ObesityPhase 4HIPNCT01775813
The Health Influences of Puberty (HIP) Study
A Phase 4 study testing Metformin in people with Obesity and Insulin Resistance, run by University of Colorado, Denver at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 9 to 17 years
- Conditions the study is for
- Obesity, Insulin Resistance, Gonadal Dysfunction
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 104 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2011to 31 May 2018
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 9 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Colorado
Aurora, Colorado, 80045
About this study
Official title: Combined Influence of Puberty and Obesity on Insulin Resistance in Adolescents
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.
Read the 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. The 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:
- Obese adolescents will show decreased improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 when compared with lean counterparts.
- 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):
- To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese and normal weight adolescents during puberty.
- 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.
- 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):
- To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese adolescents treated with metformin or placebo during puberty.
- Primary outcome: Change in Si from early puberty to puberty completion in obese controls and obese adolescents treated with metformin.
- Secondary outcome: Change in AIR and DI, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups.
- Conditions
- Obesity, Insulin Resistance, Gonadal Dysfunction, Type 2 Diabetes
- Being tested
- Metformin, Placebo
- Keywords
- Insulin resistance, Puberty, Obesity, Hypogonadism, Gonadal dysfunction, Metformin
- Medical subject headings
- Obesity, Insulin Resistance, Gonadal Disorders, Diabetes Mellitus, Type 2, Hypogonadism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage, Glumetza, Fortamet, Riomet
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.
PlaceboDrug
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
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
As measured by IVGTT as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. Please see primary outcome for more detail about timing of measurement.
Measured: 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
Please see primary outcome for more detail about timing of measurement. Disposition index is measured via (IVGTT) as calculated by Bergman's minimal model. Higher numbers indicate a better outcome. It reflects the product of outcome measures 1 and 2 (Si x AIRg).
Measured: 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
Please see primary outcome for more detail about timing of measurement.
Measured: 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
IGF-1 measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Total Testosterone
Testosterone measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Estradiol
Estradiol measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Sex Hormone Binding Globulin
SHBG measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Dehydroepiandrosterone Sulfate
DHEA-S measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
High Sensitivity C-reactive Protein
hsCRP measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Aspartate Aminotransferase (AST)
AST measured in serum at each time point
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Alanine Transaminase (ALT)
ALT measured in serum at each time point
Measured: Baseline (Tanner 2-3), Tanner 4, Tanner 5
Change in Urinary Luteinizing Hormone
LH measured in an overnight urine sample at time points below
Measured: Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)
Change in Urinary Follicle-stimulating Hormone
FSH measured in overnight urine sample at time points below
Measured: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Change in Urinary Estradiol Metabolites
estradiol metabolite (E1c) measured in an overnight urine sample at each time point
Measured: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Hemoglobin A1c
HbA1c measured by HPLC at time points below
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Leptin
Leptin measured in serum at time points below
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Percent Body Fat
% body fat measured by DXA at time points below
Measured: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Visceral Adipose
Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI
Measured: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Liver Adipose
Liver fat percent. Measured in a subset (10 per group) by fast MRI technique
Measured: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
High Density Lipoprotein
Please see primary outcome for more detail about timing of measurement.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jan 2013 (estimated)
- Study startJun 2011
- Primary completion31 May 2018
- Study completion31 May 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for ObesityStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- American Diabetes Association, National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Children's Hospital Colorado
- Responsible party
- Sponsor
- Investigators
- Megan Kelsey, MD, MS, Principal investigator, University of Colorado Denver/Children's Hospital Colorado
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01775813
- Sponsor's protocol ID
- 07-0988
- Other IDs
- Protocol 914, 1-11-JF-23, 5K12HD057022
- Acronym
- HIP
- Status last verified
- Jan 2022
- First submitted
- 5 Oct 2012
- Last updated
- 1 Feb 2022
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Boster JM, Cree MG, Kelsey MM, Nadeau KJ, Chaidez A, Pan Z, Sundaram SS. Relative Skeletal Muscle Mass Is Associated With Hepatic Steatosis in Adolescents With Overweight and Obesity. Pediatr Obes. 2026 Apr;21(4):e70108. doi: 10.1111/ijpo.70108.
