Growth Disorders, Intrauterine Growth Retardation
Conditions
Keywords
Short height, intra-uterine growth retardation, Genotonorm, continuous treatment, intermittent treatment
Brief summary
To evaluate the effect of continuous and intermittent administration of Genotonorm on stature in short prepubertal children with intra-uterine growth retardation
Interventions
DRUGGenotonorm
0.7 IU/kg/week or 0.03 mg/kg/day, daily subcutaneous injection
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Chronological age (CA) between 3 and 10 for girls * Chronological age between 3 and 12 for boys * Height for CA below - 2 SD * Birth length for CA below -2SD
Exclusion criteria
* Endocrine disease except well-substituted hypothyroidism * Sever chronic disease * Skeletal dysplasia * Known chromosomal aberration * Ongoing treatment with steroids * Known intrauterine infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm | Baseline, 2 years | Annual growth rate was expressed as height velocity (centimeter \[cm\]/year). This was derived by substracting annual growth rate at Baseline from 2-year value. (Annual growth rate was calculated each year and rescaled to 1 year if the interval between x and x-1 was not 365 days, as long as a subject remains in the study): ANGRYx = (Height Yx - Height Y{x-1}) / {(Date of Yx - Date of Y{x-1}) /365.25} |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Annual Growth Rate SDS | Baseline, 1 to 3 years | Calculated corresponding to the gender and chronological age by substracting annual growth rate SDS at Baseline from annual growth rate SDS at each year. |
| Height (cm) | Baseline, 1 to 6 years, final height | Performed by use of a wallmounted device (eg, Harpenden Stadiometer). Each subject was measured 3 times and the mean of these measurements was recorded as the present height. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. |
| Change From Baseline in Height (cm) | Baseline, 1 to 6 years, final height | Calculated by substracting height at Baseline from height at each year. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. |
| Height (SDS) | Baseline, 1 to 6 years, final height | Calculated using Sempe reference means and standard deviations for height. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. |
| Change From Baseline in Height (SDS) | Baseline, 1 to 6 years, final height | Calculated by substracting height SDS at Baseline from height SDS at each year. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls. |
| Annual Growth Rate Standard Deviation Score (SDS) | Baseline, 1 to 6 years | Calculated using Sempe reference means and standard deviations for growth rate according to age and sex. Standardization was performed for chronological age. |
| Weight | Baseline, 1 to 6 years | — |
| Change From Baseline in Bone Age | Baseline, 1 to 3 years | Bone age was determined by the Greulich-Pyle method. Calculated by substracting bone age at Baseline from bone age at each year |
| Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 1 to 3 years | Bone age was determined by the Greulich-Pyle method. Chronological Age (years) was calculated as: (Date minus Date of Birth) divided by 365.25. Chronological Age used was the age at the date that the corresponding Bone Age X-ray was performed. Ratio was calculated by change from Baseline in bone age divided by change from Baseline in chronological age. |
| Chronological Age at Onset of Puberty | Onset of puberty | Chronological age (years) at first study visit with onset of puberty = (Date of study visit minus Date of Birth) divided by 365.25. |
| Number of Subjects Reaching Puberty | Baseline, 1 to 6 years | The defined criteria for reaching puberty were: boy=if right or left testes volume ≥4 ml; girl=if breast development ≥2. Tanner Adolescent Pubertal Staging Questionnaire documents the stage of development of secondary sexual characteristics rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Onset of puberty was defined as the visit where the data recorded first met the above criteria for starting puberty. |
| Body Mass Index (BMI) | Baseline, 1 to 6 years | BMI was calculated by weight divided by height squared. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Genotonorm 0.7 (Continuous Treatment) Subjects received 0.7 IU/kg/week (0.03 mg/kg/day) of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached. | 68 |
| Genotonorm 1.4 (Continuous Treatment) Subjects received 1.4 IU/kg/week (0.06 mg/kg/day) of the growth hormone Genotonorm as a continuous treatment. Treatment was allowed to be taken until final height of the subject had been reached. | 70 |
| Genotonorm 1.4 (Intermittent Treatment) Subjects received 1.4 IU/kg/week (0.06 mg/kg/day) of the growth hormone Genotonorm as an intermittent treatment. Treatment was allowed to be taken until final height of the subject had been reached. | 68 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 4 | 9 |
| Overall Study | Ongoing at Cutoff Date | 1 | 1 | 0 |
| Overall Study | Other | 25 | 21 | 29 |
