The Health Influences of Puberty (HIP) Study | RxWiki

The Health Influences of Puberty (HIP) Study

Overview[ - collapse ][ - ]

Purpose	The Health Influences of Puberty (HIP) Study is designed to explore the relationships between puberty and the onset of type 2 diabetes in adolescents. The results of this study will help us better understand how to prevent type 2 diabetes in these youth. Children go through many changes during puberty, including important hormonal and behavioral alterations. Among these changes, it has long been known that, during puberty, insulin does not work as well as it does before and after puberty. This is called physiologic insulin resistance. In healthy children, this does not cause diabetes or affect blood sugar in any way because the body is able to compensate by making more insulin. Indeed, this is thought to be an important part of the adolescent growth spurt. However, in some children with increased risk for developing type 2 diabetes due to obesity and genetics, the worsening insulin resistance of puberty cannot be compensated for and these youth get diabetes early. The investigators believe this is because type 2 diabetes is rarely, if ever, seen before puberty begins, and the peak of diabetes onset in adolescents occurs at the time of the worst insulin resistance. This specific research project has two goals: 1. To examine effects of obesity on how well the body's insulin works during puberty, and 2. To see if treatment of obese children during this critical period of puberty with a medication that improves insulin resistance (metformin) will help prevent early onset type 2 diabetes.
Condition	Obesity Insulin Resistance Gonadal Dysfunction Type 2 Diabetes
Intervention	Drug: Metformin
Phase	Phase 4
Sponsor	University of Colorado, Denver
Responsible Party	University of Colorado, Denver
ClinicalTrials.gov Identifier	NCT01775813
First Received	October 5, 2012
Last Updated	January 25, 2013
Last verified	January 2013

Tracking Information[ + expand ][ + ]

First Received Date	October 5, 2012
Last Updated Date	January 25, 2013
Start Date	June 2011
Estimated Primary Completion Date	December 2016
Current Primary Outcome Measures	Change in insulin sensitivity [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline] [Designated as safety issue: No]As measured by in intravenous glucose tolerance test (IVGTT). Patients are randomized to receive metformin or placebo at Tanner stage 2-3 of puberty. They are reassessed at Tanner 4 and again at Tanner 5. At that point, the treatment is stopped and they are reassessed 6 months after stopping treatment to see if effects of treatment persist.
Current Secondary Outcome Measures	Change in insulin secretion [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline] [Designated as safety issue: No]As measured by IVGTT. Please see primary outcome for more detail about timing of measurement. Change in disposition index [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline] [Designated as safety issue: No]Please see primary outcome for more detail about timing of measurement. Change in lipid measures [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline, 6 mos post-treatment-average 3 yrs from baseline] [Designated as safety issue: No]Please see primary outcome for more detail about timing of measurement. Change in insulin-like growth factor 1 [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in testosterone [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in estradiol [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in sex hormone binding globulin [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in dehydroepiandrosterone sulfate [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in interleukin-6 [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in high Sensitivity C-reactive protein [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in aspartate Aminotransferase (AST) [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in alanine transaminase (ALT) [Time Frame: Baseline (Tanner 2-3), Tanner 4, Tanner 5] [Designated as safety issue: No] Change in urinary Luteinizing hormone [Time Frame: Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)] [Designated as safety issue: No] Change in urinary Follicle-stimulating hormone [Time Frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline] [Designated as safety issue: No] Change in urinary estradiol metabolites [Time Frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline] [Designated as safety issue: No] Change in hemoglobin A1c [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in leptin [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in %body fat [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No] Change in visceral adipose [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No]Measured in a subset (10 per group) by single slice MRI Change in liver adipose [Time Frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline] [Designated as safety issue: No]Measured in a subset (10 per group) by fast MRI technique

Descriptive Information[ + expand ][ + ]

