Growth Hormone Therapy, Infant, Very Low Birth Weight
Conditions
Brief summary
Safety and efficacy of Somatropin will be evaluated in short children born with a list weight below 1500 g and that did not catch up to normal height at the age of 4.
Interventions
DRUGSomatropin
Controlled, prospective, randomized, multicenter study with an untreated (control) group during the first year. The children will be randomized into treatment or untreated (control) group. After one year the control group will undergo GH-therapy, too. Children randomized to the control group will get the possibility to continue treatment for a further year. The study will end after 2 and 3 years of observation, respectively.
OTHERControl Arm
Controlled, prospective, randomized, multicenter study with an untreated (control) group during the first year. The children will be randomized into treatment or untreated (control) group. After one year the control group will undergo GH-therapy, too. The study will end after 2 and 3 years of observation, respectively. Children randomized to the control group will get the possibility to continue treatment for a further year.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial: * Prepubertal caucasian boys between 4 and 10 years of age and girls between 4 and 9 years of age. * Girls: Tanner stage 1 breast development * Boys: Testis volume \<= 3ml * Tanner stage 1 pubic hair development (to exclude confounding effect of adrenarche on growth velocity, insulin sensitivity and body composition). * (In case of any signs or symptoms of gonadal puberty a GnRH-Test must decide if the subject is still pubertal.) * Height \<=-2 SD for chronological age (Brandt/Reinken). * Growth velocity SDS below 0 SD for chronological age (Brandt/Reinken based on 12+/- 3 months observation period before screening). * Premature born defined as \<=1500 g birth weight. * GH sufficiency (GH level \> 7 ug/l following any routine GH stimulation test). * Written informed consent of both parents (legal guardians) and oral/written consent of subject due to age specific information.
Exclusion criteria
Subjects presenting with any of the following will not be included in the trial: * Other endocrine diseases except for well substituted hypothyroidism. * Severe chronic diseases or medication that might influence linear growth or insulin sensitivity (e.g. Glucocorticoids). * Positive GAD and IA-2 antibodies (for type 1 diabetes). * History of malignancy * Children who meet all of the following 4 criteria: * actual body height \< -2,5 SDS (Brandt/Reinken) and parent adjusted target height \< -1 SDS (Hermanussen and Cole, 2003) * length and/or body weight retardations adjusted to gestational age at birth \< -2,0 SDS (Lawrence et al., 1989, Voigt et al., 1996) * children with chronological age \> = 4 years and * growth velocity \< 0 SDS during the last year before inclusion. * Chromosomal aberrations or syndromes. * Suspected non-compliance or impossibility to follow the two or three year treatment schedule, respectively (e.g. social implications). * Severe hemiparesis and severe CNS defects * Retinopathia \> third degree or laser treatment as newborns. * Participation in any other clinical trial during active treatment phase. * Other severe acute or chronic medical or psychiatric condition or clinically relevant laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgement of the investigator, would make the subject inappropriate for entry into this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Height Standard Deviation Score (SDS) After 1 Year | Baseline to 1 year (Month 12) | Change in Height SDS after 1 year where SDS=height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). |
| Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year | Baseline to 1 year (Month 12) | Change in Growth Velocity (GV) SDS after 1 year where SDS=GV minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Height After 1 Year and After 2 Years | Baseline, Month 12, Month 24 | — |
| Change From Baseline in Height SDS After 2 Years | Baseline, Month 24 | Change in Height SDS after 2 years (24 months) where SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). |
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Baseline, Month 12, Month 24 | Body composition measured as skinfold thickness at tricep in millimeters (mm); measured halfway down the left upper arm with arm hanging in relaxed position at participant's side. |
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Baseline, Month 12, Month 24 | Body composition measured as subscapular skinfold thickness in millimeters (mm); measured laterally just below the angle of the left scapula. |
| Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Baseline, Month 12, Month 24 | Body composition measured as suprailiac skinfold thickness in millimeters (mm); measured just above the iliac crest in the middle-axillary line. |
| Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Baseline, Month 12, Month 24 | Volumetric Cortical BMD measured as milligrams per cubic millimeter (mg/mm3). BMD (proximal radius) SDS (number of standard deviations a participant's BMD differs from the average BMD of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Baseline, Month 12, Month 24 | Bone structure Cortical CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Baseline, Month 12, Month 24 | Bone structure Total CSA measured as millimeters squared (mm2). Total CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Baseline, Month 12, Month 24 | Bone structure Muscle CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Baseline, Month 12, Month 24 | Growth velocity measured as centimeters per year. |
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Marrow Area (MA) | Baseline, Month 12, Month 24 | Marrow Area measured as millimeters squared (mm2). MA (proximal radius) SDS (number of standard deviations a participant's MA differs from the average MA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Baseline, Month 12, Month 24 | Bone stability expressed as polar SSI in cubic millimeters (mm3). SSI (proximal radius) SDS (number of standard deviations a participant's SSI differs from the average SSI of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Baseline, Month 12, Month 24 | Muscle strength determined by measuring grip force (kilograms) using hand grip dynamometer for participants ≥6 years of age. Baseline and post-baseline SDS values transformed to age and sex specific z-score. Change in hand grip calculated as SDS where SDS = hand grip minus mean (age- and sex-matched reference) divided by SD (age- and sex-matched reference). Positive values are above the average for participant's age and sex; negative values are below the average. |
| Number of Participants With Change in Insulin Sensitivity: Somatropin | Baseline, Month 24 | Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Somatropin treatment group=Month 24). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to \>140 mg/dL; capillary (blood) with range minimum 120 mg/dL to \>120 mg/dL; or method not known with range minimum 120 mg/dL to \>120 mg/dL. |
| Number of Participants With Change in Insulin Sensitivity: Control Arm | Baseline, Month 36 | Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Control Arm=Month 36). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to \>140 mg/dL; capillary (blood) with range minimum 120 mg/dL to \>120 mg/dL; or method not known with range minimum 120 mg/dL to \>120 mg/dL. |
| Growth Curve Comparison Based on Height SDS | Month 12, Month 24 | Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). |
| Growth Curve Comparison Based on Height SDS: Control Arm | Month 36 | Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). Control Arm final visit=Month 36. |
| Growth Curve Comparison Based on Height | Month 12, Month 24 | Growth curve comparison with height in centimeters as the dependent variable. |
| Growth Curve Comparison Based on Height: Control Arm | Month 36 | Growth curve comparison with height in centimeters as the dependent variable. |
| Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Thickness (CT) | Baseline, Month 12, Month 24 | Cortical Thickness measured as millimeters (mm). CT (proximal radius) SDS (number of standard deviations a participant's CT differs from the average CT of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average. |
| Change From Baseline in Growth Velocity SDS After 2 Years | Baseline, Month 24 | Change in Growth Velocity SDS after 2 years (24 months) where SDS = growth velocity minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Somatropin The children were randomized into a treated group receiving 0.068 mg/kg/day (0.48mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation. Dose adjustments were made at 6 month intervals. (mg=milligrams, kg=kilograms) | 18 |
| Control Arm The children were randomized into control group and after 1 year underwent Growth Hormone (GH) therapy, with 0.068 mg/kg/day (0.48mg/kg/week) subcutaneous somatropin according to exact body weight specific calculation. Dose adjustments were made at 6 month intervals. mg=milligram, kg=kilogram. | 15 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Somatropin | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 5.4 years STANDARD_DEVIATION 1.6 | 5.7 years STANDARD_DEVIATION 1.9 | 5.5 years STANDARD_DEVIATION 1.7 |
| Age, Customized <4 years | 1 Participants 1.5 | 1 Participants 1.9 | 2 Participants 1.7 |
| Age, Customized ≥4 years and <8 years | 14 Participants | 11 Participants | 25 Participants |
| Age, Customized ≥8 years and <12 years | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 18 | 11 / 15 |
| serious Total, serious adverse events | 5 / 18 | 1 / 15 |
Outcome results
Primary
Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year
Change in Growth Velocity (GV) SDS after 1 year where SDS=GV minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference).