| Overall Study | Randomized But Not Treated | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 31 | 39 | 22 |
Baseline characteristics
| Characteristic | Total | Genotonorm 1.4 (Intermittent Treatment) | Genotonorm 1.4 (Continuous Treatment) | Genotonorm 0.7 (Continuous Treatment) |
|---|---|---|---|---|
| Age, Customized >= 12 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 4 - 8 years | 90 Participants | 29 Participants | 32 Participants | 29 Participants |
| Age, Customized < 4 years | 29 Participants | 6 Participants | 8 Participants | 15 Participants |
| Age, Customized 8 - 12 years | 86 Participants | 33 Participants | 30 Participants | 23 Participants |
| Sex: Female, Male Female | 95 Participants | 39 Participants | 31 Participants | 25 Participants |
| Sex: Female, Male Male | 111 Participants | 29 Participants | 39 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 68 | 42 / 70 | 35 / 68 |
| serious Total, serious adverse events | 0 / 68 | 4 / 70 | 3 / 68 |
Outcome results
Primary
Change From Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm
Annual growth rate was expressed as height velocity (centimeter \[cm\]/year). This was derived by substracting annual growth rate at Baseline from 2-year value. (Annual growth rate was calculated each year and rescaled to 1 year if the interval between x and x-1 was not 365 days, as long as a subject remains in the study): ANGRYx = (Height Yx - Height Y{x-1}) / {(Date of Yx - Date of Y{x-1}) /365.25}
Time frame: Baseline, 2 years
Population: All subjects who received at least 1 study dose of Genotonorm were included in the Full Analysis Set (FAS). Number of Participants Analyzed = number of subjects with change in annual growth rate at 2 years.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm | 3.07 cm/year | Standard Deviation 2.21 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm | 3.97 cm/year | Standard Deviation 1.72 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Annual Growth Rate Measured at 2 Years Following Treatment With Genotonorm | 2.84 cm/year | Standard Deviation 1.71 |
p-value: 0.02922Wilcoxon (Mann-Whitney)
p-value: 0.74299Wilcoxon (Mann-Whitney)
p-value: 0.00467Wilcoxon (Mann-Whitney)
Secondary
Annual Growth Rate Standard Deviation Score (SDS)
Calculated using Sempe reference means and standard deviations for growth rate according to age and sex. Standardization was performed for chronological age.
Time frame: Baseline, 1 to 6 years
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | Baseline (n=50, 42, 43) | -2.72 SDS | Standard Deviation 1.83 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 5 years (n=12, 10, 20) | 0.18 SDS | Standard Deviation 1.24 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 3 years (n=39, 34, 41) | 0.36 SDS | Standard Deviation 1.14 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 1 year (n=57, 55, 59) | 2.14 SDS | Standard Deviation 1.52 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 6 years (n=11, 7, 19) | 0.90 SDS | Standard Deviation 1.92 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 2 years (n=53, 49, 56) | 0.77 SDS | Standard Deviation 1.57 |
| Genotonorm 0.7 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 4 years (n=21, 18, 27) | 0.13 SDS | Standard Deviation 1.55 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 3 years (n=39, 34, 41) | 1.35 SDS | Standard Deviation 1.78 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 4 years (n=21, 18, 27) | 0.61 SDS | Standard Deviation 1.2 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | Baseline (n=50, 42, 43) | -2.58 SDS | Standard Deviation 1.39 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 1 year (n=57, 55, 59) | 3.97 SDS | Standard Deviation 2.26 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 5 years (n=12, 10, 20) | 0.09 SDS | Standard Deviation 0.88 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 6 years (n=11, 7, 19) | 0.59 SDS | Standard Deviation 1.61 |
| Genotonorm 1.4 (Continuous Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 2 years (n=53, 49, 56) | 2.00 SDS | Standard Deviation 1.73 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 6 years (n=11, 7, 19) | 0.05 SDS | Standard Deviation 1.2 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 5 years (n=12, 10, 20) | -0.02 SDS | Standard Deviation 1.46 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | Baseline (n=50, 42, 43) | -2.75 SDS | Standard Deviation 1.73 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 1 year (n=57, 55, 59) | 1.71 SDS | Standard Deviation 1.51 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 3 years (n=39, 34, 41) | 0.31 SDS | Standard Deviation 1.12 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 4 years (n=21, 18, 27) | 0.34 SDS | Standard Deviation 1.2 |
| Genotonorm 1.4 (Intermittent Treatment) | Annual Growth Rate Standard Deviation Score (SDS) | 2 years (n=53, 49, 56) | 0.67 SDS | Standard Deviation 1.22 |
Secondary
Body Mass Index (BMI)
BMI was calculated by weight divided by height squared.
