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CompletedNCT01775813HIPUpdated Feb 1, 2022Results posted

The Health Influences of Puberty (HIP) Study

A Phase 4 interventional study of Metformin and Placebo in Obesity, Insulin Resistance and Gonadal Dysfunction, sponsored by University of Colorado, Denver. Completed at 1 site in United States. Open to participants aged 9 Years to 17 Years. Per ClinicalTrials.gov, last updated 2022-02-01.

Sponsored by University of Colorado, Denver · Phase 4, Interventional, and Prevention

From the registry’s dates

  • Registered 1 year 4 months after the study started (first participant enrolled Jun 2011, registered Oct 2012).
Phase
Phase 4
Study type
Interventional
Enrollment
104
Allocation
Randomized
Ages
9 Years to 17 Years
Sex
All
01

Study 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.

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:

  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.
02

Conditions studied

  • Obesity
  • Insulin Resistance
  • Gonadal Dysfunction
  • Type 2 Diabetes

Keywords

  • Insulin resistance
  • Puberty
  • Obesity
  • Hypogonadism
  • Gonadal dysfunction
  • Metformin
03

In context

Obesity

6,296 studies on the registry are indexed under Obesity; 1,692 are open to participants now.

This study's enrollment of 104 is above the median of 78 across 4,878 interventional studies indexed under Obesity.

Browse Obesity studies →

Lead sponsor

University of Colorado, Denver is the lead sponsor of 1,499 studies on the registry; 315 are open to participants now.

Of its 139 completed or terminated interventional studies of FDA-regulated products, 89 (64%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
9 Years to 17 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
104 participants (actual)

Study arms

  • Experimental
    Obese metformin arm

    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

  • Placebo comparator
    Obese placebo arm

    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

  • No intervention
    Obese - NT

    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

  • No intervention
    Normal weight

    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

  • DrugMetformin

    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

  • DrugPlacebo

    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

06

What researchers measure

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.

    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

Secondary outcomes

  1. 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.

    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

  2. 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).

    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

  3. Low Density Lipoprotein

    Please see primary outcome for more detail about timing of measurement.

    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

  4. Insulin-like Growth Factor 1

    IGF-1 measured in serum at each time point

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

  5. Total Testosterone

    Testosterone measured in serum at each time point

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

  6. Estradiol

    Estradiol measured in serum at each time point

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

  7. Sex Hormone Binding Globulin

    SHBG measured in serum at each time point

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

  8. Dehydroepiandrosterone Sulfate

    DHEA-S measured in serum at each time point

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

  9. High Sensitivity C-reactive Protein

    hsCRP measured in serum at each time point

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

  10. Aspartate Aminotransferase (AST)

    AST measured in serum at each time point

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

  11. Alanine Transaminase (ALT)

    ALT measured in serum at each time point

    Time frame: Baseline (Tanner 2-3), Tanner 4, Tanner 5

  12. Change in Urinary Luteinizing Hormone

    LH measured in an overnight urine sample at time points below

    Time frame: Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)

  13. Change in Urinary Follicle-stimulating Hormone

    FSH measured in overnight urine sample at time points below

    Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline

  14. Change in Urinary Estradiol Metabolites

    estradiol metabolite (E1c) measured in an overnight urine sample at each time point

    Time frame: Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline

  15. Hemoglobin A1c

    HbA1c measured by HPLC at time points below

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

  16. Leptin

    Leptin measured in serum at time points below

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

  17. Percent Body Fat

    % body fat measured by DXA at time points below

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

  18. Visceral Adipose

    Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI

    Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline

  19. Liver Adipose

    Liver fat percent. Measured in a subset (10 per group) by fast MRI technique

    Time frame: Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline

  20. High Density Lipoprotein

    Please see primary outcome for more detail about timing of measurement.

    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

07

Results

Posted Feb 1, 2022

Participant flow

Participant flow — Overall Study
MilestoneNormal WeightObese - NTObese - PlaceboObese - Metformin
Started47132420
Study visit 2 (tanner 4)3641111
Study visit 3 (tanner 5)3481211
Study visit 4 (post-puberty)1001311
Completed3481211
Not completed135129

Outcome measures

PrimaryInsulin 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.