Time frame: Baseline to 1 year (Month 12)
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year | 7.117 centimeters per year | Standard Error 0.4384 |
| Control Arm | Change in Growth Velocity Standard Deviation Score (SDS) After 1 Year | 1.502 centimeters per year | Standard Error 0.4814 |
Comparison: Treatment differencep-value: <0.00195% CI: [4.266, 6.963]ANCOVA
Primary
Change in Height Standard Deviation Score (SDS) After 1 Year
Change in Height SDS after 1 year where SDS=height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference).
Time frame: Baseline to 1 year (Month 12)
Population: Full Analysis Set (FAS; all randomized subjects who had at least 1 post-baseline efficacy measurement); Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Change in Height Standard Deviation Score (SDS) After 1 Year | 1.099 centimeters | Standard Error 0.0714 |
| Control Arm | Change in Height Standard Deviation Score (SDS) After 1 Year | 0.108 centimeters | Standard Error 0.0783 |
Comparison: Treatment differencep-value: <0.00195% CI: [0.773, 1.21]ANCOVA
Secondary
Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular
Body composition measured as subscapular skinfold thickness in millimeters (mm); measured laterally just below the angle of the left scapula.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. N=number of participants with evaluable data at observation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Month 12 | 0.08 millimeters | Standard Error 0.276 |
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Month 24 | 0.27 millimeters | Standard Error 0.231 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Month 12 | 0.46 millimeters | Standard Error 0.286 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Subscapular | Month 24 | 0.50 millimeters | Standard Error 0.247 |
Comparison: Treatment difference Month 12p-value: 0.36495% CI: [-1.21, 0.46]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.50695% CI: [-0.94, 0.48]ANCOVA
Secondary
Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac
Body composition measured as suprailiac skinfold thickness in millimeters (mm); measured just above the iliac crest in the middle-axillary line.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. N=number of participants with evaluable data at observation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Month 12 | 0.51 millimeters | Standard Error 0.783 |
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Month 24 | 0.90 millimeters | Standard Error 0.688 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Month 12 | 0.45 millimeters | Standard Error 0.849 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Suprailiac | Month 24 | 0.79 millimeters | Standard Error 0.774 |
Comparison: Treatment difference Month 12p-value: 0.95995% CI: [-2.42, 2.54]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.91995% CI: [-2.11, 2.32]ANCOVA
Secondary
Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps
Body composition measured as skinfold thickness at tricep in millimeters (mm); measured halfway down the left upper arm with arm hanging in relaxed position at participant's side.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. N=number of participants with evaluable data at observation.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Month 12 | -2.20 millimeters | Standard Error 0.341 |
| Somatropin | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Month 24 | -1.30 millimeters | Standard Error 0.511 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Month 12 | 0.50 millimeters | Standard Error 0.353 |
| Control Arm | Change From Baseline in Body Composition (Skinfold Thickness) After 1 Year and After 2 Years: Triceps | Month 24 | -0.83 millimeters | Standard Error 0.548 |
Comparison: Treatment difference Month 12p-value: <0.00195% CI: [-3.73, -1.68]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.53795% CI: [-2.04, 1.09]ANCOVA
Secondary
Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI)
Bone stability expressed as polar SSI in cubic millimeters (mm3). SSI (proximal radius) SDS (number of standard deviations a participant's SSI differs from the average SSI of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Month 12 (n=2, 6) | 0.648 z-score | Standard Error 0.4224 |
| Somatropin | Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Month 24 (n=2, 6) | 0.477 z-score | Standard Error 0.3925 |
| Control Arm | Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Month 12 (n=2, 6) | 0.088 z-score | Standard Error 0.2243 |
| Control Arm | Change From Baseline in Bone Stability Using pQCT After 1 Year and After 2 Years: Strength-strain Index (SSI) | Month 24 (n=2, 6) | 0.363 z-score | Standard Error 0.2084 |
Comparison: Treatment difference Month 12p-value: 0.33195% CI: [-0.846, 1.965]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.8295% CI: [-1.192, 1.42]ANCOVA
Secondary
Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA)
Bone structure Total CSA measured as millimeters squared (mm2). Total CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Month 12 (n=2, 5) | 0.375 z-score | Standard Error 0.9345 |
| Somatropin | Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Month 24 (n=2, 6) | 0.243 z-score | Standard Error 0.3694 |
