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Pediatric ObesityPhase 4NCT00667498

Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance

A Phase 4 study testing Metformin in people with Pediatric Obesity and Insulin Resistance, run by Yale University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The primary objective of this randomized, parallel group, double-blind, placebo-controlled study is to determine whether treatment with metformin enhances insulin sensitivity in a group of ethnically diverse obese insulin-resistant adolescents with normal glucose tolerance. Read more about this study

Who is it for?
Ages 13 to 17 yearsHealthy volunteers can take part
What is being tested?
Metformin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
28 participants
Where
1 siteUnited States
Study dates
Mar 2004to Dec 2007
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 13 to 17 years
  • All sexes
  • Healthy volunteers accepted
  • Child

Who may be able to join

  • Attending weight management clinic at Yale New Haven Hospital
  • Good general health, taking no other medication on a chronic basis
  • Age 13 to 17 yrs in puberty (girls: breast Tanner stage II to IV, and boys: testes size > 6 ml)
  • The presence of insulin resistance, defined by fasting insulin levels greater than 30 µU/ml, and HOMA insulin resistance index > 6
  • Normal glucose tolerance based on a 2-hr plasma glucose (<140 mg/dl) after the OGTT.
  • All female subjects must have a negative urine pregnancy test during the study visits and must use an effective method of contraception if they are sexually active. Without their parent(s) present, all potential female subjects will be asked about their sexual activity and the specific form of contraception they are using.

Who cannot join

  • Baseline creatinine > 1.0 mg/dl
  • Hepatic disease with elevated liver function test (ALT or AST) ≥ 2 X the upper limits of normal
  • Pregnancy
  • Presence of other endocrinopathies; except treated hypothyroidism on stable replacement doses of thyroid hormone
  • Presence of cardiac, pulmonary or other significant chronic illness
  • Adolescents with psychiatric disorder, claustrophobia or with substance abuse
Show all 10Show fewer
  • Recent use (within six months) of anorexic agents
  • Presence of anemia (hematocrit < 35)
  • Mixed ethnic background (defined as two parents of different ethnicity)
  • Adolescents with metal implants (i.e. cardiac pace maker, metal prostheses, bullet remnants)

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Yale Center for Clinical Investigation (YCCI)

    New Haven, Connecticut, 06511

Other trials in United States

About this study

The primary objective of this randomized, parallel group, double-blind, placebo-controlled study is to determine whether treatment with metformin enhances insulin sensitivity in a group of ethnically diverse obese insulin-resistant adolescents with normal glucose tolerance.

Read the detailed description

First Visit

Patients who agree to participate in this research study, will have an initial screening where the subject will be asked about his/her health, a sample of blood will be drawn, the subject will be examined, and an oral glucose tolerance (OGTT) test will be done.

  • OGTT: The study takes about four hours and will begin on an "empty stomach." A small I.V. will be placed in a vein in the subject's arm. The I.V. will allow a member of the research team to take small amounts of blood for measuring glucose and other substances that circulate in the blood. About 7 tablespoons of blood will be drawn in total during the OGTT. The I.V. will remain in place all during the study. At the beginning of the study, the subject will be asked to drink about 8 ounces (one cup) of a high sugar cola- or orange-flavored drink.

If the subject meets all the requirements to be in the study and has a normal glucose tolerance test, he/she will be randomized to either the intensely (Euglycemic hyperinsulinemic clamp) or standard studied group and have the following six or seven tests performed: DEXA scan and Tanita, exercise step test, PAT test, MRI (Abdominal scan), MRS (leg scan), and Euglycemic hyperinsulinemic clamp (intensely studied group only). All of the tests are described below. Females will have a urine pregnancy test before each of these tests. If positive, the subject will not be allowed to participate/continue with the study.

