Obesity
Conditions
Keywords
Obesity, Adolescent, Insulin resistance, Growth hormone, Visceral fat, Adolescent obesity
Brief summary
Teenagers and adults who are overweight or obese have an increase in fat in the abdomen, which increases their risk for diabetes and heart disease. Reducing abdominal fat is important to reduce risk for diabetes and for heart disease. Overweight teenagers also have low levels of growth hormone compared to normal weight teenagers, and teenagers with the lowest growth hormone levels also have the greatest abdominal fat. In children who are unable to make growth hormone for other reasons, giving back growth hormone leads to a decrease in abdominal fat. We are studying whether giving growth hormone in small doses to overweight teenagers can change body composition. We hypothesize that growth hormone will cause abdominal fat to decrease and reduce the risk markers for diabetes and heart disease.
Interventions
DRUGrecombinant human growth hormone (rhGH)
Initial rhGH dose 0.4mg administered by subcutaneous injection daily. Dose will be increased to 0.6 mg after one week and then increased to 0.8mg after two weeks.
DRUGPlacebo
Placebo will be administered by daily subcutaneous injections. Sham increases will be used.
Sponsors
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
13 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Adolescent girls 13-21 years old with bone age ≥ 14 years * Overweight girls: Body Mass Index (BMI) greater than the 95th percentile for age * Waist/Hip ratio ≥ 0.85 * Insulin Like Growth Factor -1 (IGF-1) below -0.5 standard deviations (SD) for pubertal stage or age
Exclusion criteria
* Pregnancy (positive pregnancy test) prior to enrollment in the study * Significant weight gain or loss within 3 months of study (more than 5 kg) * Use of medications that affect GH or cortisol levels (such as estrogen including oral contraceptive pills, oral glucocorticoids) * Use of medications such as Meridian and Orlistat * Presence of diabetes mellitus * Uncontrolled Thyroid disorders * Chronic renal insufficiency * Participation in another simultaneous medical investigation or trial * Active neoplasm or history of cancer * Prader-Willi syndrome * History of scoliosis if bone age is \<15 years * Hypersensitivity to rhGH or constituents of the injections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months | Baseline and 6 months | Visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) were assessed using single slice MR imaging (MRI) |
| Changes in Lipid Panel | Baseline and 6 months | Lipid profile will be obtained using established methods. Total Cholesterol, Triglycerides, LDL and HDL measurements will be obtained at baseline, and then at the six-month visits to determine the rate at which lipid measures change with rhGH therapy |
| Change in High-sensitivity C-reactive Protein (Hs-CRP) Over 6 Months | Baseline and 6 months | As a marker of cardiovascular risk, hs-CRP will be assessed at baseline and 6 months to assess the rate at which hs-CRP levels change with rhGH therapy. |
| Change in Soluble Intercellular Adhesion Molecule-1 (sICAM) Over 6 Months | Baseline and 6 months | Soluble intercellular adhesion molecule-1 (sICAM) was used as a surrogate marker of cardiovascular risk |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Score | Baseline and 6 months | Homeostasis model assessment of insulin resistance (HOMA-IR) was used as a validated measure of insulin resistance. A 2-hour Oral Glucose Tolerance Test (OGTT) using 1.75 gram/kilogram of oral glucose (maximum 75 gram) will be performed at baseline and six months after administration of rhGH/placebo/ no therapy. Fasting insulin and glucose will be used to determine HOMA-IR: \[fasting glucose (mmol/l) x fasting insulin (µU/ml)\]/22.5\] |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at Massachusetts General Hospital between September 2010 and October 2012 through area pediatric and obesity clinics and advertisements.
Pre-assignment details
Of the 32 subjects who were screened, 22 were eligible & randomized. 5 subjects were ineligible due to Insulin Like Growth Factor levels above the eligibility limit for pubertal stage or age. 2 were excluded due to planned initiation of medications that were on the exclusion criteria list and 3 voluntarily withdrew consent prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Human Growth Hormone Forty subjects will be randomized to receive either recombinant human growth hormone or placebo/no treatment.
recombinant human growth hormone (rhGH) : Initial rhGH dose 0.4mg administered by subcutaneous injection daily. Dose will be increased to 0.6 mg after one week and then increased to 0.8mg after two weeks. | 11 |
| Placebo/no Treatment Forty subjects will be randomized to receive either recombinant human growth hormone or placebo.
