Mellitus, Type 2 and Thyroid Nodule (Benign), run by Centre Hospitalier Universitaire de la Guadeloupe at 4 sites in 3 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 65 years
What is being tested?
METFORMIN and Sitagliptin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
90 participants
Where
4 sitesin 3 countries
Study dates
1 Jan 2021to 1 Jul 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with T2DM aged 18 to 65 years;
  • Uncomplicated T2DM, evolving for less than 3 years;
  • Patients with HbA1c levels between 7 and 8% (after the run-in period)
  • Patients with at least one TN ≥ 2 cm non-cystic, whose benignity will be confirmed by a fine-needle aspiration cytology performed twice regardless of ultrasound TIRADS score;
  • Naive subjects of any treatment: never received an anti-diabetic treatment OR received an anti-diabetic treatment of less than 30 days since diagnosis OR did not receive an anti-diabetic treatment during the 30 days before screening;
  • Patients with a creatinine clearance > 60 ml/min;
  • Informed and written consent signed by the patient and the investigator;
  • Affiliation to the national social health system or equivalent.

Who cannot join

  • Subjects without adequate or impaired decisional abilities for consent to research and placed under guardianship, trusteeship or safeguard of justice
  • Pregnant or breastfeeding woman
  • Woman of childbearing potential without effective contraception (estroprogestative, presentative, intrauterine device)
  • Suspect thyroid nodules in ultrasound (TIRADS 4 to 5) with confirmation after a fine-needle aspiration cytology;
  • Thyroid function abnormalities or a history of thyroid disease;
  • Thyroid nodules whose size or symptoms (compressive signs) require surgery
Show all 25Show fewer
  • Ioduria <100ug /L
  • Thyroid autoimmunity: positive anti-peroxidase, thyroglobulin or anti-TSH receptors antibodies
  • Levothyroxine treatment
  • History of cervical radiotherapy or thyroid surgery
  • Type 1 diabetes
  • Insulin deficiency
  • History of hypersensitivity to one of the active substances
  • History of pancreatitis
  • Obesity linked to endocrine disease
  • Presence of severe complications of T2DM (ischemic heart disease, heart failure with reduced left ventricular ejection fraction, severe lower extremity arteritis, gangrene, retinopathy, end-stage renal failure, cerebrovascular accident)
  • HbA1c levels > 8% after the run-in period
  • Liver diseases (liver failure, cirrhosis, viral hepatitis B or C)
  • Acute alcoholic intoxication, chronic alcoholism
  • Psychiatric diseases (depression, schizophrenia)
  • Neurological diseases (epilepsy, demyelinating diseases, etc.)
  • Treatment influencing the morphology or thyroid function: corticosteroids, lithium, iodized products etc. ...
  • Acute conditions that may impair renal function such as: dehydration, severe infection, shock
  • Respiratory failure
  • Metabolic acidosis

Trial locations and contacts

4 sites in 3 countries.

Valerie VS HAMONY SOTER contact

+590590934686

valerie.soter@chu-guadeloupe.fr

Mélanie MP PETAPERMAL contact

melanie.petapermal@chu-guadeloupe.fr

4 sites in 3 countries

France2 sites

  • CHU Bordeaux

    Bordeaux, 33000

    Bogdan BC CATARGI, MD PhD, bogdan.catargi@chu-bordeaux.fr

  • CHU Limoges

    Limoges, 87042

    Marie-Pierre MT TEISSIER, M.D. Ph D, +335 55 05 68 51, marie-pierre.teissier@chu-limoges.fr

Other trials in France

Guadeloupe1 site

  • University Hospital Center of Guadeloupe

    Pointe-à-Pitre, 97159

    Valérie VS SOTER, Project Manager, 0590 93 46 86, valerie.soter@chu-guadeloupe.fr

    Melanie MP PETAPERMAL, Monito manager, 0590 93 46 86, melanie.eptapermal@chu-guadeloupe.fr

Other trials in Guadeloupe

Reunion1 site

  • CHU de la Réunion

    Saint-Pierre, 97400

    Xavier XD DEBUSSCHE, MD PHD, xavier.debussche@chu-reunion.fr

Other trials in Reunion

About this study

Official title: Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules Size in Type 2 Diabetes: a 2-years Prospective Multicentric Study

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.

