Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-Center, Randomized, Placebo Controlled, Double Blind Trial of Metformin in Obese Adolescents.
Brief Summary: This study will determine if the drug metformin, coupled with diet and exercise counseling, will help obese adolescents lose weight.


Options:
A: Inclusion Criteria:

* Subject's body mass index (BMI) was \>= 27 kg/m(2) and \<= 45 kg/m(2) or their BMI was \>= 25 kg/m(2) and \< 27 kg/m(2) with waist circumference of \>= 102 cm in males or \>= 88 cm in females.
* Medical history positive for:

  * Preexisting cardiovascular disease (i.e., coronary artery disease, cerebrovascular disease, or peripheral arterial occlusive disease) and/or
  * Type 2 diabetes mellitus with at least 1 other risk factor (i.e., dyslipidemia, controlled hypertension, current smoker, or diabetic nephropathy with evidence of microalbuminuria)

Exclusion Criteria:

* History of recent myocardial infarction.
* Heart failure symptoms greater than New York Heart Association Functional Class II.
* Hemodynamically significant valvular or left ventricular (LV) tract obstruction.
* Subjects without a pacemaker and with any of the following:

  * Sinus bradycardia (\< 50 bpm)
  * Sick sinus syndrome
  * Atrioventricular block of more than 1st degree
* Mean sitting systolic blood pressure (SBP) \> 160 mmHg. Mean sitting diastolic blood pressure (DBP) \> 100 mmHg. Mean sitting heart rate (HR) \> 100 bpm.
* Syncopal episodes presumed to be due to uncontrolled life-threatening arrhythmias.
* Planned cardiac surgery or coronary angioplasty within 6 months of screening.
* History of recent non-hemorrhagic stroke or transient ischemic attack (TIA), history of hemorrhagic stroke.
* Hyperthyroidism.
* Known chronic liver disease or endstage renal disease.
* Severe, symptomatic benign prostatic hyperplasia which may require surgery.
* Known pheochromocytoma, history of narrow angle glaucoma, Gilles de la Tourette syndrome, history of seizures, history of bariatric or abdominal obesity surgery (excluding liposuction).
* Concomitant use of monoamine oxidase inhibitors or drugs that increase levels of serotonin in the brain.
* Treated hypertension stabilized for less than 3 months.
* Inability to perform regular physical activity.
B: Inclusion Criteria:

* Ages 7-18 years.
* Greater than the 95th percentile body mass index for their age and gender.
* Children are in Tanner Stage I or IV or V.
* Normal Blood Pressure.
* Normal fasting glucose.
* Normal lipids.
* Menstruating girls must have completed their most recent period at least 2 weeks prior to blood draw.
* No recent illness, no chronic illnesses, no routine medications, no smoking or alcohol intake.
* Must pass the screening test done in Protocol #1.
* Must have higher values than normal for certain blood tests related to heart disease that were measured in Protocol #1.

Exclusion Criteria:

* Chronic active illnesses.
* Recent illnesses.
* Use of routine medications, vitamins, herbal remedies, oral contraceptive pills, or other over the counter medications within 4 weeks of blood draw.
* History of recent or chronic smoking.
* Currently pregnant.
* Impaired fasting glucose.
* Dyslipidemia.
* Actively in puberty.
* Weight greater than 300 pounds.
* Metal in the abdomen.
* History of being overweight greater than 5 years.
C: Inclusion Criteria:

* Subjects must be between the ages of 13.00 and 17.99 at week 0 (Baseline).
* Subjects must have a BMI ≥ 95th percentile for age and gender using the CDC data (see Appendix), but must weigh less than 300 pounds (\<136 kilograms) when measured during the initial physical exam at week 0 (Baseline). BMI will be calculated as follows; weight in kilograms  \[height in meters\]2. This cutoff has been established due to the weight-bearing limits of the table used in performing the DXA scan. Once enrolled, if a subject's weight progresses above 300 pounds, s/he may continue in the study whether it is possible to perform DXA or not.
* Completion of informed consent/assent process

Exclusion Criteria:

