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

September 10, 2020 updated by: Centre Hospitalier Universitaire de Pointe-a-Pitre

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

90

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin
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.
Drug: METFORMIN

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.
Placebo Comparator: Sitagliptin
In arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months.
Drug: Sitagliptin

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
Time Frame: 24 months
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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of thyroid surgery observed in each group at 2 years.
Time Frame: 24 months after treatment initiation
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
Time Frame: Baseline and 24 months after treatment initiation
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
Time Frame: Baseline, every 6 months after treatment initiation until 24 months

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)
Baseline, every 6 months after treatment initiation until 24 months
Proportion of subjects with improvement of the HOMA-IR index
Time Frame: Baseline, every 6 months after treatment initiation until 24 months
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
Time Frame: Baseline and 24 months after treatment initiation
Among the adipokines, we will measure the plasmatic Leptin, Adiponectin and Vifastin levels
Baseline and 24 months after treatment initiation
Plasmatic thyroid hormon levels
Time Frame: Baseline, every 6 months after treatment initiation until 24 months
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
Time Frame: through study completion, an average of 1 year
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
Time Frame: through study completion, an average of 1 year
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire de Pointe-a-Pitre

Investigators

  • Study Director: Fritz-Line FLV VELAYOUDOM, MD, CHU de la Guadeloupe

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

January 1, 2021

Primary Completion (Anticipated)

February 1, 2022

Study Completion (Anticipated)

July 1, 2024

Study Registration Dates

First Submitted

February 5, 2020

First Submitted That Met QC Criteria

March 4, 2020

First Posted (Actual)

March 6, 2020

Study Record Updates

Last Update Posted (Actual)

September 11, 2020

Last Update Submitted That Met QC Criteria

September 10, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PAP_RI1_2019/1
  • 2019-000676-42 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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