| Control Arm | Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Month 12 (n=2, 5) | 0.239 z-score | Standard Error 0.5537 |
| Control Arm | Change From Baseline in Bone Structure Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and 2 Years: Total Cross-sectional Area (CSA) | Month 24 (n=2, 6) | -0.049 z-score | Standard Error 0.1955 |
Comparison: Treatment difference Month 12p-value: 0.91495% CI: [-3.524, 3.795]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.54795% CI: [-0.939, 1.522]ANCOVA
Secondary
Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA)
Bone structure Cortical CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Month 12 (n=2, 5) | -0.465 z-score | Standard Error 0.7799 |
| Somatropin | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Month 24 (n=2, 6) | -0.595 z-score | Standard Error 0.7462 |
| Control Arm | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Month 12 (n=2, 5) | 0.017 z-score | Standard Error 0.4559 |
| Control Arm | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Cross-sectional Area (CSA) | Month 24 (n=2, 6) | 0.609 z-score | Standard Error 0.3907 |
Comparison: Treatment difference Month 12p-value: 0.65395% CI: [-3.558, 2.595]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.25195% CI: [-3.701, 1.292]ANCOVA
Secondary
Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Cortical Thickness (CT)
Cortical Thickness measured as millimeters (mm). CT (proximal radius) SDS (number of standard deviations a participant's CT differs from the average CT of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. Cortical thickness was not analyzed as planned.
Secondary
Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Marrow Area (MA)
Marrow Area measured as millimeters squared (mm2). MA (proximal radius) SDS (number of standard deviations a participant's MA differs from the average MA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. Marrow Area was not analyzed as planned.
Secondary
Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA)
Bone structure Muscle CSA measured as millimeters squared (mm2). CSA (proximal radius) SDS (number of standard deviations a participant's CSA differs from the average CSA of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Month 12 (n=2, 6) | 2.084 z-score | Standard Error 0.3628 |
| Somatropin | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Month 24 (n=2, 6) | 2.402 z-score | Standard Error 0.5221 |
| Control Arm | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Month 12 (n=2, 6) | -0.227 z-score | Standard Error 0.1688 |
| Control Arm | Change From Baseline in Bone Structure Using pQCT After 1 Year and 2 Years: Muscle Cross-sectional Area (CSA) | Month 24 (n=2, 6) | 0.776 z-score | Standard Error 0.2428 |
Comparison: Treatment difference Month 12p-value: 0.00795% CI: [1.049, 3.572]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.06895% CI: [-0.189, 3.44]ANCOVA
Secondary
Change From Baseline in Growth Velocity After 1 Year and After 2 Years
Growth velocity measured as centimeters per year.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Month 12 | 5.110 centimeters per year | Standard Error 0.2623 |
| Somatropin | Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Month 24 | 3.049 centimeters per year | Standard Error 0.3546 |
| Control Arm | Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Month 12 | 0.695 centimeters per year | Standard Error 0.2881 |
| Control Arm | Change From Baseline in Growth Velocity After 1 Year and After 2 Years | Month 24 | 3.934 centimeters per year | Standard Error 0.3893 |
Comparison: Treatment difference Month 12p-value: <0.00195% CI: [3.605, 5.225]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.10895% CI: [-1.977, 0.208]ANCOVA
Secondary
Change From Baseline in Growth Velocity SDS After 2 Years
Change in Growth Velocity SDS after 2 years (24 months) where SDS = growth velocity minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference).
Time frame: Baseline, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Change From Baseline in Growth Velocity SDS After 2 Years | 4.751 centimeters per year | Standard Error 0.4716 |
| Control Arm | Change From Baseline in Growth Velocity SDS After 2 Years | 5.825 centimeters per year | Standard Error 0.5177 |
Comparison: Treatment differencep-value: 0.14195% CI: [-2.524, 0.376]ANCOVA
Secondary
Change From Baseline in Height After 1 Year and After 2 Years
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Height After 1 Year and After 2 Years | Month 12 | 10.467 centimeters | Standard Error 0.2439 |
| Somatropin | Change From Baseline in Height After 1 Year and After 2 Years | Month 24 | 18.908 centimeters | Standard Error 0.6507 |
| Control Arm | Change From Baseline in Height After 1 Year and After 2 Years | Month 12 | 5.927 centimeters | Standard Error 0.2677 |
| Control Arm | Change From Baseline in Height After 1 Year and After 2 Years | Month 24 | 14.844 centimeters | Standard Error 0.7149 |
Comparison: Treatment difference Month 12p-value: <0.00195% CI: [3.789, 5.291]ANCOVA
Comparison: Treatment difference Month 24p-value: <0.00195% CI: [2.049, 6.08]ANCOVA
Secondary
Change From Baseline in Height SDS After 2 Years
Change in Height SDS after 2 years (24 months) where SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference).