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
Reported as:
Mean · x10-4/min-1/mIU/mL
Insulin Sensitivity
x10-4/min-1/mIU/mLNormal WeightObese - NTObese - PlaceboObese - Metformin
Baseline8.559 ± 5.7553.425 ± 4.1973.756 ± 4.9702.985 ± 2.656
Tanner 46.661 ± 4.4181.995 ± 0.9591.868 ± 1.1022.873 ± 2.155
Tanner 56.438 ± 3.8352.082 ± 1.7642.383 ± 2.0562.990 ± 3.038
Post-PubertyNA ± NANA ± NA3.017 ± 3.4492.182 ± 2.353
SecondaryInsulin 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.

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
Reported as:
Mean · µIU/mL
Insulin Secretion (Acute Insulin Response to Glucose, AIRg)
µIU/mLNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline583.535 ± 432.7531877.895 ± 1052.3281858.16 ± 1079.1282368.931 ± 1616.348
Tanner 4783.191 ± 623.9461951.323 ± 1035.6971996.867 ± 1215.0172157.349 ± 1099.876
Tanner 5680.858 ± 572.8842103.309 ± 1505.0402013.628 ± 1417.4071804.026 ± 761.849
Post-PubertyNA ± NANA ± NA1943.542 ± 1353.0361667.713 ± 917.270
SecondaryDisposition 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).

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
Reported as:
Mean · x10-4/min-1
Disposition Index
x10-4/min-1Normal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline3750.463 ± 1625.0154195.921 ± 1743.3454286.209 ± 1966.9204438.821 ± 2420.123
Tanner 43706.940 ± 1972.5633269.039 ± 1500.2612897.689 ± 1553.9485046.218 ± 2858.784
Tanner 53234.061 ± 2474.7542897.244 ± 1547.5153194.773 ± 1918.8123537.273 ± 768.858
Post-PubertyNA ± NANA ± NA3627.762 ± 2375.1662539.933 ± 1393.267
SecondaryLow Density Lipoprotein

Please see primary outcome for more detail about timing of measurement.

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
Reported as:
Mean · mg/dl
Low Density Lipoprotein
mg/dlNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline79.488 ± 22.69186.533 ± 22.54388.583 ± 23.82483.779 ± 25.029
Tanner 475.367 ± 15.85296.636 ± 19.46496.636 ± 19.46481.818 ± 24.677
Tanner 578.485 ± 20.52096.222 ± 24.42297.667 ± 27.65575.000 ± 27.799
Post-PubertyNA ± NANA ± NA103.154 ± 26.62086.545 ± 28.507
SecondaryInsulin-like Growth Factor 1

IGF-1 measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · ng/ml
Insulin-like Growth Factor 1
ng/mlNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline313.500 ± 103.339262.278 ± 91.924243.042 ± 85.040281.700 ± 86.014
Tanner 4405.389 ± 116.845370.800 ± 89.816380.273 ± 77.040410.300 ± 116.467
Tanner 5398.000 ± 97.117389.800 ± 116.087351.833 ± 74.909404.800 ± 88.745
Post-PubertyNA ± NANA ± NA319.692 ± 93.694395.818 ± 114.417
SecondaryTotal Testosterone

Testosterone measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · ng/dl
Total Testosterone
ng/dlNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline108.625 ± 135.37735.278 ± 28.37530.125 ± 20.42241.050 ± 32.705
Tanner 4145.972 ± 159.86687.933 ± 103.90289.364 ± 105.331121.727 ± 113.418
Tanner 5235.559 ± 235.224158.300 ± 234.056165.750 ± 282.171117.909 ± 132.301
Post-PubertyNA ± NANA ± NA152.692 ± 168.109150.727 ± 161.357
SecondaryEstradiol