Time frame: Baseline, 1 to 6 years
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 1 year (n=56, 55, 59) | 14.82 kg/m^2 | Standard Deviation 1.52 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 6 years (n=11, 7, 20) | 16.21 kg/m^2 | Standard Deviation 1.46 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | Baseline (n=58, 56, 60) | 14.74 kg/m^2 | Standard Deviation 1.48 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 2 years (n=53, 49, 56) | 15.33 kg/m^2 | Standard Deviation 1.78 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 3 years (n=39, 34, 41) | 15.59 kg/m^2 | Standard Deviation 2.02 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 4 years (n=21, 18, 27) | 15.32 kg/m^2 | Standard Deviation 1.56 |
| Genotonorm 0.7 (Continuous Treatment) | Body Mass Index (BMI) | 5 years (n=12, 10, 21) | 15.80 kg/m^2 | Standard Deviation 1.57 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 5 years (n=12, 10, 21) | 16.25 kg/m^2 | Standard Deviation 1.7 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | Baseline (n=58, 56, 60) | 15.14 kg/m^2 | Standard Deviation 1.76 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 4 years (n=21, 18, 27) | 17.03 kg/m^2 | Standard Deviation 3.7 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 2 years (n=53, 49, 56) | 15.92 kg/m^2 | Standard Deviation 2.15 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 3 years (n=39, 34, 41) | 16.65 kg/m^2 | Standard Deviation 2.92 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 1 year (n=56, 55, 59) | 15.44 kg/m^2 | Standard Deviation 1.94 |
| Genotonorm 1.4 (Continuous Treatment) | Body Mass Index (BMI) | 6 years (n=11, 7, 20) | 16.34 kg/m^2 | Standard Deviation 1.8 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 3 years (n=39, 34, 41) | 15.58 kg/m^2 | Standard Deviation 2.11 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 6 years (n=11, 7, 20) | 17.28 kg/m^2 | Standard Deviation 4.21 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | Baseline (n=58, 56, 60) | 14.59 kg/m^2 | Standard Deviation 1.51 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 1 year (n=56, 55, 59) | 14.87 kg/m^2 | Standard Deviation 1.76 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 5 years (n=12, 10, 21) | 16.69 kg/m^2 | Standard Deviation 3.92 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 2 years (n=53, 49, 56) | 15.29 kg/m^2 | Standard Deviation 2 |
| Genotonorm 1.4 (Intermittent Treatment) | Body Mass Index (BMI) | 4 years (n=21, 18, 27) | 15.80 kg/m^2 | Standard Deviation 2.37 |
Secondary
Change From Baseline in Annual Growth Rate SDS
Calculated corresponding to the gender and chronological age by substracting annual growth rate SDS at Baseline from annual growth rate SDS at each year.