Brief Title	The Health Influences of Puberty (HIP) Study
Official Title	Combined Influence of Puberty and Obesity on Insulin Resistance in Adolescents
Brief Summary	The Health Influences of Puberty (HIP) Study is designed to explore the relationships between puberty and the onset of type 2 diabetes in adolescents. The results of this study will help us better understand how to prevent type 2 diabetes in these youth. Children go through many changes during puberty, including important hormonal and behavioral alterations. Among these changes, it has long been known that, during puberty, insulin does not work as well as it does before and after puberty. This is called physiologic insulin resistance. In healthy children, this does not cause diabetes or affect blood sugar in any way because the body is able to compensate by making more insulin. Indeed, this is thought to be an important part of the adolescent growth spurt. However, in some children with increased risk for developing type 2 diabetes due to obesity and genetics, the worsening insulin resistance of puberty cannot be compensated for and these youth get diabetes early. The investigators believe this is because type 2 diabetes is rarely, if ever, seen before puberty begins, and the peak of diabetes onset in adolescents occurs at the time of the worst insulin resistance. This specific research project has two goals: 1. To examine effects of obesity on how well the body's insulin works during puberty, and 2. To see if treatment of obese children during this critical period of puberty with a medication that improves insulin resistance (metformin) will help prevent early onset type 2 diabetes.
Detailed Description	Specific Aims: Pediatric insulin resistance and related disorders, such as type 2 diabetes mellitus (T2DM), are increasing in prevalence, and portend significant end-organ and cardiovascular morbidity and mortality. Thus, measures aimed at understanding its causes and preventing its onset are critical. The physiologic decrease in insulin sensitivity in all adolescents during puberty is well-established. It is also known that obese adolescents start out less insulin sensitive at the onset of puberty than lean adolescents, and that their insulin sensitivity worsens as puberty progresses. While there are both longitudinal and cross-sectional data confirming the natural recovery of pre-pubertal insulin sensitivity in normal weight adolescents after puberty is completed, it is unknown whether obese adolescents recover their pre-pubertal insulin sensitivity. Failure to regain pre-pubertal insulin sensitivity at the end of puberty, and failure of compensatory insulin secretion, may accelerate progression from obesity to insulin resistance to T2DM in at-risk youth and contribute to long-term cardiovascular risk. In addition, obesity and insulin resistance are associated with earlier onset of puberty and premature adrenarche in females. Insulin resistance also contributes to the gonadal dysfunction of polycystic ovarian disease in fully pubertal females and is associated with hypogonadism in older adult males. Little is known about effects of obesity and insulin resistance on gonadal function in young males. However, persistent metabolic changes at the end of puberty may contribute to gonadal dysfunction in obese youth. Currently, there are few longitudinal studies in either sex that evaluate the interactions among obesity, insulin resistance and gonadal function during puberty. The investigators' long-term goal is to better understand the metabolic changes that occur during puberty, their underlying mechanisms, and their potential contribution to adult disease. Our overall aim is to evaluate the effects of obesity on the evolution of insulin sensitivity and gonadal function during puberty. In addition, because improvement in insulin action during puberty may slow β-cell deterioration, the investigators will evaluate whether compensatory insulin secretion is also affected in obese adolescents and whether treatment with metformin improves β-cell response. HYPOTHESES: 1. Obese adolescents will show decreased improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 when compared with lean counterparts. 2. Obese adolescents treated with metformin will have greater improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 vs. those treated with placebo. (See hypothesis schematics below) To test these hypotheses, we propose to address the following Specific Aims: SPECIFIC AIM 1 (Observational Arm): 1. To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese and normal weight adolescents during puberty. 1. Primary outcome: Change in insulin sensitivity (Si), as measured by frequently sampled intravenous glucose tolerance test (IVGTT), from early puberty to puberty completion in obese and normal weight adolescents. 2. Secondary outcomes: Change in insulin secretion (AIR) and disposition index (DI) as measured by IVGTT, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups. SPECIFIC AIM 2 (Treatment Arm): 2. To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese adolescents treated with metformin or placebo during puberty. 1. Primary outcome: Change in Si from early puberty to puberty completion in obese controls and obese adolescents treated with metformin. 2. Secondary outcome: Change in AIR and DI, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups.
Study Type	Interventional
Study Phase	Phase 4
Study Design	Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Condition	Obesity Insulin Resistance Gonadal Dysfunction Type 2 Diabetes
Intervention	Drug: Metformin After randomization, the study drug (metformin or placebo) is gradually titrated to full dose of 1000 mg BID (or to maximum tolerated, at least 500 mg BID) over a period of 4 weeks to minimize adverse gastrointestinal effects. Participants are seen every three months to measure compliance and dispense new study drug. Every 6 months, they also have a physical examination in order to determine puberty staging. Study measurements (IVGTT, bloodwork, DXA) are performed at Tanner 4 puberty and Tanner 5 (puberty completion), at which time the study drug is stopped. Study measurements will be performed again 6 months after study drug is completed to assess if effects are persistent after study drug is stopped. During the treatment period, all participants receive standard lifestyle counseling. Other Names: Glucophage Glumetza Fortamet Riomet
Study Arm (s)	Experimental: Metformin Dosage form: Metformin 1000 mg tablets Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 3-4) until puberty completion (Tanner 5), approximately 3 years Placebo Comparator: Sugar pill Dosage form: Stamped placebo pill to look like the 1000 mg metformin pill Dosage: 1 pill taken orally twice daily Duration: From early puberty (Tanner 3-4) until puberty completion (Tanner 5), approximately 3 years

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	156
Estimated Completion Date	December 2016
Estimated Primary Completion Date	December 2016
Eligibility Criteria	Inclusion Criteria: - BMI ≥ 95th percentile - At least Tanner 2, but no more than Tanner 3 - Age ≥ 9 years - Absence of impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or Type 2 diabetes mellitus (T2DM) Exclusion Criteria: - Presence of T2DM, IGT or IFG - Any disorder or medication known to effect glucose tolerance; - Hypertension or hyperlipidemia requiring pharmacological intervention; - Weight >300lbs. due to limits of imaging tables. - Chronic illness
Gender	Both
Ages	9 Years
Accepts Healthy Volunteers	No
Contacts	Contact: Allison Hilkin, BS 720-777-6148 Allison.Hilkin@childrenscolorado.org
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01775813
Other Study ID Numbers	07-0988
Has Data Monitoring Committee	Yes
Information Provided By	University of Colorado, Denver
Study Sponsor	University of Colorado, Denver
Collaborators	American Diabetes Association National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators	Principal Investigator: Megan Kelsey, MD, MS University of Colorado Denver/Children's Hospital Colorado
Verification Date	January 2013

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