PubMed 42014131Cohen CC, Moore JM, Bothwell S, Pyle L, Lopez-Paniagua D, Ware MA, Whooten R, Zeitler PS, Nadeau KJ, Kelsey MM. Adipose Depot Changes and Associated Metabolic Risk in the Longitudinal Health Influences of Puberty Study. Pediatr Obes. 2026 Mar;21(3):e70083. doi: 10.1111/ijpo.70083.
PubMed 41771666Kelsey 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.
PubMed 33728428Kelsey 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.
PubMed 31996919
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combined Influence of Puberty and Obesity on Insulin Resistance in Adolescents
- ClinicalTrials.gov ID
- NCT01775813
- Acronym / sponsor ID
- HIP / 07-0988
- Conditions
- Obesity, Insulin Resistance, Gonadal Dysfunction, Type 2 Diabetes
- Keywords
- Insulin resistance, Puberty, Obesity, Hypogonadism, Gonadal dysfunction, Metformin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 104 participants (actual)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- American Diabetes Association, National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Children's Hospital Colorado
- Study start
- Jun 2011 (actual)
- Primary completion
- 31 May 2018 (actual)
- Study completion
- 31 May 2018 (actual)
- First posted
- 25 Jan 2013 (estimated)
- Results
- Posted 1 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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. The 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:
- Obese adolescents will show decreased improvement in insulin sensitivity from Tanner stage 2/3 to Tanner 5 when compared with lean counterparts.
- 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):
- To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese and normal weight adolescents during puberty.
- 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.
- 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):
- To compare longitudinal changes in insulin sensitivity and secretion and their correlates in obese adolescents treated with metformin or placebo during puberty.
- Primary outcome: Change in Si from early puberty to puberty completion in obese controls and obese adolescents treated with metformin.
- Secondary outcome: Change in AIR and DI, body composition, fat distribution, markers of gonadal function, and inflammatory markers over time in these groups.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Obese metformin arm | Experimental | Drug: MetforminDouble-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 |
| Obese placebo arm | Placebo comparator | Drug: PlaceboDouble-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 |
| 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 |
Who may qualify
- Ages
- 9 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: Glucophage, Glumetza, Fortamet, RiometAfter 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. | Drug | Obese metformin arm |
| PlaceboStamped 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 | Drug | Obese placebo arm |
Primary outcome
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
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.
20 secondary outcomes
Insulin Secretion (Acute Insulin Response to Glucose, AIRg)
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
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
Low Density Lipoprotein
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
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
Total Testosterone
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Estradiol
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
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
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
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
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
Alanine Transaminase (ALT)
Time frame: Baseline (Tanner 2-3), Tanner 4, Tanner 5
Change in Urinary Luteinizing Hormone
Time frame: Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)
Change in Urinary Follicle-stimulating Hormone
Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Change in Urinary Estradiol Metabolites
Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
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
Leptin
Time frame: Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Percent 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
Visceral Adipose
Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Liver Adipose
Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
High Density Lipoprotein
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42014131Boster JM, Cree MG, Kelsey MM, Nadeau KJ, Chaidez A, Pan Z, Sundaram SS. Relative Skeletal Muscle Mass Is Associated With Hepatic Steatosis in Adolescents With Overweight and Obesity. Pediatr Obes. 2026 Apr;21(4):e70108. doi: 10.1111/ijpo.70108.
- Derived from this study: PubMed 41771666Cohen CC, Moore JM, Bothwell S, Pyle L, Lopez-Paniagua D, Ware MA, Whooten R, Zeitler PS, Nadeau KJ, Kelsey MM. Adipose Depot Changes and Associated Metabolic Risk in the Longitudinal Health Influences of Puberty Study. Pediatr Obes. 2026 Mar;21(3):e70083. doi: 10.1111/ijpo.70083.
- Derived from this study: PubMed 33728428Kelsey 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.
- Derived from this study: PubMed 31996919Kelsey 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Megan Kelsey, MD, MS principal investigator
University of Colorado Denver/Children's Hospital Colorado
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metformin in people with Obesity and Insulin Resistance, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01775813, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2022.