Time frame: Baseline, 1 to 3 years
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at 1 year. n = number of subjects with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 3 years (n=34, 25, 32) | 3.31 SDS | Standard Deviation 2.06 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 2 years (n=47, 37, 40) | 3.51 SDS | Standard Deviation 2.5 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 1 year (n=49, 42, 42) | 4.81 SDS | Standard Deviation 2.27 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 3 years (n=34, 25, 32) | 3.80 SDS | Standard Deviation 2.2 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 1 year (n=49, 42, 42) | 6.56 SDS | Standard Deviation 2.55 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Annual Growth Rate SDS | 2 years (n=47, 37, 40) | 4.53 SDS | Standard Deviation 1.89 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Annual Growth Rate SDS | 2 years (n=47, 37, 40) | 3.37 SDS | Standard Deviation 2.33 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Annual Growth Rate SDS | 1 year (n=49, 42, 42) | 4.37 SDS | Standard Deviation 2.16 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Annual Growth Rate SDS | 3 years (n=34, 25, 32) | 3.17 SDS | Standard Deviation 1.86 |
Comparison: 3 yearsp-value: 0.63956Wilcoxon (Mann-Whitney)
Comparison: 3 yearsp-value: 0.16421Wilcoxon (Mann-Whitney)
Comparison: 1 yearp-value: 0.00125Wilcoxon (Mann-Whitney)
Comparison: 1 yearp-value: 0.25995Wilcoxon (Mann-Whitney)
Comparison: 1 yearp-value: 0.00008Wilcoxon (Mann-Whitney)
Comparison: 2 yearsp-value: 0.03273Wilcoxon (Mann-Whitney)
Comparison: 2 yearsp-value: 0.68581Wilcoxon (Mann-Whitney)
Comparison: 2 yearsp-value: 0.0053Wilcoxon (Mann-Whitney)
Comparison: 3 yearsp-value: 0.57556Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Bone Age
Bone age was determined by the Greulich-Pyle method. Calculated by substracting bone age at Baseline from bone age at each year
Time frame: Baseline, 1 to 3 years
Population: Safety population = all subjects who received at least 1 study dose of GH. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at Baseline and each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age | 1 year (n=53, 60, 56) | 1.17 Years | Standard Deviation 0.51 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age | 3 years (n=41, 39, 35) | 3.53 Years | Standard Deviation 1.22 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age | 2 years (n=52, 51, 49) | 2.40 Years | Standard Deviation 0.9 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age | 2 years (n=52, 51, 49) | 2.50 Years | Standard Deviation 1.08 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age | 3 years (n=41, 39, 35) | 4.06 Years | Standard Deviation 1.05 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age | 1 year (n=53, 60, 56) | 1.27 Years | Standard Deviation 0.72 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age | 3 years (n=41, 39, 35) | 3.67 Years | Standard Deviation 0.97 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age | 2 years (n=52, 51, 49) | 2.58 Years | Standard Deviation 0.97 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age | 1 year (n=53, 60, 56) | 1.25 Years | Standard Deviation 0.54 |
Secondary
Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio
Bone age was determined by the Greulich-Pyle method. Chronological Age (years) was calculated as: (Date minus Date of Birth) divided by 365.25. Chronological Age used was the age at the date that the corresponding Bone Age X-ray was performed. Ratio was calculated by change from Baseline in bone age divided by change from Baseline in chronological age.
Time frame: 1 to 3 years
Population: Safety population = all subjects who received at least 1 study dose of GH. Number of Participants Analyzed = number of subjects with evaluable data at 1 year. n = number of subjects with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 3 years (n=35, 37, 35) | 1.09 ratio | Standard Deviation 0.39 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 1 year (n=53, 60, 56) | 0.96 ratio | Standard Deviation 0.41 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 2 years (n=51, 51, 49) | 1.06 ratio | Standard Deviation 0.41 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 1 year (n=53, 60, 56) | 1.07 ratio | Standard Deviation 0.62 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 2 years (n=51, 51, 49) | 1.14 ratio | Standard Deviation 0.5 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 3 years (n=35, 37, 35) | 1.26 ratio | Standard Deviation 0.32 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 2 years (n=51, 51, 49) | 1.18 ratio | Standard Deviation 0.44 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 1 year (n=53, 60, 56) | 1.06 ratio | Standard Deviation 0.45 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Bone Age/Change From Baseline in Chronological Age Ratio | 3 years (n=35, 37, 35) | 1.14 ratio | Standard Deviation 0.29 |
Secondary
Change From Baseline in Height (cm)
Calculated by substracting height at Baseline from height at each year. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls.