Estradiol measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · pg/mL
Estradiol
pg/mLNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline22.375 ± 34.06815.722 ± 7.75615.833 ± 7.73814.750 ± 6.695
Tanner 450.583 ± 70.88835.867 ± 49.69344.545 ± 56.07723.364 ± 14.123
Tanner 557.382 ± 79.25142.800 ± 38.32448.833 ± 47.61048.000 ± 29.192
Post-PubertyNA ± NANA ± NA70.923 ± 91.31669.636 ± 85.940
SecondarySex Hormone Binding Globulin

SHBG measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · nmol/l
Sex Hormone Binding Globulin
nmol/lNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline61.958 ± 21.68020.417 ± 8.31018.958 ± 6.80517.550 ± 8.451
Tanner 450.417 ± 24.09817.200 ± 7.58016.364 ± 6.74219.545 ± 14.348
Tanner 543.500 ± 15.49816.250 ± 5.58115.750 ± 6.46816.455 ± 8.825
Post-PubertyNA ± NANA ± NA15.538 ± 4.40917.273 ± 10.640
SecondaryDehydroepiandrosterone Sulfate

DHEA-S measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · mcg/dl
Dehydroepiandrosterone Sulfate
mcg/dlNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline90.146 ± 60.52296.750 ± 63.59291.167 ± 60.501107.600 ± 64.722
Tanner 4101.889 ± 62.016101.533 ± 67.038116.182 ± 71.822129.545 ± 69.398
Tanner 5130.206 ± 69.229137.250 ± 74.248137.083 ± 86.885145.818 ± 66.535
Post-PubertyNA ± NANA ± NA132.154 ± 68.295176.818 ± 110.840
SecondaryHigh Sensitivity C-reactive Protein

hsCRP measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · units on a scale
High Sensitivity C-reactive Protein
units on a scaleNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline1.001 ± 2.6042.523 ± 2.6443.117 ± 3.0603.962 ± 3.608
Tanner 40.305 ± 0.6314.530 ± 5.0344.357 ± 5.6611.841 ± 1.494
Tanner 51.015 ± 3.2653.331 ± 3.8143.985 ± 4.6810.961 ± 0.915
Post-PubertyNA ± NANA ± NA3.958 ± 3.5102.667 ± 4.647
SecondaryAspartate Aminotransferase (AST)

AST measured in serum at each time point

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · international units per liter
Aspartate Aminotransferase (AST)
international units per literNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline42.174 ± 14.68541.250 ± 18.13043.542 ± 20.15654.150 ± 28.117
Tanner 435.706 ± 11.20244.429 ± 25.62143.636 ± 26.07040.273 ± 14.065
Tanner 533.364 ± 11.81136.650 ± 17.45842.333 ± 20.33134.091 ± 11.122
Post-PubertyNA ± NANA ± NA39.077 ± 21.27836.273 ± 17.396
SecondaryAlanine Transaminase (ALT)

ALT measured in serum at each time point

Time frame:
Baseline (Tanner 2-3), Tanner 4, Tanner 5
Reported as:
Mean · international units per liter
Alanine Transaminase (ALT)
international units per literNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline25.022 ± 9.55635.194 ± 22.13241.125 ± 24.55252.400 ± 50.296
Tanner 427.059 ± 7.67144.571 ± 40.83951.182 ± 43.82942.545 ± 18.753
Tanner 526.121 ± 6.85938.650 ± 23.08947.500 ± 25.99539.636 ± 17.328
Post-PubertyNA ± NANA ± NA50.231 ± 36.96745.000 ± 30.864
SecondaryChange in Urinary Luteinizing Hormone

LH measured in an overnight urine sample at time points below

Time frame:
Baseline, every 6 months during the trial, Final visit (average 3 yrs after baseline)
Reported as:
Mean · international units per liter
Change in Urinary Luteinizing Hormone
international units per literNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Tanner 2/33.849 ± 4.5302.257 ± 2.1862.257 ± 2.1863.809 ± 3.667
Tanner 44.518 ± 8.4963.310 ± 3.7933.310 ± 3.7933.729 ± 4.036
Tanner 54.494 ± 7.6162.014 ± 1.4422.014 ± 1.4428.993 ± 14.725
Post-PubertyNA ± NA5.373 ± 11.3635.373 ± 11.36330.861 ± 62.387
SecondaryChange in Urinary Follicle-stimulating Hormone