  • DEXA / Tanita: The DEXA scan will measure how much muscle and fat is in the subject's body and how dense the subject's bones are using an x-ray technique. Directly after the DEXA Scan, the subject's percentage of body fat will be measured using a Tanita scale.
  • Exercise Step Test: The subject will be asked to step up and down two steps 20 times at their own pace. We will measure the subject's heart rate directly before and for three minutes after this exercise. After a ten minute break, the test will be repeated.
  • Peripheral Arterial Tonometry (PAT): This test will allow us to evaluate the response of the small blood vessels in the subject's arm to changes in nerve signals to them. During this test, we will put a probe (similar to a tight-fitting glove) on one finger of each of the subject's hands and take some measurements for about five minutes. The probes contain latex, so this test will not be performed on subjects who are allergic to latex. Following these measurements, we will block blood flow to one of the hands for five minutes by putting a blood pressure cuff on one of the arms and inflating the cuff. After the pressure in the cuff is released, we will take more measurements for about five minutes.
  • MRI (Belly Scan): Magnetic Resonance Imaging (MRI) will be used to take pictures of the subject's belly. These pictures will allow us to calculate how much fat the subject has just below the skin and how much fat is deeper inside the belly. We will also be able to estimate the percentage of fat in the subject's liver.
  • MRS (Leg scan): We will measure how much fat is in the subject's calf muscle using magnetic resonance spectroscopy (MRS).
  • Insulin, Glucose and Glycerol Infusion Study (Euglycemic hyperinsulinemic clamp): A small I.V. will be placed into a vein in each arm. One I.V. will be used to take out small amounts of blood for measuring the blood sugar and other substances that circulate in the blood. The other I.V. will be used to infuse insulin, glucose, and glycerol into the subject's blood. Insulin is a hormone that helps bring blood sugar into the cells. Glycerol is a component of fat that is normally present in a person's body.

This infusion will not affect the subject's blood sugar in a harmful manner. It will allow us to follow the release of glucose from the liver and glycerol from fat tissue.

The subject's blood sugar will be checked closely during the study by taking blood samples from the second I.V. Readings of the blood sugar on each sample will be made at the bedside. If the blood sugar starts to fall, it can be fixed right away. At the end of another three hours, the infusion will be stopped and the subject will eat a meal that will be provided for him/her. The infusion of glucose will be reduced while the subject is eating until the subject's blood sugar is stable. This test takes about 6 hours. The total amount of blood drawn during this test will be less than 8 tablespoons or about half a cup.

Indirect calorimetry is a way to measure how much sugar and fat a person is burning when we give insulin. Testing how much fat and sugar a subject burns is an important part of the insulin, glucose, and glycerol infusion study. Therefore we will ask the subject to wear a plastic hood (like an astronaut space helmet) before starting the infusion of insulin and at two other times during the study.

Taking Metformin or Placebo

Once the subject has completed the six (standard studied group) or seven (intensely studied group only) tests described above, as well as two urine tests for protein, he/she will be randomized to either:

  • Take Metformin; or
  • Take a placebo pill

The subject will begin by taking one pill (either Metformin or placebo) every day, just before supper. The dose will be slowly increased as follows:

Week 1: Before breakfast = 0 and Before supper = 1 (500mg); Week 2: Before breakfast = 1 (500mg) and Before supper = 1 (500mg); Week 3-14: Before breakfast = 1 (500mg) and Before supper = 2 (500mg)

The subject will be taking the pills for 3 1/2 months, during which time we will ask that he/she keep a diary of any complaints, problems, or symptoms. Neither the subject, the subject's doctor, nor any of the members of the research team will find out which pill the subject was taking until the end of the study.

Monthly Follow-up

Subjects will be asked to come back every month for a physical exam. We will measure their height, weight, and blood pressure each time. A urine pregnancy test will be done on all female participants at every visit. At the subject's first follow up visit we will draw a small amount of blood and run tests to make sure the subject is healthy. We will ask the subject and his/her parent about any symptoms that the subject has had, any pills that he/she might have missed taking, and the use of other medications. We will measure the subject's vitamin B12 level on his/her third follow up visit.

End of Study

About three months after the subject begins taking the Metformin or placebo pills, he/she will repeat the tests described above (oral glucose tolerance test, DEXA and Tanita, exercise step test, PAT test, MRI, and MRS). In the sub-group of participants who had the glucose, insulin, and glycerol infusion test, this will also be repeated at the end of the study.