Time frame: Baseline, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Change From Baseline in Height SDS After 2 Years | 1.710 centimeters | Standard Error 0.1075 |
| Control Arm | Change From Baseline in Height SDS After 2 Years | 0.991 centimeters | Standard Error 0.1179 |
Comparison: Treatment difference Month 24p-value: <0.00195% CI: [0.39, 1.047]ANCOVA
Secondary
Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years
Muscle strength determined by measuring grip force (kilograms) using hand grip dynamometer for participants ≥6 years of age. Baseline and post-baseline SDS values transformed to age and sex specific z-score. Change in hand grip calculated as SDS where SDS = hand grip minus mean (age- and sex-matched reference) divided by SD (age- and sex-matched reference). Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants ≥6 years of age with evaluable data at observation for Somatropin and Control Arm, respectively. SDS reference values used were for the right hand but the hand grip strength measured for this study was for the dominant hand (may not have been the right hand).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Month 12 (n=7, 5) | 0.37 z-score | Standard Error 0.268 |
| Somatropin | Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Month 24 (n=7, 6) | 1.14 z-score | Standard Error 0.218 |
| Control Arm | Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Month 12 (n=7, 5) | 0.28 z-score | Standard Error 0.318 |
| Control Arm | Change From Baseline in Muscle Strength: Hand Grip SDS After 1 Year and After 2 Years | Month 24 (n=7, 6) | 0.92 z-score | Standard Error 0.236 |
Comparison: Treatment difference Month 12p-value: 0.84495% CI: [-0.88, 1.05]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.51995% CI: [-0.52, 0.96]ANCOVA
Secondary
Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years
Volumetric Cortical BMD measured as milligrams per cubic millimeter (mg/mm3). BMD (proximal radius) SDS (number of standard deviations a participant's BMD differs from the average BMD of their age and sex). Baseline and post-baseline SDS values transformed to age and sex specific z-score (Ln(test result/M)\]/S); Ln=natural logarithm; M=age- or height-) and sex-specific mean value; S=age-(or height-) and sex-specific coefficient of variation) then change from baseline is calculated. Positive values are above the average for participant's age and sex; negative values are below the average.
Time frame: Baseline, Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards; (n)=number of participants from FAS with evaluable pQCT data for somatropin and control arm groups, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Month 12 (n=2, 6) | -1.055 z-score | Standard Error 0.6802 |
| Somatropin | Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Month 24 (n=2, 6) | 0.284 z-score | Standard Error 0.5023 |
| Control Arm | Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Month 12 (n=2, 6) | -0.162 z-score | Standard Error 0.36 |
| Control Arm | Change From Baseline in Volumetric Cortical Bone Mineral Density (BMD) Using Peripheral Quantitative Computed Tomography (pQCT) After 1 Year and After 2 Years | Month 24 (n=2, 6) | -0.433 z-score | Standard Error 0.2658 |
Comparison: Treatment difference Month 12p-value: 0.33695% CI: [-3.158, 1.374]ANCOVA
Comparison: Treatment difference Month 24p-value: 0.395% CI: [-0.956, 2.391]ANCOVA
Secondary
Growth Curve Comparison Based on Height
Growth curve comparison with height in centimeters as the dependent variable.
