Metformin to Treat Obesity in Children With Insulin Resistance

NCT00005669 | Completed Phase 2 Results DMC

• 2 other identifiers: 00013400-CH-0134
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine the safety and effectiveness of the medicine metformin to help overweight children control their food intake, weight, insulin, cholesterol, and triglyceride (blood fat) levels. Obesity and high insulin levels can lead to high blood pressure, diabetes, high cholesterol and triglyceride levels and heart disease. Metformin-approved by the Food and Drug Administration to treat adults with type 2 diabetes mellitus-helps lower insulin levels and may control weight gain in adults. Overweight children 6 to 11 years old who are in general good health may be eligible for this study. Children will be studied at the National Institutes of Health in Bethesda, Maryland. Candidates will have a medical history and physical examination and fasting blood test, and will provide a 7-day record of their food intake as part of the screening process. Those enrolled will be randomly assigned to receive either metformin or placebo (a look-alike tablet with no active medicine) twice a day for a six month period. After the 6 month study period, all children will be offered the opportunity to take metformin for another 6 months. Participants will be hospitalized for 2-3 days for the following procedures: history and physical examination; fasting blood test; several urine collections; X-ray studies to determine bone age and amount of body fat and muscle; magnetic resonance imaging (MRI) scan to measure body fat; "hyperglycemic clamp study" to evaluate insulin resistance; food intake testing; nutrition consultation; resting metabolic rate; and a "doubly labeled water" test. For the hyperglycemic clamp study, a catheter (thin flexible tube) is inserted into a vein in each arm. A sugar solution is given through one tube and blood samples are drawn every 5 minutes through the other to measure insulin. For the food intake testing, the child is asked about his or her hunger level, then given various foods he or she may choose to eat, then questioned again at various intervals both during and after finishing eating about his or her hunger level. The doubly labeled water study involves drinking "heavy water" (water which is enriched to have special kinds of hydrogen and oxygen). Urine specimens are collected 2, 3 and 4 hours after drinking the water. The child also drinks a special milk shake called a Scandishake and repeats the calorie intake and hunger study. (Two food intake studies are done on separate days.) One week after the heavy water test, additional urine samples are collected one week later. After completing the tests, the child will begin treatment with metformin or placebo, plus a daily vitamin tablet. Participants will be followed once a month with a brief history and physical examination, including a blood test. After 6 months, all of the tests described above will be repeated. All children who complete the second round of tests-both those who took metformin and those who took placebo-will be offered metformin for an additional 6 months and will be seen once a month for follow-up evaluations. Parents will not be told which children received metformin and which received placebo until all children in the study complete the first 6 months of the trial.

Conditions

Hyperinsulinemia; Obesity

Keywords

Child; Body Fat; Food Intake; Diabetes Mellitus; Dyslipidemia; Vitamin B12; Childhood Obesity

Outcome Measures

Primary Outcomes (1)

• Changes in Body Weight as Determined by Body Mass Index-standard Deviation Score (BMI-SDS).

  Change in Body Mass Index standard deviation score (BMI-SDS) determined using tables created by the CDC in 2000. BMI-SDS is a unitless transformation of the body mass index (measured in kg divided by the squared height in meters) using the L M S method. Possible values range from -3 to +3. See http://www.cdc.gov/growthcharts/percentile\_data\_files.htm for details.

  6 months

Secondary Outcomes (4)

• Change in Body Weight as Determined by BMI

  6 months

• Change in Body Weight

  6 months

• Change in Body Fat by DEXA

  6 months

• Change in Body Fat by Bod Pod

  6 months

Study Arms (2)

1 - Metformin HCL

ACTIVE COMPARATOR

Subjects receive metformin plus a weight loss program

Drug: Metformin HCL

2 - Placebo

PLACEBO COMPARATOR

Subjects receive placebo plus a weight loss program

Drug: Placebo

Interventions

Metformin HCL DRUG

Medication studied for ability to alter body weight and body composition.

1 - Metformin HCL

Placebo DRUG

Control capsules for metformin

2 - Placebo

Eligibility Criteria

• Age: 6 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Good general health.
• Age greater than or equal to 6 and less than 13 years.
• Pre-pubertal or having at most early puberty (breast Tanner I, II or III for girls, testes size less than or equal to 8 mL for boys).
• Hyperinsulinemia, defined as fasting insulin concentration greater than or equal to 15 mIU/mL. The insulin level must be greater than or equal to 15 at either the NIH Clinical Center lab or the NIDDK lab at PIMC in Phoenix.
• Obesity, defined as body mass index greater than or equal to 95th percentile determined by NHANES I age and sex specific data.
• Subjects must have fasting plasma glucose less than 126 mg/dl
• Subjects must have glycosylated hemoglobin (HgbA1C) of less than or equal to 6.5%.
• Females who begin menstruating (or who are at risk for pregnancy) during the study must have a negative pregnancy test and must use an effective method of contraception if they are engaging in sexual intercourse.