FSH measured in overnight urine sample at time points below

Time frame:
Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Reported as:
Mean · international units per milliliter (IU/m
Change in Urinary Follicle-stimulating Hormone
international units per milliliter (IU/mNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Tanner 2/33.911 ± 5.5903.837 ± 4.2643.837 ± 4.2643.615 ± 4.356
Tanner 42.555 ± 2.5414.874 ± 3.5864.874 ± 3.5863.162 ± 2.686
Tanner 56.540 ± 9.3604.093 ± 3.9624.093 ± 3.9623.213 ± 3.323
Post-PubertyNA ± NA5.993 ± 6.4295.993 ± 6.4293.911 ± 2.689
SecondaryChange in Urinary Estradiol Metabolites

estradiol metabolite (E1c) measured in an overnight urine sample at each time point

Time frame:
Baseline, every 6 months during the trial, Final visit-average 3 yrs after baseline
Reported as:
Mean · ng/mgCr
Change in Urinary Estradiol Metabolites
ng/mgCrNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Tanner 2/37.711 ± 22.53117.353 ± 17.21417.353 ± 17.21428.451 ± 26.082
Tanner 422.919 ± 37.8358.584 ± 9.9328.584 ± 9.93237.722 ± 34.648
Tanner 541.036 ± 78.1607.825 ± 2.5867.825 ± 2.58671.546 ± 77.343
Post-PubertyNA ± NA26.402 ± 38.29926.402 ± 38.29930.883 ± 33.674
SecondaryHemoglobin A1c

HbA1c measured by HPLC at time points below

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · mmol/mol
Hemoglobin A1c
mmol/molNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline5.139 ± 0.2505.336 ± 0.4885.336 ± 0.4885.400 ± 0.286
Tanner 45.200 ± 0.2605.627 ± 0.5315.627 ± 0.5315.570 ± 0.250
Tanner 55.233 ± 0.2935.476 ± 0.3605.500 ± 0.3985.473 ± 0.552
Post-PubertyNA ± NANA ± NA5.515 ± 0.5195.691 ± 0.929
SecondaryLeptin

Leptin measured in serum at time points below

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · ng/mL
Leptin
ng/mLNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline5.956 ± 5.61632.097 ± 13.62433.917 ± 15.20732.215 ± 17.027
Tanner 45.964 ± 4.58236.867 ± 20.51944.036 ± 19.12129.791 ± 21.892
Tanner 58.338 ± 7.08838.155 ± 21.06147.642 ± 21.26931.182 ± 20.982
Post-PubertyNA ± NANA ± NA53.200 ± 41.32348.445 ± 31.855
SecondaryPercent Body Fat

% body fat measured by DXA at time points below

Time frame:
Baseline, Tanner (puberty) stage 4-average 1.5 years from baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · percentage of body fat
Percent Body Fat
percentage of body fatNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline24.883 ± 6.45242.126 ± 5.25944.700 ± 3.30443.826 ± 5.412
Tanner 425.054 ± 6.15943.380 ± 3.64944.264 ± 3.48940.610 ± 7.906
Tanner 525.500 ± 7.47842.889 ± 4.68844.555 ± 3.69239.964 ± 6.490
Post-PubertyNA ± NANA ± NA43.962 ± 5.70141.418 ± 5.669
SecondaryVisceral Adipose

Percent Visceral Fat, Measured in a subset (10 per group) by single slice MRI

Time frame:
Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · Percent
Visceral Adipose
PercentNormal WeightObese - NT/PlaceboObese - MetforminObese - Placebo
Baseline7.647 ± 3.70212.007 ± 2.26312.076 ± 3.96812.007 ± 2.263
Tanner 56.322 ± 2.67612.236 ± 1.56410.079 ± 1.88612.236 ± 1.564
SecondaryLiver Adipose

