The Health Influences of Puberty (HIP) Study

NCT01775813 | Completed Phase 4 Results FDA Drug

• 4 other identifiers: 07-0988Protocol 9141-11-JF-235K12HD057022
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; Insulin Resistance; Gonadal Dysfunction; Type 2 Diabetes

Keywords

Insulin resistance; Puberty; Obesity; Hypogonadism; Gonadal dysfunction; Metformin

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity

  As measured by in intravenous glucose tolerance test (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. 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.

  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

Secondary Outcomes (20)

• Insulin Secretion (Acute Insulin Response to Glucose, AIRg)

  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

• Disposition Index

  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

• Low Density Lipoprotein

  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

• Insulin-like Growth Factor 1

  Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline

• Total Testosterone

  Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline

Study Arms (4)

Obese metformin arm

EXPERIMENTAL

Double-blinded placebo-controlled trial of metformin during puberty, treatment arm Dosage form: Metformin 1000 mg tablets Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years

Drug: Metformin

Obese placebo arm

PLACEBO COMPARATOR

Double-blinded placebo-controlled trial of metformin during puberty, placebo arm Dosage form: Placebo stamped to match 1000 mg metformin tablets Placebo comparator: Stamped placebo pill matching metformin dose Dosage: 1000 mg by mouth twice daily Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years

Drug: Placebo

Obese - NT

NO INTERVENTION

Comparator group for the observational comparison of metabolic changes in youth with normal weight and obesity as they progress through puberty. Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years

Normal weight

NO INTERVENTION

Comparator group for the observational comparison of metabolic changes in youth with normal weight and obesity as they progress through puberty. Duration: From early puberty (Tanner 2-3) until puberty completion (Tanner 5), approximately 3 years

Interventions

Metformin DRUG

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.

Also known as: Glucophage, Glumetza, Fortamet, Riomet

Obese metformin arm

Placebo DRUG

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

Obese placebo arm

Eligibility Criteria

• Age: 9 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Colorado, Denver: lead
• American Diabetes Association: collaborator
• National Institutes of Health (NIH): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• Children's Hospital Colorado: collaborator

Study Sites (1)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Related Publications (2)

• Kelsey MM, Hilkin A, Pyle L, Severn C, Utzschneider K, Van Pelt RE, Zeitler PS, Nadeau KJ. Two-Year Treatment With Metformin During Puberty Does Not Preserve beta-Cell Function in Youth With Obesity. J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2622-e2632. doi: 10.1210/clinem/dgab170.

  PMID: 33728428 DERIVED

• Kelsey MM, Pyle L, Hilkin A, Severn CD, Utzschneider K, Van Pelt RE, Nadeau KJ, Zeitler PS. The Impact of Obesity On Insulin Sensitivity and Secretion During Pubertal Progression: A Longitudinal Study. J Clin Endocrinol Metab. 2020 May 1;105(5):e2061-8. doi: 10.1210/clinem/dgaa043.

  PMID: 31996919 DERIVED

MeSH Terms

Conditions

Obesity; Insulin Resistance; Gonadal Disorders; Diabetes Mellitus, Type 2; Hypogonadism

Interventions

Metformin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Megan Kelsey
• Organization: University of Colorado School of Medicine

megan.kelsey@childrenscolorado.org

720-777-0991

Study Officials

• Megan Kelsey, MD, MS

  University of Colorado Denver/Children's Hospital Colorado

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2012
• First Posted: January 25, 2013
• Study Start: June 1, 2011
• Primary Completion: May 31, 2018
• Study Completion: May 31, 2018
• Last Updated: February 1, 2022
• Results First Posted: February 1, 2022

Record last verified: 2022-01

Locations

US (1)