Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
Primary Purpose
Pediatric Obesity, Insulin Resistance, Hyperinsulinemia
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Pediatric Obesity focused on measuring Pediatric Obesity, Insulin Resistance, Hyperinsulinemia, Metformin, Glucose Tolerance, Microalbuminuria, Adolescents, Visceral Fat
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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
- 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)
Sites / Locations
- Yale Center for Clinical Investigation (YCCI)
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
1
2
Arm Description
Outcomes
Primary Outcome Measures
Assessment of insulin sensitivity: Whole Body Insulin Sensitivity Index (WBISI), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and Euglycemic hyperinsulinemic clamp
Secondary Outcome Measures
Body mass index (BMI)
Waist to hip circumference ratio
Muscle lipid content
Total body fat
Abdominal fat mass
Hepatic fat fraction
Hepatic iron concentration
Plasma ghrelin levels
Adiponectin levels
Leptin levels
Blood pressure
Lipid profile
Microalbuminuria
Inflammatory markers (Plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), homocysteine, tumor necrosis factor (TNF)-α, Interleukin (IL)-6)
Self-paced step test (Heart rate recovery after exercise)
Peripheral Arterial Tonometry (PAT)
Females only: Markers of polycystic ovarian syndrome (PCOS) - Adrenal androgens (17 Hydroxyprogesterone, Dehydroepiandrosterone), sex hormone binding globulin (SHBG), free testosterone, LH/FSH ratio
Females only: Menstrual pattern
Ethnic stratification (Hispanic, African American or Caucasian)
Full Information
NCT ID
NCT00667498
First Posted
April 24, 2008
Last Updated
February 16, 2009
Sponsor
Yale University
Collaborators
National Institutes of Health (NIH)
1. Study Identification
Unique Protocol Identification Number
NCT00667498
Brief Title
Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
Official Title
Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
Study Type
Interventional
2. Study Status
Record Verification Date
February 2009
Overall Recruitment Status
Completed
Study Start Date
March 2004 (undefined)
Primary Completion Date
December 2007 (Actual)
Study Completion Date
December 2007 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
Yale University
Collaborators
National Institutes of Health (NIH)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Obesity, Insulin Resistance, Hyperinsulinemia
Keywords
Pediatric Obesity, Insulin Resistance, Hyperinsulinemia, Metformin, Glucose Tolerance, Microalbuminuria, Adolescents, Visceral Fat
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Title
2
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
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).
Secondary Outcome Measure Information:
Title
Body mass index (BMI)
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Waist to hip circumference ratio
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Muscle lipid content
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Total body fat
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Abdominal fat mass
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Hepatic fat fraction
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Hepatic iron concentration
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Plasma ghrelin levels
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Adiponectin levels
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Leptin levels
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Blood pressure
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Lipid profile
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Microalbuminuria
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Inflammatory markers (Plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), homocysteine, tumor necrosis factor (TNF)-α, Interleukin (IL)-6)
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Self-paced step test (Heart rate recovery after exercise)
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Peripheral Arterial Tonometry (PAT)
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Females only: Markers of polycystic ovarian syndrome (PCOS) - Adrenal androgens (17 Hydroxyprogesterone, Dehydroepiandrosterone), sex hormone binding globulin (SHBG), free testosterone, LH/FSH ratio
Time Frame
Baseline (month 0), post 3-month intervention (month 4), and post 6-month extension (month 10).
Title
Females only: Menstrual pattern
Time Frame
Throughout study
Title
Ethnic stratification (Hispanic, African American or Caucasian)
Time Frame
Baseline (month 0)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
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.
Exclusion Criteria:
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
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tania S Burgert, MD
Organizational Affiliation
Yale University Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale Center for Clinical Investigation (YCCI)
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06511
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
18761646
Citation
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.
Results Reference
result
Learn more about this trial
Metabolic Effect of Metformin in Obese Insulin Resistant Adolescents With Normal Glucose Tolerance
We'll reach out to this number within 24 hrs