You may not qualify if:

• Baseline creatinine greater or equal to 1.0 mg/dl.
• Significant cardiac or pulmonary disease likely to or resulting in hypoxia or decreased perfusion.
• Hepatic disease with elevated liver function tests (ALT or AST) greater than or equal to 1.5 the upper limits of normal.
• An alcohol history concerning for development of hepatic toxicity.
• Pregnancy.
• Evidence for Type 2 diabetes, including fasting plasma glucose greater than or equal to 126 mg/dl or HgbA1C greater than 6.5%.
• Weight loss of greater than 2% of bodyweight within the past 6 months.
• Presence of other endocrinologic disorders leading to obesity (e.g. Cushing's Syndrome).
• Individuals who have, or whose parent or guardians have current substance abuse or a psychiatric disorder or other condition that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study.
• Recent use (within six months) of anorexiant medications.
• Individuals receiving medical treatment other than diet for hypertension or dyslipidemia.
• Individuals with evidence of precocious puberty.

Sponsors & Collaborators

• Jack Yanovski, M.D.: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (7)

• Bao W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood. The Bogalusa Heart Study. Arch Intern Med. 1994 Aug 22;154(16):1842-7.

  PMID: 8053753 BACKGROUND

• Wilson DM, Abrams SH, Aye T, Lee PD, Lenders C, Lustig RH, Osganian SV, Feldman HA; Glaser Pediatric Research Network Obesity Study Group. Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up. Arch Pediatr Adolesc Med. 2010 Feb;164(2):116-23. doi: 10.1001/archpediatrics.2009.264.

  PMID: 20124139 BACKGROUND

• Melnik TA, Rhoades SJ, Wales KR, Cowell C, Wolfe WS. Overweight school children in New York City: prevalence estimates and characteristics. Int J Obes Relat Metab Disord. 1998 Jan;22(1):7-13. doi: 10.1038/sj.ijo.0800537.

  PMID: 9481594 BACKGROUND

• Manoli I, Sysol JR, Head PE, Epping MW, Gavrilova O, Crocker MK, Sloan JL, Koutsoukos SA, Wang C, Ktena YP, Mendelson S, Pass AR, Zerfas PM, Hoffmann V, Vernon HJ, Fletcher LA, Reynolds JC, Tsokos MG, Stratakis CA, Voss SD, Chen KY, Brown RJ, Hamosh A, Berry GT, Chen XS, Yanovski JA, Venditti CP. Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation. JCI Insight. 2024 Feb 22;9(4):e174097. doi: 10.1172/jci.insight.174097.

  PMID: 38271099 DERIVED

• Han JC, Reyes-Capo DP, Liu CY, Reynolds JC, Turkbey E, Turkbey IB, Bryant J, Marshall JD, Naggert JK, Gahl WA, Yanovski JA, Gunay-Aygun M. Comprehensive Endocrine-Metabolic Evaluation of Patients With Alstrom Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2707-2719. doi: 10.1210/jc.2018-00496.

  PMID: 29718281 DERIVED

• Adeyemo MA, McDuffie JR, Kozlosky M, Krakoff J, Calis KA, Brady SM, Yanovski JA. Effects of metformin on energy intake and satiety in obese children. Diabetes Obes Metab. 2015 Apr;17(4):363-70. doi: 10.1111/dom.12426. Epub 2015 Jan 11.

  PMID: 25483291 DERIVED

• Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M, Sebring NG, Reynolds JC, Brady SM, Calis KA. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes. 2011 Feb;60(2):477-85. doi: 10.2337/db10-1185. Epub 2011 Jan 12.

  PMID: 21228310 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hyperinsulinism; Obesity; Diabetes Mellitus; Dyslipidemias; Pediatric Obesity

Interventions

Metformin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Endocrine System Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Jack A. Yanovski, MD, PhD, Chief, Unit on Growth and Obesity
• Organization: National Institute of Child Health and Human Development, NIH

yanovskj@mail.nih.gov

301-496-0858

Study Officials

• Jack A Yanovski, MD, PhD

  NICHD, NIH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief, Section on Growth and Obestiy, PDEGEN, NICHD

Study Record Dates

• First Submitted: May 19, 2000
• First Posted: May 22, 2000
• Study Start: May 1, 2000
• Primary Completion: August 1, 2009
• Study Completion: May 1, 2011
• Last Updated: May 8, 2015
• Results First Posted: April 7, 2011

Record last verified: 2015-04

Locations

US (1)