Time frame: Baseline, 1 to 6 years, final height
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at Baseline and each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 5 years (n=12, 10, 21) | 32.23 cm | Standard Deviation 5.92 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 4 years (n=21, 18, 27) | 26.36 cm | Standard Deviation 4.37 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 3 years (n=39, 34, 41) | 20.62 cm | Standard Deviation 3 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | Final height (n=17, 12, 22) | 45.39 cm | Standard Deviation 13.08 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 6 years (n=11, 7, 20) | 38.20 cm | Standard Deviation 6.66 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 1 year (n=57, 55, 59) | 8.21 cm | Standard Deviation 1.38 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (cm) | 2 years (n=53, 49, 56) | 14.77 cm | Standard Deviation 2.45 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | Final height (n=17, 12, 22) | 45.30 cm | Standard Deviation 13.72 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 5 years (n=12, 10, 21) | 35.70 cm | Standard Deviation 4.27 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 2 years (n=53, 49, 56) | 17.01 cm | Standard Deviation 2.21 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 3 years (n=39, 34, 41) | 24.49 cm | Standard Deviation 3.04 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 4 years (n=21, 18, 27) | 30.77 cm | Standard Deviation 3.43 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 6 years (n=11, 7, 20) | 44.03 cm | Standard Deviation 3.09 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (cm) | 1 year (n=57, 55, 59) | 9.21 cm | Standard Deviation 1.45 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 4 years (n=21, 18, 27) | 25.83 cm | Standard Deviation 3.26 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 5 years (n=12, 10, 21) | 32.16 cm | Standard Deviation 3.81 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | Final height (n=17, 12, 22) | 40.93 cm | Standard Deviation 9.22 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 1 year (n=57, 55, 59) | 7.33 cm | Standard Deviation 1.32 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 3 years (n=39, 34, 41) | 20.14 cm | Standard Deviation 2.78 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 2 years (n=53, 49, 56) | 13.92 cm | Standard Deviation 2.03 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (cm) | 6 years (n=11, 7, 20) | 38.01 cm | Standard Deviation 4.82 |
Secondary
Change From Baseline in Height (SDS)
Calculated by substracting height SDS at Baseline from height SDS at each year. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls.
Time frame: Baseline, 1 to 6 years, final height
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at Baseline and each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 2 years (n=53, 49, 56) | 0.94 SDS | Standard Deviation 0.45 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 6 years (n=11, 7, 19) | 1.54 SDS | Standard Deviation 1.12 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | Final height (n=14, 9, 18) | 1.00 SDS | Standard Deviation 0.53 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 1 year (n=57, 55, 59) | 0.67 SDS | Standard Deviation 0.28 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 5 years (n=12, 10, 21) | 1.37 SDS | Standard Deviation 1.12 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 4 years (n=21, 18, 27) | 1.20 SDS | Standard Deviation 0.81 |
| Genotonorm 0.7 (Continuous Treatment) | Change From Baseline in Height (SDS) | 3 years (n=39, 34, 41) | 1.06 SDS | Standard Deviation 0.54 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 1 year (n=57, 55, 59) | 0.88 SDS | Standard Deviation 0.3 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 3 years (n=39, 34, 41) | 1.70 SDS | Standard Deviation 0.54 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 4 years (n=21, 18, 27) | 1.98 SDS | Standard Deviation 0.69 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 6 years (n=11, 7, 19) | 2.60 SDS | Standard Deviation 0.66 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 2 years (n=53, 49, 56) | 1.40 SDS | Standard Deviation 0.43 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | 5 years (n=12, 10, 21) | 2.03 SDS | Standard Deviation 0.87 |
| Genotonorm 1.4 (Continuous Treatment) | Change From Baseline in Height (SDS) | Final height (n=14, 9, 18) | 0.97 SDS | Standard Deviation 0.95 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 3 years (n=39, 34, 41) | 0.99 SDS | Standard Deviation 0.51 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | Final height (n=14, 9, 18) | 0.86 SDS | Standard Deviation 1.16 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 5 years (n=12, 10, 21) | 1.46 SDS | Standard Deviation 0.69 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 6 years (n=11, 7, 19) | 1.54 SDS | Standard Deviation 0.86 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 4 years (n=21, 18, 27) | 1.21 SDS | Standard Deviation 0.54 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 1 year (n=57, 55, 59) | 0.53 SDS | Standard Deviation 0.28 |
| Genotonorm 1.4 (Intermittent Treatment) | Change From Baseline in Height (SDS) | 2 years (n=53, 49, 56) | 0.84 SDS | Standard Deviation 0.37 |
Comparison: 3 yearsp-value: 0.0001Wilcoxon (Mann-Whitney)
Comparison: 3 yearsp-value: 0.58324Wilcoxon (Mann-Whitney)
Comparison: 3 yearsp-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Chronological Age at Onset of Puberty
Chronological age (years) at first study visit with onset of puberty = (Date of study visit minus Date of Birth) divided by 365.25.