Placebo : Placebo will be administered by daily subcutaneous injections. Sham increases will be used. Due to expiration of placebo medication, placebo subjects who enrolled after 6/2012 were randomized to no treatment. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo/no Treatment | Recombinant Human Growth Hormone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 9 Participants | 17 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 16.9 years STANDARD_DEVIATION 2.1 | 16.2 years STANDARD_DEVIATION 2.6 | 16.6 years STANDARD_DEVIATION 2.34 |
| Region of Enrollment United States | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 11 | 7 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Change in High-sensitivity C-reactive Protein (Hs-CRP) Over 6 Months
As a marker of cardiovascular risk, hs-CRP will be assessed at baseline and 6 months to assess the rate at which hs-CRP levels change with rhGH therapy.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Human Growth Hormone | Change in High-sensitivity C-reactive Protein (Hs-CRP) Over 6 Months | -0.77 mg/L | Standard Deviation 2.4 |
| Placebo/no Treatment | Change in High-sensitivity C-reactive Protein (Hs-CRP) Over 6 Months | -0.09 mg/L | Standard Deviation 1.8 |
p-value: 0.58t-test, 2 sided
Primary
Change in Soluble Intercellular Adhesion Molecule-1 (sICAM) Over 6 Months
Soluble intercellular adhesion molecule-1 (sICAM) was used as a surrogate marker of cardiovascular risk
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Human Growth Hormone | Change in Soluble Intercellular Adhesion Molecule-1 (sICAM) Over 6 Months | -22.2 ng/mL | Standard Deviation 30.3 |
| Placebo/no Treatment | Change in Soluble Intercellular Adhesion Molecule-1 (sICAM) Over 6 Months | 21.1 ng/mL | Standard Deviation 33.3 |
p-value: 0.04t-test, 2 sided
Primary
Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months
Visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) were assessed using single slice MR imaging (MRI)
Time frame: Baseline and 6 months
Population: Due to scheduling difficulties one no treatment subject did not perform the MRI portion of the study at either the baseline or the 6 month visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Human Growth Hormone | Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months | Change in SAT | -111 mm^2 | Standard Deviation 6078 |
| Recombinant Human Growth Hormone | Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months | Change in VAT | 57 mm^2 | Standard Deviation 2993 |
| Placebo/no Treatment | Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months | Change in VAT | 799 mm^2 | Standard Deviation 3184 |
| Placebo/no Treatment | Change in Visceral and Subcutaneous Abdominal Adipose Tissue Over 6 Months | Change in SAT | 3634 mm^2 | Standard Deviation 5161 |
Comparison: We assumed that mean decrease in visceral fat in our population would be 0.85\*standard deviation score (SDS). Therefore, 18 subjects in each group would be required in order for us to have an 81.7% chance of detecting a significant difference in the mean 6-month changes in visceral adiposity between the groups at a 5% significance level by rejecting the null hypothesis that there is no difference in change in visceral fat following administration of rhGH or placebo in obese adolescent girls.p-value: 0.7t-test, 2 sided
Comparison: Change in SAT p-valuep-value: 0.3t-test, 2 sided
Primary
Changes in Lipid Panel
Lipid profile will be obtained using established methods. Total Cholesterol, Triglycerides, LDL and HDL measurements will be obtained at baseline, and then at the six-month visits to determine the rate at which lipid measures change with rhGH therapy
Time frame: Baseline and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Human Growth Hormone | Changes in Lipid Panel | Change in Total Cholesterol | -37.8 mg/dL | Standard Deviation 23.9 |
| Recombinant Human Growth Hormone | Changes in Lipid Panel | Change in Triglycerides | -27.8 mg/dL | Standard Deviation 46.8 |
| Recombinant Human Growth Hormone | Changes in Lipid Panel | Change in LDL | -25.8 mg/dL | Standard Deviation 12.8 |
| Recombinant Human Growth Hormone | Changes in Lipid Panel | Change in HDL | -6.6 mg/dL | Standard Deviation 6.1 |
| Placebo/no Treatment | Changes in Lipid Panel | Change in HDL | 1 mg/dL | Standard Deviation 5.1 |
| Placebo/no Treatment | Changes in Lipid Panel | Change in Total Cholesterol | -8.6 mg/dL | Standard Deviation 15.5 |
| Placebo/no Treatment | Changes in Lipid Panel | Change in LDL | -10.7 mg/dL | Standard Deviation 11.9 |
| Placebo/no Treatment | Changes in Lipid Panel | Change in Triglycerides | 6.1 mg/dL | Standard Deviation 58.4 |
Comparison: Change in Total Cholesterol p-valuep-value: 0.03t-test, 2 sided
Comparison: Change in Triglyceride p-valuep-value: 0.57Wilcoxon (Mann-Whitney)
Comparison: Change in Low-density lipoprotein p-valuep-value: 0.062t-test, 2 sided
Comparison: Change in High-density lipoprotein p-valuep-value: 0.0396t-test, 2 sided
Secondary
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Score
Homeostasis model assessment of insulin resistance (HOMA-IR) was used as a validated measure of insulin resistance. A 2-hour Oral Glucose Tolerance Test (OGTT) using 1.75 gram/kilogram of oral glucose (maximum 75 gram) will be performed at baseline and six months after administration of rhGH/placebo/ no therapy. Fasting insulin and glucose will be used to determine HOMA-IR: \[fasting glucose (mmol/l) x fasting insulin (µU/ml)\]/22.5\]
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Human Growth Hormone | Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Score | -0.52 HOMA-IR score | Standard Deviation 2.63 |
| Placebo/no Treatment | Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Score | -2.92 HOMA-IR score | Standard Deviation 8.23 |
p-value: 0.93Wilcoxon (Mann-Whitney)