Idiopathic Short Stature
Conditions
Keywords
ISS, human growth hormone
Brief summary
To demonstrate that an individualized, formula-based Genotropin regimen for children with Idiopathic Short Stature will lead to a targeted height gain (to reach the target of 10th percentile (%), or -1.3 SDS) during 24 months of treatment. The endpoint at 4 years is to explore treatment efficiency over four years of two formula-based dose regimens (sub-arms) compared to standard treatment
Interventions
DRUGGenotropin
Compare daily injections of formula-based HGH treatment to daily injections of standard HGH treatment in subjects with Idiopathic Short Stature over 24 months period followed by an exploratory 24 months period.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
* Prepubertal children with bone ages between 3 and 10 years of age for males and 3 and 9 years of age for females * Naive to Growth Hormone treatment
Exclusion criteria
* Abnormal karyotype. Small Gestational Age and Skeletal dysplasia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute On-target Difference (AOTD) at 24 Months | 2 years | This was defined as an absolute difference between the 24-month height standard deviation score (SDS) and targeted 24-month height SDS (10th percentile (%), or -1.3 SDS). SDS indicates how similar the participant was to the reference population. These were calculated using 2000 Center for the Disease Control (CDC) growth reference tables (by age and gender). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Variability of Height SDS at 24 Months | 2 years | The continuous endpoint of variability of height SDS at 24 months was defined as the SD of the 24 month height SDS. |
| Time Cost (Months Until >= -2 SDS) | 2 years | Time cost was defined as the number of months needed until height SDS was within the normal limit (ie, \>= -2SDS). |
| Computed Cost of Height Gain at 48 Months | 4 years | The computed cost of height gain was defined as the amount of drug used relative to the observed height-gain, in terms of mg/cm, this was calculated at Month 48. |
| Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months | 4 years | The estimated cost of long-term height gain until FAH was calculated. |
| Change From Baseline in Height SDS at 48 Months. | 4 years | Change in height SDS was measured at 48 months. |
Countries
United States
Participant flow
Recruitment details
This was a 4-year, open-label, randomized study conducted at 40 centers across United States of America (USA). The first 2-years of the study constituted core phase and the last 2 years constituted the maintenance phase.
Pre-assignment details
The participants were randomized in 2:1 manner to formula-based dosing arm and standard dosing arm for initial 2 years of treatment, following which the participants in formula-based dosing arm were re-randomized in a 1:1 manner to one of two physiological doses, for next 2 years, to identify the minimum genotropin dosage to maintain the growth.
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose Arm The participants received subcutaneous genotropin daily, at a maintained standard dose of 0.37 mg/kg/week, throughout the four years. | 114 |
| Individualized Dose Arm The participants received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses (0.18 mg/kg/week or 0.24 mg/kg/week) for the remaining 2 years. | 202 |
| Total | 316 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 |
| Overall Study | Insufficient Clinical Response | 1 | 4 |
| Overall Study | Lost to Follow-up | 4 | 9 |
| Overall Study | Other | 3 | 5 |
| Overall Study | Protocol Violation | 0 | 6 |
| Overall Study | Withdrawal by Subject | 17 | 17 |
Baseline characteristics
| Characteristic | Standard Dose Arm | Individualized Dose Arm | Total |
|---|---|---|---|
| Age, Continuous | 8.3 Years STANDARD_DEVIATION 2.1 | 8.4 Years STANDARD_DEVIATION 2.3 | 8.4 Years STANDARD_DEVIATION 2.2 |
| Age, Customized <= 7 years | 37 Participants | 70 Participants | 107 Participants |
| Age, Customized >=7 years | 77 Participants | 132 Participants | 209 Participants |
| Sex: Female, Male Female | 31 Participants | 58 Participants | 89 Participants |
| Sex: Female, Male Male | 83 Participants | 144 Participants | 227 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 118 | 165 / 198 |
| serious Total, serious adverse events | 13 / 118 | 7 / 198 |
Outcome results
Primary
Absolute On-target Difference (AOTD) at 24 Months
This was defined as an absolute difference between the 24-month height standard deviation score (SDS) and targeted 24-month height SDS (10th percentile (%), or -1.3 SDS). SDS indicates how similar the participant was to the reference population. These were calculated using 2000 Center for the Disease Control (CDC) growth reference tables (by age and gender).
Time frame: 2 years
Population: The Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. Last observation carried forward (LOCF) rule was applied to impute Month 24 missing height SDS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose Arm | Absolute On-target Difference (AOTD) at 24 Months | 0.603 Standard Deviation Score (SDS) | Standard Deviation 0.2948 |
| Individualized Dose Arm | Absolute On-target Difference (AOTD) at 24 Months | 0.625 Standard Deviation Score (SDS) | Standard Deviation 0.3003 |
Comparison: The null hypothesis was that the individualized treatment arm was not superior to the standard treatment arm; alternative hypothesis that the individualized treatment arm was superior to the standard treatment arm with respect to the mean 24-month AOTD. Using a 2:1 randomization, a two sided sample t-test comparing the root AOTD between the 2 treatment arms with 80% power at a 5% level required 260 subjects. Assuming a 20% attrition rate, approximately 312 subjects were needed for this study.p-value: 0.5762ANCOVA
Secondary
Change From Baseline in Height SDS at 48 Months.