Time frame: Onset of puberty
Population: Safety population. Number of participants analyzed = number of subjects who started puberty by the end of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Chronological Age at Onset of Puberty | 11.88 Years | Standard Deviation 2.22 |
| Genotonorm 1.4 (Continuous Treatment) | Chronological Age at Onset of Puberty | 11.12 Years | Standard Deviation 1.74 |
| Genotonorm 1.4 (Intermittent Treatment) | Chronological Age at Onset of Puberty | 11.58 Years | Standard Deviation 1.42 |
p-value: 0.068195% CI: [-0.05, 1.39]ANCOVA
p-value: 0.897195% CI: [-0.65, 0.74]ANCOVA
p-value: 0.058395% CI: [-1.27, 0.02]ANCOVA
Secondary
Height (cm)
Performed by use of a wallmounted device (eg, Harpenden Stadiometer). Each subject was measured 3 times and the mean of these measurements was recorded as the present height. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls.
Time frame: Baseline, 1 to 6 years, final height
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 3 years (n=39, 34, 41) | 123.92 cm | Standard Deviation 15.08 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 6 years (n=11, 7, 20) | 133.29 cm | Standard Deviation 10.46 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | Final height (n=17, 12, 22) | 146.86 cm | Standard Deviation 11.26 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 1 year (n=57, 55, 59) | 113.38 cm | Standard Deviation 15.09 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 2 years (n=53, 49, 56) | 119.67 cm | Standard Deviation 15.18 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 5 years (n=12, 10, 21) | 126.73 cm | Standard Deviation 10.01 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | Baseline (n=58, 56, 60) | 105.22 cm | Standard Deviation 15.04 |
| Genotonorm 0.7 (Continuous Treatment) | Height (cm) | 4 years (n=21, 18, 27) | 124.67 cm | Standard Deviation 13.14 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | Baseline (n=58, 56, 60) | 107.06 cm | Standard Deviation 12.29 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 6 years (n=11, 7, 20) | 138.84 cm | Standard Deviation 8.69 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 2 years (n=53, 49, 56) | 124.11 cm | Standard Deviation 13.02 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | Final height (n=17, 12, 22) | 151.98 cm | Standard Deviation 6.52 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 3 years (n=39, 34, 41) | 131.75 cm | Standard Deviation 13.76 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 5 years (n=12, 10, 21) | 131.01 cm | Standard Deviation 9.26 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 4 years (n=21, 18, 27) | 132.30 cm | Standard Deviation 13.23 |
| Genotonorm 1.4 (Continuous Treatment) | Height (cm) | 1 year (n=57, 55, 59) | 116.31 cm | Standard Deviation 12.24 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | Final height (n=17, 12, 22) | 149.13 cm | Standard Deviation 9.07 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 5 years (n=12, 10, 21) | 129.98 cm | Standard Deviation 9.93 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 2 years (n=53, 49, 56) | 120.64 cm | Standard Deviation 12.34 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 3 years (n=39, 34, 41) | 125.39 cm | Standard Deviation 12.52 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 4 years (n=21, 18, 27) | 127.59 cm | Standard Deviation 11.51 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | Baseline (n=58, 56, 60) | 106.44 cm | Standard Deviation 12.04 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 6 years (n=11, 7, 20) | 135.45 cm | Standard Deviation 10.1 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (cm) | 1 year (n=57, 55, 59) | 113.71 cm | Standard Deviation 12.01 |
Secondary
Height (SDS)
Calculated using Sempe reference means and standard deviations for height. Final Height: Children are defined as reaching their final height when annual Growth Rate is less than 2 cm in the previous year and bone age is equal to or greater than 17 years in boys and equal to or greater than 15 years in girls.