* Known diabetes as defined by the American Diabetes Association criteria
* Prior drug therapy to treat diabetes or insulin insensitivity, including any form of insulin or insulin analogs; or any oral antidiabetic medication; acarbose, acetohexamide, chlorpropamide, glimepiride, glipizide, glyburide, metformin, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide or troglitazone.
* Prior use of drugs to aid in weight loss, including but not limited to: Benzphetamine Hcl, Diethylpropion Hcl, Fenfluramine Hcl, Phendimetrazine Tartrate, Phentermine Hcl, Orlistat, Sibutramine Hcl Monohydrate, Didrex, Tenuate, Pondimin, Bontril-SR, Adipex-P, Fastin, Ionamin, Phentrol, Xenical, Meridia.
* Subject is currently taking the following medications at the time of the Screening visit: Cimetidine, amiloride, digoxin, furosemide, morphine, nifedipine, procainamide, ranitidine, triamterene, trimethoprim, vancomycin and quinidine, as these medications may increase metformin levels.
* Subjects will be excluded from the study if they have taken prescription-strength glucocorticoids (by any route) within three months of the screening visit. Topical glucocorticoids are acceptable if their strength is no greater than the equivalent of 1% hydrocortisone cream.
* History of any syndrome or medical disorder associated with significant obesity, including but not limited to: Prader Willi Syndrome, Bardet-Biedl Syndrome, Cohen Syndrome, Cushing syndrome or disease.
* Prior surgical therapy for obesity
* Subject to be excluded if s/he has attended a formal weight loss program within 6 months prior to the Screening visit.
* In the 6 months prior to Screening, subject has consumed alcohol more frequently than twice per week and/or subject has had more than three alcohol-containing beverages in a 24 hour period.
* Elevated creatinine (\> 1.2 mg/dl)
* Untreated disorders of thyroid function
* Elevated liver enzymes (Alanine Aminotransferase \[ALT\] or Aspartate Aminotransferase \[AST\]) \> 80 (approximately 2 times upper limit of normal)
* Mobility impairment that prevents full participation in recommended physical activity
* Other serious medical condition that the Principal Investigator or Lead Site Investigator determines may put the patient at undue risk if enrolled in the study
* Unable to comply with the protocol in the opinion of the Principal Investigator or the Lead Site Investigator
* Subjects with child-bearing potential who are unwilling to remain abstinent or use an effective method of birth control
* Previous pregnancy
D: * INCLUSION CRITERIA:

Good general health. Individuals taking medications for obesity-related comorbid conditions will not be excluded.

Obesity: body mass index for age and triceps skinfold above the 95th percentile (determined by NHANES I age-, sex-, and race- specific data). All subjects will be required to be over 60 kg in body weight.

Evidence for a quantifiable obesity-related comorbidity. Examples include: systolic or diastolic hypertension (determined by age-specific charts); frank Type 2 diabetes, impaired glucose tolerance assessed by oral glucose tolerance testing; hyperinsulinemia (defined as a fasting insulin greater than 15 mIU/mL); significant hyperlipidemia (total cholesterol greater than 200 mg/dL, LDL cholesterol greater than 129 mg/dL or fasting triglycerides greater than 200 mg/dL); hepatic steatosis (SGPT or SGOT above normal range with negative hepatitis studies) or sleep apnea documented by a sleep study.

Age 12 to 17 years at the start of the study.

For girls with childbearing potential, a negative pregnancy test before taking and while taking study medication. Sexually active females must be using an effective form of birth control. These methods include total abstinence (no sex), oral contraceptives ("the pill"), an intrauterine device (IUD), levonogestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended.

Race of all four grandparents self-identified as either all Caucasian or all African American.

EXCLUSION CRITERIA:

Volunteers will be excluded (and referred to non-experimental treatment programs) for the following reasons:

Presence of renal, hepatic (other than obesity-related steatosis), gastrointestinal, most endocrinologic (e.g., Cushing syndrome), or pulmonary disorders (other than either asthma not requiring continuous medication or sleep apnea-related disorders);

Adolescent girls who are pregnant, who are currently nursing an infant, or who are having unprotected intercourse;

Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or other condition which, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study;

Subjects who regularly use prescription medications unrelated to the complications of obesity. Oral contraceptive use will be permitted, provided the contraceptive has been used for at least two months before starting study medication. The use of over-the-counter and prescription medications will be reviewed on a case-by-case basis; depending on the medication, subjects who have continued to take prescription medication for at least 3 months prior to study entry may be eligible;

Recent use (within six months) of anorexiant medications for the purpose of weight reduction;

Inability to undergo MRI (e.g., volunteers with metal within their bodies including cardiac pacemakers, neural pacemakers, aneurysmal clips, shrapnel, ocular foreign bodies, cochlear implants, non-detachable electronic or electromechanical devices such as infusion pumps, nerve stimulators, bone growth stimulators, etc. that are contraindications).

For pilot study participants, hypersensitivity or allergy to methylene blue. Individuals with documented G6PD deficiency will be excluded.

INCLUSION CRITERIA: HEALTHY CONTROL CHILDREN AND ADOLESCENTS:

Volunteers will qualify for inclusion if they meet the following criteria:

1. Good general health.
2. Age 12-17 years at study entry.
3. Body mass index (BMI) for age above the 5th percentile and below 85th percentile, which is considered normal weight by CDC growth chart standards.
4. For females with childbearing potential, a negative pregnancy test at initial evaluation.
5. Race of all four grandparents self-identified as either all Caucasian or all African American.

EXCLUSION CRITERIA: HEALTHY CONTROL CHILDREN AND ADOLESCENTS:

Volunteers will be excluded for the following reasons:

1. Presence of past or present medical problems which would impair performance during the exercise tests;
2. Females who are pregnant, or who are currently nursing an infant;
3. Individuals who have, or whose parent or guardian has, current substance abuse or a psychiatric disorder or other condition that in the opinion of the investigators would impede competence or possibly hinder completion of the study;
4. Recent weight change of more than 3% of body weight in the past two months;
5. Recent use (within six months) of anorexiant medications for the purpose of weight reduction;
6. Physical impairments that would prevent completion of either the walk/run test or the cycle test.

Answer: C