Time frame: Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. Data for Month 36 (applicable only to the Control Arm) is reported in a separate outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Growth Curve Comparison Based on Height | Month 12 | 114.228 centimeters | Standard Error 0.333 |
| Somatropin | Growth Curve Comparison Based on Height | Month 24 | 123.351 centimeters | Standard Error 0.483 |
| Control Arm | Growth Curve Comparison Based on Height | Month 12 | 109.644 centimeters | Standard Error 0.3733 |
| Control Arm | Growth Curve Comparison Based on Height | Month 24 | 119.788 centimeters | Standard Error 0.5255 |
Comparison: Treatment difference Month 12p-value: <0.00195% CI: [3.806, 5.363]Mixed models analysis
Comparison: Treatment difference Month 24p-value: <0.00195% CI: [2.134, 4.992]Mixed models analysis
Secondary
Growth Curve Comparison Based on Height: Control Arm
Growth curve comparison with height in centimeters as the dependent variable.
Time frame: Month 36
Population: FAS; Control group received Somatropin from Month 12 onwards. N=number of subjects with evaluable data at observation. Month 36 visit not applicable to Somatropin treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Growth Curve Comparison Based on Height: Control Arm | 128.049 centimeters | Standard Error 0.7821 |
Secondary
Growth Curve Comparison Based on Height SDS
Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference).
Time frame: Month 12, Month 24
Population: FAS; Control group received Somatropin from Month 12 onwards. Data for Month 36 (applicable only to the Control Arm) is reported in a separate outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Growth Curve Comparison Based on Height SDS | Month 12 | -2.260 centimeters | Standard Error 0.0735 |
| Somatropin | Growth Curve Comparison Based on Height SDS | Month 24 | -1.638 centimeters | Standard Error 0.1016 |
| Control Arm | Growth Curve Comparison Based on Height SDS | Month 12 | -3.259 centimeters | Standard Error 0.0802 |
| Control Arm | Growth Curve Comparison Based on Height SDS | Month 24 | -2.327 centimeters | Standard Error 0.1122 |
Comparison: Treatment difference Month 12p-value: <0.00195% CI: [0.778, 1.219]Mixed models analysis
Comparison: Treatment difference Month 24p-value: <0.00195% CI: [0.382, 0.994]Mixed models analysis
Secondary
Growth Curve Comparison Based on Height SDS: Control Arm
Growth curve comparison with height SDS in centimeters as the dependent variable; SDS = height minus mean (age-and sex-matched reference) divided by SD (age and sex-matched reference). Control Arm final visit=Month 36.
Time frame: Month 36
Population: FAS; Control group received Somatropin from Month 12 onwards. N=number of subjects with evaluable data at observation. Month 36 visit not applicable to Somatropin treatment group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Growth Curve Comparison Based on Height SDS: Control Arm | -1.794 centimeters | Standard Error 0.1318 |
Secondary
Number of Participants With Change in Insulin Sensitivity: Control Arm
Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Control Arm=Month 36). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to \>140 mg/dL; capillary (blood) with range minimum 120 mg/dL to \>120 mg/dL; or method not known with range minimum 120 mg/dL to \>120 mg/dL.
Time frame: Baseline, Month 36
Population: FAS; Control group received Somatropin from Month 12 onwards.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Control Arm | Baseline: tolerant | 14 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Control Arm | Baseline: intolerant | 1 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Control Arm | Month 36: tolerant | 11 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Control Arm | Month 36: intolerant | 2 participants |
Secondary
Number of Participants With Change in Insulin Sensitivity: Somatropin
Insulin sensitivity calculated as incidence of pathological glucose intolerance assessed prior to randomization (Screening Day -3 to Baseline Day 0) and at final visit (final visit: Somatropin treatment group=Month 24). Pathological glucose intolerance (oral glucose tolerance test) measured as venous (blood or plasma) with range minimum 120 milligrams per deciliter (mg/dL) to \>140 mg/dL; capillary (blood) with range minimum 120 mg/dL to \>120 mg/dL; or method not known with range minimum 120 mg/dL to \>120 mg/dL.
Time frame: Baseline, Month 24
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Somatropin | Baseline: tolerant | 18 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Somatropin | Baseline: intolerant | 0 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Somatropin | Month 24: tolerant | 16 participants |
| Somatropin | Number of Participants With Change in Insulin Sensitivity: Somatropin | Month 24: intolerant | 0 participants |