Time frame: Baseline, 1 to 6 years, final height
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 2 years (n=53, 49, 56) | -2.21 SDS | Standard Deviation 0.66 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 5 years (n=12, 10, 21) | -1.95 SDS | Standard Deviation 1.26 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 6 years (n=11, 7, 19) | -1.80 SDS | Standard Deviation 1.28 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 4 years (n=21, 18, 27) | -2.16 SDS | Standard Deviation 1.03 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | Baseline (n=58, 56, 60) | -3.16 SDS | Standard Deviation 0.52 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 3 years (n=39, 34, 41) | -2.17 SDS | Standard Deviation 0.7 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | Final height (n=14, 9, 18) | -2.06 SDS | Standard Deviation 0.76 |
| Genotonorm 0.7 (Continuous Treatment) | Height (SDS) | 1 year (n=57, 55, 59) | -2.49 SDS | Standard Deviation 0.54 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 2 years (n=53, 49, 56) | -1.68 SDS | Standard Deviation 0.52 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 4 years (n=21, 18, 27) | -1.16 SDS | Standard Deviation 0.73 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 6 years (n=11, 7, 19) | -0.67 SDS | Standard Deviation 0.66 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | Final height (n=14, 9, 18) | -1.97 SDS | Standard Deviation 0.95 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | Baseline (n=58, 56, 60) | -3.07 SDS | Standard Deviation 0.46 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 1 year (n=57, 55, 59) | -2.17 SDS | Standard Deviation 0.5 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 3 years (n=39, 34, 41) | -1.38 SDS | Standard Deviation 0.57 |
| Genotonorm 1.4 (Continuous Treatment) | Height (SDS) | 5 years (n=12, 10, 21) | -1.15 SDS | Standard Deviation 0.83 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 3 years (n=39, 34, 41) | -2.24 SDS | Standard Deviation 0.9 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 1 year (n=57, 55, 59) | -2.68 SDS | Standard Deviation 0.69 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 4 years (n=21, 18, 27) | -2.09 SDS | Standard Deviation 0.96 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | Baseline (n=58, 56, 60) | -3.21 SDS | Standard Deviation 0.65 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | Final height (n=14, 9, 18) | -2.29 SDS | Standard Deviation 1.35 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 5 years (n=12, 10, 21) | -1.96 SDS | Standard Deviation 1.1 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 2 years (n=53, 49, 56) | -2.38 SDS | Standard Deviation 0.75 |
| Genotonorm 1.4 (Intermittent Treatment) | Height (SDS) | 6 years (n=11, 7, 19) | -1.93 SDS | Standard Deviation 1.18 |
Secondary
Number of Subjects Reaching Puberty
The defined criteria for reaching puberty were: boy=if right or left testes volume ≥4 ml; girl=if breast development ≥2. Tanner Adolescent Pubertal Staging Questionnaire documents the stage of development of secondary sexual characteristics rated in 5 stages: stage 1 (no development) to 5 (adult-like development in quantity and size). Onset of puberty was defined as the visit where the data recorded first met the above criteria for starting puberty.