Change in height SDS was measured at 48 months.
Time frame: 4 years
Population: FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose Arm | Change From Baseline in Height SDS at 48 Months. | 1.33 Standard Deviation Score (SDS) | Standard Deviation 0.717 |
| Individualized Dose Arm | Change From Baseline in Height SDS at 48 Months. | 1.24 Standard Deviation Score (SDS) | Standard Deviation 0.668 |
| Individualized Dose Arm 0.18 mg/kg/Week | Change From Baseline in Height SDS at 48 Months. | 1.33 Standard Deviation Score (SDS) | Standard Deviation 0.637 |
| Individualized Dose Arm 0.24 mg/kg/Week | Change From Baseline in Height SDS at 48 Months. | 1.34 Standard Deviation Score (SDS) | Standard Deviation 0.633 |
p-value: 0.261895% CI: [-0.068, 0.249]ANCOVA
p-value: 0.892695% CI: [-0.172, 0.198]ANCOVA
p-value: 0.956695% CI: [-0.192, 0.181]ANCOVA
Secondary
Computed Cost of Height Gain at 48 Months
The computed cost of height gain was defined as the amount of drug used relative to the observed height-gain, in terms of mg/cm, this was calculated at Month 48.
Time frame: 4 years
Population: FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose Arm | Computed Cost of Height Gain at 48 Months | 72.77 mg/cm | Standard Deviation 17.914 |
| Individualized Dose Arm | Computed Cost of Height Gain at 48 Months | 67.30 mg/cm | Standard Deviation 24.382 |
| Individualized Dose Arm 0.18 mg/kg/Week | Computed Cost of Height Gain at 48 Months | 63.07 mg/cm | Standard Deviation 21.656 |
| Individualized Dose Arm 0.24 mg/kg/Week | Computed Cost of Height Gain at 48 Months | 69.62 mg/cm | Standard Deviation 21.903 |
p-value: 0.010195% CI: [1.395, 10.249]ANCOVA
p-value: 0.000295% CI: [4.417, 14.145]ANCOVA
p-value: 0.200195% CI: [-1.707, 8.114]ANCOVA
Secondary
Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months
The estimated cost of long-term height gain until FAH was calculated.
Time frame: 4 years
Population: Full analysis set (FAS) included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose Arm | Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months | 127.99 mg/cm | Standard Deviation 29.708 |
| Individualized Dose Arm | Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months | 91.34 mg/cm | Standard Deviation 31.854 |
| Individualized Dose Arm 0.18 mg/kg/Week | Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months | 80.06 mg/cm | Standard Deviation 21 |
| Individualized Dose Arm 0.24 mg/kg/Week | Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months | 92.24 mg/cm | Standard Deviation 25.213 |
p-value: <0.000195% CI: [30.181, 43.618]ANCOVA
p-value: <0.000195% CI: [42.054, 54.98]ANCOVA
p-value: <0.000195% CI: [27.936, 40.951]ANCOVA
Secondary
Time Cost (Months Until >= -2 SDS)
Time cost was defined as the number of months needed until height SDS was within the normal limit (ie, \>= -2SDS).
Time frame: 2 years
Population: Full analysis set (FAS) included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dose Arm | Time Cost (Months Until >= -2 SDS) | 12.00 Months |
| Individualized Dose Arm | Time Cost (Months Until >= -2 SDS) | 12.00 Months |
p-value: 0.801695% CI: [0.802, 1.33]Regression, Cox
Secondary
Variability of Height SDS at 24 Months
The continuous endpoint of variability of height SDS at 24 months was defined as the SD of the 24 month height SDS.
Time frame: 2 years
Population: FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose Arm | Variability of Height SDS at 24 Months | Change from baseline at 24 months (n=101,184) | 1.12 Standard Deviation Score (SDS) | Standard Deviation 0.408 |
| Standard Dose Arm | Variability of Height SDS at 24 Months | Change from baseline at 24 months LOCF (n=114,202) | 1.03 Standard Deviation Score (SDS) | Standard Deviation 0.475 |
| Individualized Dose Arm | Variability of Height SDS at 24 Months | Change from baseline at 24 months (n=101,184) | 1.11 Standard Deviation Score (SDS) | Standard Deviation 0.518 |
| Individualized Dose Arm | Variability of Height SDS at 24 Months | Change from baseline at 24 months LOCF (n=114,202) | 1.04 Standard Deviation Score (SDS) | Standard Deviation 0.544 |
p-value: 0.627ANOVA (Levene's Test)