Open Label Phase (Taking Metformin)

After the tests described above are completed, all participants (even if they had been assigned a placebo pill) will be given the choice of taking Metformin for the next six months. If the subject does choose to continue, we will continue to monitor him/her monthly, as described in the section above on monthly follow-up. At the end of the additional six months, we will repeat all the tests that the subject had at the beginning of the study. For the intensely studied group, this includes the insulin, glucose and glycerol infusion.

Being tested
Metformin, Placebo
Keywords
Pediatric Obesity, Insulin Resistance, Hyperinsulinemia, Metformin, Glucose Tolerance, Microalbuminuria, Adolescents, Visceral Fat
Medical subject headings
Pediatric Obesity, Insulin Resistance, Hyperinsulinism

What participants receive

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

  • MetforminDrug

    Also called Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet

    The subject will receive either metformin or placebo drug, given as 500mg tablets (or corresponding placebos) necessary to increase the dose incrementally over a three week period.

    The time it takes to incrementally increase the dose to the desired dose of 500mg in am and 1000mg in pm will count as intervention time. Both the metformin and placebo group will also be given a multivitamin with vitamin B12 to avoid potential anemia.

  • PlaceboDrug

    The subject will receive either metformin or placebo drug, given as 500mg tablets (or corresponding placebos) necessary to increase the dose incrementally over a three week period.

    The time it takes to incrementally increase the dose to the desired dose of 500mg in am and 1000mg in pm will count as intervention time. Both the metformin and placebo group will also be given a multivitamin with vitamin B12 to avoid potential anemia.

Study groups in NCT00667498
Study groupRoleWhat they receive
1ExperimentalNot described
Receives: Drug: Metformin
2Placebo comparatorNot described
Receives: Drug: Placebo

What is being measured

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

  1. Assessment of insulin sensitivity: Whole Body Insulin Sensitivity Index (WBISI), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and Euglycemic hyperinsulinemic clamp

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

Secondary outcomes (19)
  1. Body mass index (BMI)

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  2. Waist to hip circumference ratio

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  3. Muscle lipid content

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  4. Total body fat

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  5. Abdominal fat mass

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  6. Hepatic fat fraction

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  7. Hepatic iron concentration

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  8. Plasma ghrelin levels

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  9. Adiponectin levels

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  10. Leptin levels

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  11. Blood pressure

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  12. Lipid profile

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  13. Microalbuminuria

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  14. Inflammatory markers (Plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), homocysteine, tumor necrosis factor (TNF)-α, Interleukin (IL)-6)

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  15. Self-paced step test (Heart rate recovery after exercise)

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  16. Peripheral Arterial Tonometry (PAT)

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  17. Females only: Markers of polycystic ovarian syndrome (PCOS) - Adrenal androgens (17 Hydroxyprogesterone, Dehydroepiandrosterone), sex hormone binding globulin (SHBG), free testosterone, LH/FSH ratio

    Measured: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).

  18. Females only: Menstrual pattern

    Measured: Throughout study

  19. Ethnic stratification (Hispanic, African American or Caucasian)

    Measured: Baseline (month 0)

Timeline

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

  1. First posted28 Apr 2008 (estimated)
  2. Study startMar 2004
  3. Primary completionDec 2007
  4. Study completionDec 2007

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
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00667498
Sponsor's protocol ID
0311026134
Status last verified
Feb 2009
First submitted
24 Apr 2008
Last updated
18 Feb 2009
Results posted
No
Data monitoring committee
No

Publications

  • Burgert TS, Duran EJ, Goldberg-Gell R, Dziura J, Yeckel CW, Katz S, Tamborlane WV, Caprio S. Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance. Pediatr Diabetes. 2008 Dec;9(6):567-76. doi: 10.1111/j.1399-5448.2008.00434.x. Epub 2008 Aug 27.

    PubMed 18761646

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Metformin in people with Pediatric Obesity and Insulin Resistance, run by Yale University at 1 site in United States.

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 6 inclusion and 10 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: finished, as of the sponsor's last update on 18 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Assessment of insulin sensitivity: Whole Body Insulin Sensitivity Index (WBISI), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and Euglycemic hyperinsulinemic clamp (time frame: Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).). 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 NCT00667498, which also lists 1 linked publication.

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 18 Feb 2009.

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