Idiopathic Short Stature
Conditions
Keywords
Aromatase, Growth, Letrozole, Anastrozole, GH, Children, Puberty
Brief summary
When treating very short children in puberty we are time-limited, as sex hormones cause the growth plates to fuse and growth to end. Growth Hormone (GH), plus drugs that stop puberty, increase height potential, but leave children sexually infantile at a critical time in development. Human and animal data show that estrogen, in females and males, is a principal regulator of the fusion of the growth plate in puberty. Using aromatase inhibitors (AIs), which block testosterone to estrogen conversion, in boys with different growth disorders, we have shown that AIs may have beneficial effects enhancing height potential in growth-retarded males, without affecting their puberty. However, no direct comparison of the effect of AIs alone vs. conventional GH treatment has been done to date. This study will assess the effect of AIs alone, GH alone and combination treatment in enhancing height potential in adolescent boys with idiopathic short stature.
Interventions
DRUGAromatase Inhibitor
DRUGGrowth Hormone
DRUGAromatase Inhibitor and Growth Hormone
Sponsors
Thrasher Research Fund
Genentech, Inc.
Novartis
AstraZeneca
Pfizer
Nemours Children's Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Males: Ages: 12 - less than 18 years. * Bone age less than 14 ½ years at study initiation. * Presence of puberty. * Idiopathic short stature will be defined as a short child equal or less than -2SD for height, with normal GH responses to stimuli (\> or = 5ng/ml to at least 2 secretagogues) or a normal IGF-I and BP-3, normal body proportions and no other identifiable growth pathology. * Accurate growth data for at least 6 months at baseline is available.
Exclusion criteria
* Chronic illnesses. * Chronic use of glucocorticosteroids. * Previous use of hormonal treatment with AIs, sex steroids or GH in the preceding 6 months. * Birth weight small for gestational age (SGA).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Height | 0 to 24 months | Differences in height gains |
| Change in Predicted Height | 0 to 24 months | Primary efficacy end point: change in predicted height (cm) from baseline at 24 months based on change in bone age (years) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Testosterone | 0 to 24 months | — |
| Change in Bone Density z Score Adjusted for Height | 0 to 24 months | — |
| Change in Body Mass Index | 0 to 24 months | — |
| Change in Estradiol | 0 to 24 months | Those taking AI alone or AI/GH combined were grouped by type, either anastrozole or letrozole. |
| Change in Estrone | 0 to 24 months | — |
| Change in Lean Body Mass | 0 to 24 months | — |
| Change in IGF-I Concentrations | 0 to 24 months | — |
Countries
Chile, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aromatase Inhibitor Anastrozole 1mg or Letrozole 2.5mg daily orally for 2 to 3 years
Aromatase Inhibitor | 25 |
| Growth Hormone Somatropin 0.3mg/kg/week divided daily subcutaneously for 2 to 3 years
Growth Hormone | 25 |
| Aromatase Inhibitor and Growth Hormone Anastrozole 1mg or Letrozole 2.5mg orally daily for 2 to 3 years and Somatropin 0.3mg/kg/week divided daily subcutaneously for 2 to 3 years
Aromatase Inhibitor
Growth Hormone
Aromatase Inhibitor and Growth Hormone | 26 |
| Total | 76 |
Baseline characteristics
| Characteristic | Aromatase Inhibitor and Growth Hormone | Total | Aromatase Inhibitor | Growth Hormone |
|---|---|---|---|---|
| Age, Continuous | 14.0 years STANDARD_DEVIATION 1.1 | 14.1 years STANDARD_DEVIATION 1.1 | 14.2 years STANDARD_DEVIATION 1 | 14.1 years STANDARD_DEVIATION 1.2 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 26 Participants | 76 Participants | 25 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 26 |
| other Total, other adverse events | 0 / 25 | 0 / 25 | 0 / 26 |
| serious Total, serious adverse events | 4 / 25 | 2 / 25 | 2 / 26 |
Outcome results
Primary
Change in Height
Differences in height gains
Time frame: 0 to 24 months
Population: Differences in height gains from 0 to 24 months; Of the 76 Subjects, 65 completed all procedures at 24 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Height | 14 Centimeters | Standard Error 0.8 |