Read the detailed description

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.

Being tested
METFORMIN, Sitagliptin
Keywords
type 2 diabetes mellitus, thyroid nodule, metformin, insulin resistance
Medical subject headings
Diabetes Mellitus, Type 2, Thyroid Nodule, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • METFORMINDrug

    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.

  • SitagliptinDrug

    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.

Study groups in NCT04298684
Study groupRoleWhat they receive
MetforminExperimentalIn 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.
Receives: Drug: METFORMIN
SitagliptinPlacebo comparatorIn arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months.
Receives: Drug: Sitagliptin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 24 months

Secondary outcomes (8)

  1. Percentage of thyroid surgery observed in each group at 2 years.

    Record the number of thyroid surgeries performed after inclusion for 2 years

    Measured: 24 months after treatment initiation

  2. Number of new TN (≥ 10mm) after 2 years of follow-up

    Detection of new TN (≥ 10mm) by thyroid ultrasonography. The operator will be the same throughout the follow-up and in each center

    Measured: Baseline and 24 months after treatment initiation

  3. 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):

    • Men - greater than 40 inches (102 cm)
    • Women - greater than 35 inches (88cm) Triglycerides plasmatic levels greater than or equal to 150 mg/dL (1.7 mmol/L)

    HDL cholesterol :

    • Men - Less than 40 mg/dL (1.03 mmol/L)
    • Women - Less than 50 mg/dL (1.29 mmol/L) Blood pressure greater than or equal to 130/85 mm Hg Fasting glucose greater than or equal to 110 mg/dL (6.1 mmol/L)

    Measured: Baseline, every 6 months after treatment initiation until 24 months

  4. 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

    Measured: Baseline, every 6 months after treatment initiation until 24 months

  5. Proportion of subjects with improvement of adipokine concentrations

    Among the adipokines, we will measure the plasmatic Leptin, Adiponectin and Vifastin levels

    Measured: Baseline and 24 months after treatment initiation

  6. 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

    Measured: Baseline, every 6 months after treatment initiation until 24 months

  7. 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.

    Measured: through study completion, an average of 1 year

  8. 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.

    Measured: through study completion, an average of 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Mar 2020
  2. Study start1 Jan 2021 (estimated)
  3. Primary completion1 Feb 2022 (estimated)
  4. Study completion1 Jul 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
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.
Masking
None (open label)
Enrolment
90 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04298684
Sponsor's protocol ID
PAP_RI1_2019/1
Other IDs
2019-000676-42, 2019
Acronym
METNODTHYR
Status last verified
Sep 2020
First submitted
5 Feb 2020
Last updated
11 Sep 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 23395200

  • 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.

    PubMed 19633072

  • Barbesino G. Drugs affecting thyroid function. Thyroid. 2010 Jul;20(7):763-70. doi: 10.1089/thy.2010.1635.

    PubMed 20578900

  • 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.

    PubMed 27987248

  • Chen G, Xu S, Renko K, Derwahl M. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 2012 Apr;97(4):E510-20. doi: 10.1210/jc.2011-1754. Epub 2012 Jan 25.

    PubMed 22278418

  • 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.

    PubMed 2480830

  • 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.

    PubMed 19860577

  • 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.

    PubMed 25734734

  • 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.

    PubMed 26154837

  • 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.

    PubMed 16950706

  • 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.

    PubMed 9839117

  • 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.

    PubMed 29858981

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9. doi: 10.1007/BF00280883.

    PubMed 3899825

  • 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.

    PubMed 12525244

  • 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.

    PubMed 28196954

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing METFORMIN and Sitagliptin in people with Diabetes Mellitus, Type 2 and Thyroid Nodule (Benign), run by Centre Hospitalier Universitaire de la Guadeloupe at 4 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 11 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in France, Guadeloupe, Reunion. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Valerie VS HAMONY SOTER (+590590934686, valerie.soter@chu-guadeloupe.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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. (time frame: 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04298684, which also lists 24 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2020.

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