Time frame: Baseline, 1 to 6 years
Population: Safety population. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years. Started = started puberty; Not Started = not started puberty yet as per Tanner scale.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Not Started) | 36 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Started) | 2 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Started) | 9 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | Baseline (Female, Not Started) | 25 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Not Started) | 16 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Not Started) | 6 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Started) | 3 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Not Started) | 19 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Started) | 2 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Started) | 6 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Started) | 1 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Not Started) | 5 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Not Started) | 10 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Not Started) | 10 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Started) | 2 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Started) | 1 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Started) | 4 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Not Started) | 20 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Not Started) | 5 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Started) | 3 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Not Started) | 24 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Started) | 3 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | Baseline (Male, Not Started) | 43 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Not Started) | 3 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Not Started) | 31 participants |
| Genotonorm 0.7 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Started) | 3 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | Baseline (Female, Not Started) | 31 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Not Started) | 27 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Not Started) | 28 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Not Started) | 15 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Started) | 1 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Started) | 2 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Started) | 1 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Started) | 3 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Not Started) | 20 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Started) | 7 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Started) | 7 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Not Started) | 10 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Started) | 9 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Started) | 7 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Not Started) | 7 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Started) | 5 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Not Started) | 5 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Started) | 2 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Not Started) | 4 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Started) | 3 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Not Started) | 6 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Not Started) | 3 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Not Started) | 4 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | Baseline (Male, Not Started) | 39 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Started) | 3 participants |
| Genotonorm 1.4 (Continuous Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Not Started) | 35 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Not Started) | 37 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Started) | 10 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Not Started) | 16 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Not Started) | 31 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Not Started) | 4 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Not Started) | 20 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 5 years (Male, Started) | 1 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Started) | 1 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 1 year (Male, Not Started) | 27 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Not Started) | 3 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 3 years (Female, Started) | 11 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 6 years (Female, Started) | 12 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Not Started) | 1 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 1 year (Female, Started) | 2 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 6 years (Male, Started) | 4 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Not Started) | 10 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 2 years (Male, Started) | 6 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 4 years (Female, Started) | 7 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | Baseline (Male, Not Started) | 29 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Not Started) | 7 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | Baseline (Female, Not Started) | 39 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 4 years (Male, Started) | 3 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Started) | 4 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 2 years (Female, Started) | 6 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 5 years (Female, Not Started) | 5 participants |
| Genotonorm 1.4 (Intermittent Treatment) | Number of Subjects Reaching Puberty | 3 years (Male, Not Started) | 9 participants |
Secondary
Weight
Time frame: Baseline, 1 to 6 years
Population: FAS. Number of Participants Analyzed = number of subjects with evaluable data at Baseline. n = number of subjects with evaluable data at each time point. Data beyond 6 years are not reported due to the low proportion of subjects followed up beyond 6 years.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Genotonorm 0.7 (Continuous Treatment) | Weight | 1 year (n=56, 55, 59) | 19.71 kg | Standard Deviation 6.28 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | 4 years (n=21, 18, 27) | 24.30 kg | Standard Deviation 7.01 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | 3 years (n=39, 34, 41) | 24.77 kg | Standard Deviation 8.8 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | Baseline (n=58, 56, 60) | 16.77 kg | Standard Deviation 5.43 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | 6 years (n=11, 7, 21) | 29.13 kg | Standard Deviation 6.42 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | 5 years (n=12, 10, 21) | 25.74 kg | Standard Deviation 6.22 |
| Genotonorm 0.7 (Continuous Treatment) | Weight | 2 years (n=53, 49, 56) | 22.66 kg | Standard Deviation 7.62 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 3 years (n=39, 34, 41) | 29.61 kg | Standard Deviation 9.62 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | Baseline (n=58, 56, 60) | 17.70 kg | Standard Deviation 5.12 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 1 year (n=56, 55, 59) | 21.29 kg | Standard Deviation 6.04 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 2 years (n=53, 49, 56) | 25.08 kg | Standard Deviation 7.43 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 4 years (n=21, 18, 27) | 30.56 kg | Standard Deviation 10.42 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 5 years (n=12, 10, 21) | 28.07 kg | Standard Deviation 5.22 |
| Genotonorm 1.4 (Continuous Treatment) | Weight | 6 years (n=11, 7, 21) | 31.94 kg | Standard Deviation 7.28 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 4 years (n=21, 18, 27) | 26.28 kg | Standard Deviation 7.94 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 1 year (n=56, 55, 59) | 19.56 kg | Standard Deviation 5.17 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 6 years (n=11, 7, 21) | 32.30 kg | Standard Deviation 10.32 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 5 years (n=12, 10, 21) | 28.52 kg | Standard Deviation 8.96 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 3 years (n=39, 34, 41) | 24.98 kg | Standard Deviation 7.05 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | 2 years (n=53, 49, 56) | 22.64 kg | Standard Deviation 6.05 |
| Genotonorm 1.4 (Intermittent Treatment) | Weight | Baseline (n=58, 56, 60) | 16.79 kg | Standard Deviation 4.35 |