| Growth Hormone | Change in Height | 17.1 Centimeters | Standard Error 0.9 |
| Aromatase Inhibitor and Growth Hormone | Change in Height | 18.9 Centimeters | Standard Error 0.8 |
p-value: <0.006ANCOVA
Primary
Change in Predicted Height
Primary efficacy end point: change in predicted height (cm) from baseline at 24 months based on change in bone age (years)
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Predicted Height | 0.5 centimeters | Standard Error 1 |
| Growth Hormone | Change in Predicted Height | 4.9 centimeters | Standard Error 0.9 |
| Aromatase Inhibitor and Growth Hormone | Change in Predicted Height | 7.4 centimeters | Standard Error 0.9 |
Secondary
Change in Body Mass Index
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Body Mass Index | 2.5 kg/m^2 | Standard Error 0.3 |
| Growth Hormone | Change in Body Mass Index | 1.7 kg/m^2 | Standard Error 0.4 |
| Aromatase Inhibitor and Growth Hormone | Change in Body Mass Index | 2.5 kg/m^2 | Standard Error 0.4 |
Secondary
Change in Bone Density z Score Adjusted for Height
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months, however, 2 Subjects had a screw/pin in their leg/hip at the 24 month visit, and therefore, could not have a DEXA scan performed (N=63).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Bone Density z Score Adjusted for Height | -1.061 z-score | Standard Error 0.313 |
| Growth Hormone | Change in Bone Density z Score Adjusted for Height | -0.586 z-score | Standard Error 0.244 |
| Aromatase Inhibitor and Growth Hormone | Change in Bone Density z Score Adjusted for Height | -0.605 z-score | Standard Error 0.257 |
p-value: 0.906ANOVA
Secondary
Change in Estradiol
Those taking AI alone or AI/GH combined were grouped by type, either anastrozole or letrozole.
Time frame: 0 to 24 months
Population: Of the 51 AI alone or AI/GH combined Subjects, 41 completed all procedures at 24 months, however, 1 Subject did not have Estrone results available for the 24 month visit (N=40).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Estradiol | 8 pg/mL | Standard Error 1 |
| Growth Hormone | Change in Estradiol | 4 pg/mL | Standard Error 1 |
p-value: 0.0003ANCOVA
Secondary
Change in Estrone
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months, however, 1 Subject, did not have Estrone results available for the 24 month visit (N=64).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Estrone | 0.0 pg/mL | Standard Error 1.7 |
| Growth Hormone | Change in Estrone | 6.1 pg/mL | Standard Error 0.9 |
| Aromatase Inhibitor and Growth Hormone | Change in Estrone | -0.9 pg/mL | Standard Error 1.3 |
Secondary
Change in IGF-I Concentrations
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months, however, 1 Subject, did not have IGF-1 results available for the 24 month visit (N=64).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in IGF-I Concentrations | 158 ng/mL | Standard Error 14 |
| Growth Hormone | Change in IGF-I Concentrations | 280 ng/mL | Standard Error 16 |
| Aromatase Inhibitor and Growth Hormone | Change in IGF-I Concentrations | 303 ng/mL | Standard Error 27 |
p-value: <0.0001ANOVA
Secondary
Change in Lean Body Mass
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months, however, 2 Subjects had a screw/pin in their leg/hip at the 24 month visit, and therefore, could not have a DEXA scan performed (N=63).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Lean Body Mass | 42.2 kg | Standard Error 1.6 |
| Growth Hormone | Change in Lean Body Mass | 42.0 kg | Standard Error 1.3 |
| Aromatase Inhibitor and Growth Hormone | Change in Lean Body Mass | 46.5 kg | Standard Error 1.2 |
p-value: 0.015ANOVA
Secondary
Change in Testosterone
Time frame: 0 to 24 months
Population: Of the 76 Subjects, 65 completed all procedures at 24 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aromatase Inhibitor | Change in Testosterone | 737 ng/dL | Standard Error 79 |
| Growth Hormone | Change in Testosterone | 372 ng/dL | Standard Error 33 |
| Aromatase Inhibitor and Growth Hormone | Change in Testosterone | 668 ng/dL | Standard Error 37 |
p-value: <0.0001ANOVA