Liver fat percent. Measured in a subset (10 per group) by fast MRI technique

Time frame:
Baseline, Tanner (puberty) stage 5-average 2.5 yrs from baseline
Reported as:
Mean · percentage of liver mass
Liver Adipose
percentage of liver massNormal WeightObese NT/PlaceboObese - MetforminObese - Placebo
Baseline1.376 ± 0.5948.290 ± 7.17713.765 ± 5.4578.290 ± 7.177
Tanner 52.208 ± 0.6378.219 ± 5.75710.327 ± 8.0238.291 ± 5.757
SecondaryHigh Density Lipoprotein

Please see primary outcome for more detail about timing of measurement.

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
Reported as:
Mean · mg/dL
High Density Lipoprotein
mg/dLNormal WeightObese - NT/PlaceboObese - PlaceboObese - Metformin
Baseline51.442 ± 8.92139.306 ± 6.51138.917 ± 7.00341.368 ± 7.274
Tanner 451.667 ± 11.73439.455 ± 9.53339.455 ± 9.53342.273 ± 4.735
Tanner 546.909 ± 8.49838.944 ± 8.75539.333 ± 8.89743.000 ± 5.916
Post-PubertyNA ± NANA ± NA40.923 ± 8.64541.818 ± 8.171

Adverse events

Collected over Adverse event data were collected at each med visit approximately every 6 months. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Obese - Metformin0/20 (0%)0/20 (0%)11/20 (55%)
Obese - Placebo0/24 (0%)0/24 (0%)14/24 (58.3%)
Normal Weight (No Treatment)0/47 (0%)0/47 (0%)0/47 (0%)
Obese (No Treatment)0/13 (0%)0/13 (0%)0/13 (0%)
Most frequent other events
Most frequent other events
EventObese - MetforminObese - PlaceboNormal Weight (No Treatment)Obese (No Treatment)
NauseaGastrointestinal disorders7/2011/240/470/13
DiarrheaGastrointestinal disorders6/2010/240/470/13
BloatingGastrointestinal disorders7/207/240/470/13

Baseline characteristics

Both the Obese - NT participants and Obese - Placebo participants were included in the "observational arm" of the study. Thus, this arm was a comparison between youth with normal weight and untreated and youth with obesity who were either a) untreated or b) treated with placebo

Age, Continuous
Age, Continuous(years)Normal WeightObese - NTObese - PlaceboObese - MetforminTotal
Mean12.070 ± 1.51311.274 ± 1.13811.146 ± 1.08811.863 ± 1.56211.754 ± 1.437
Sex: Female, Male
Sex: Female, Male(Participants)Normal WeightObese - NTObese - PlaceboObese - MetforminTotal
Female22617954
Male25771150
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Normal WeightObese - NTObese - PlaceboObese - MetforminTotal
Hispanic127191654
Non-Hispanic White2342130
Black812213
Asian30003
Other11103
Native American00011
Region of Enrollment
Region of Enrollment(participants)Normal WeightObese - NTObese - PlaceboObese - MetforminTotal
United States47132420104
08

Study locations

1 site
  • Children's Hospital Colorado
    Aurora, Colorado 80045, United States
09

References and documents

Publications

  • 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. PubMed 33728428 ↗
  • 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. PubMed 31996919 ↗

Study documents

  • Protocol and statistical analysis plan · Mar 25, 2016

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 1, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT01775813
Lead 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), Children's Hospital Colorado
Responsible party
Sponsor
First posted
Jan 25, 2013
Start date
Jun 2011
Primary completion
May 31, 2018
Completion
May 31, 2018
Results posted
Feb 1, 2022
Last update
Feb 1, 2022

Study contacts

Megan Kelsey, MD, MS
principal investigator · University of Colorado Denver/Children's Hospital Colorado

Oversight

FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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