Small for Gestational Age
Conditions
Keywords
Small for Gestational Age, Omnitrope®/Somatropin, rhGH,SGA
Brief summary
This study is performed to investigate the long-term safety, in particular the diabetogenic potential and immunogenicity of rhGH therapy in short children born small for gestational age (SGA).
Detailed description
Prospective, open label, non-comparative, multicenter study. Short children born SGA were to be treated until they reached final height, but treatment could be discontinued earlier if medically indicated or if there was inadequate response to treatment.
Interventions
DRUGOmnitrope
All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits.
Sponsors
Sandoz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pre-pubertal (Tanner stage I) children born SGA Boys: 4 years of age or older Girls: 4 years of age or older * Growth disturbance defined as current height SDS \< -2.5 (and parental adjusted SDS \<-1) for chronological age and sex according to country specific references. * Birth weight and/or length below -2 standard deviations (SD) for gestational age
Exclusion criteria
* Onset of puberty * Closed epiphyses * Diabetes mellitus type I or type II * Fasting blood glucose greater than 100 mg/dl or greater than 5.6 mmol/l measured in venous blood sample * Abnormal findings in Oral Glucose Tolerance Test (OGTT) defined by greater than 140 mg/dl or greater than 7.8 mmol/l after 120 minutes * Known IGF-I level above +2SD for sex and age * Acute critical illness * Previous treatment with any hGH preparation * Treatment with antidiabetic medication (e.g. metformin, insulin) * Drug abuse, substance abuse, or alcohol abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Development of Diabetes in Short Children Born SGA During Treatment | throughout the study, approximately 13 years | The development of diabetes in short children born SGA during treatment was evaluated based on the carbohydrate metabolism parameters FPG, HbA1c and OGTT (basal and 2-h plasma glucose). Only cases which were confirmed by the investigator were included. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Height Standard Deviation Score Over Time From Baseline | Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years | SDS reflects the deviation of a measured value from the mean value of normally growing children of the same sex and chronological age, expressed in units of the standard deviation (SD) of normally growing children of the same sex and chronological age. SDS was calculated according to the formula SDS=(X1-X2)/SD, where X1 is the measured value, X2 the mean value for the relevant chronological age and sex, and SD the reference standard deviation for the relevant sex and age. Refer to SAP page 14 for the formula and to Appendix B (H SDS) and D (HV SDS) for the applied reference Table. In general, a negative SDS indicates that the value is below average or mean and a positive value means it is above the average or mean. The calculated mean change compared to baseline reflects the catch-up growth over time towards average normal growth starting from below average. |
| Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | Baseline, 3 months, 1 year, 2 years, 5 years and 9 years | Mean change in Height velocity (HV) (cm/year) over time from baseline was reported. |
| Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years | SDS reflects the deviation of a measured value from the mean value of normally growing children of the same sex and chronological age, expressed in units of the standard deviation (SD) of normally growing children of the same sex and chronological age. SDS was calculated according to the formula SDS=(X1-X2)/SD, where X1 is the measured value, X2 the mean value for the relevant chronological age and sex, and SD the reference standard deviation for the relevant sex and age. Refer to SAP page 14 for the formula and to Appendix B (H SDS) and D (HV SDS) for the applied reference Table. In general, a negative SDS indicates that the value is below average or mean and a positive value means it is above the average or mean. The calculated mean change compared to baseline reflects the initial high increase in height velocity which remains positive over years, but is decreasing over time. |
| Mean Change in Height (H) (cm) From Baseline | Baseline, 3 months, 1 year, 2 years, 5 years and 9 years | Mean change in Height from baseline for all patients was reported. |
| Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | Baseline, 3 months, 1 year, 2 years, 5 years and 9 years | Mean change in IGFBP-3 levels (nmol/L) from baseline was reported. |
| Number of Participants With the Development of Anti-rhGH Antibodies During Omnitrope Treatment | throughout the study, approximately 13 years | Number of participants with the development of anti-rhGH antibodies with positive test result were reported. |
| Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | Baseline, 3 months, 1 year, 2 years, 5 years and 9 years | Mean change in serum IGF-1 level (nmol/L) from baseline was reported. |
Countries
Belgium, Czechia, Georgia, Germany, Hungary, Poland, Romania
Participant flow
Recruitment details
Study was carried out in 31 centers in 7 countries (Poland, Romania, Hungary, Czech Republic, Germany, Belgium and Georgia).
Pre-assignment details
This study was not randomized. All enrolled patients received Omnitrope
Participants by arm
| Arm | Count |
|---|---|
| Omnitrope All enrolled patients received Omnitrope. The median daily dose varied between 0.0340 and 0.0351 mg/kg/day and the maximum range was 0.000 to 0.040 mg/kg/day over all visits. | 278 |
| Total | 278 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 19 |
| Overall Study | patients documented other as reason for study discontinuation | 16 |
| Overall Study | Treatment failure | 10 |
| Overall Study | Withdrawal of informed consent | 59 |
Baseline characteristics
| Characteristic | Omnitrope |
|---|---|
| Age, Continuous | 7.36 years STANDARD_DEVIATION 2.7 |
| Race/Ethnicity, Customized Black | 0 participants |
| Race/Ethnicity, Customized Caucasian | 276 participants |
| Race/Ethnicity, Customized Oriental | 1 participants |
| Race/Ethnicity, Customized Other: specified as Mixed ethnic origin (Arabic/ Caucasian) | 1 participants |
| Sex: Female, Male Female | 130 Participants |
| Sex: Female, Male Male | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 277 |
| other Total, other adverse events | 210 / 277 |
| serious Total, serious adverse events | 74 / 277 |
Outcome results
Primary
Number of Participants With Development of Diabetes in Short Children Born SGA During Treatment
The development of diabetes in short children born SGA during treatment was evaluated based on the carbohydrate metabolism parameters FPG, HbA1c and OGTT (basal and 2-h plasma glucose). Only cases which were confirmed by the investigator were included.
Time frame: throughout the study, approximately 13 years
Population: Safety analysis set: SAF comprised all patients who received at least 1 dose of study medication and had at least 1 post-baseline safety assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omnitrope | Number of Participants With Development of Diabetes in Short Children Born SGA During Treatment | 0 Participants |
Secondary
Mean Change in Height (H) (cm) From Baseline
Mean change in Height from baseline for all patients was reported.
Time frame: Baseline, 3 months, 1 year, 2 years, 5 years and 9 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in Height (H) (cm) From Baseline | 2 years | 16.52 cm |
| Omnitrope | Mean Change in Height (H) (cm) From Baseline | 3 months | 2.74 cm |
| Omnitrope | Mean Change in Height (H) (cm) From Baseline | 1 year | 9.08 cm |
| Omnitrope | Mean Change in Height (H) (cm) From Baseline | 5 years | 35.10 cm |
| Omnitrope | Mean Change in Height (H) (cm) From Baseline | 9 years | 58.07 cm |
Secondary
Mean Change in Height Standard Deviation Score Over Time From Baseline
SDS reflects the deviation of a measured value from the mean value of normally growing children of the same sex and chronological age, expressed in units of the standard deviation (SD) of normally growing children of the same sex and chronological age. SDS was calculated according to the formula SDS=(X1-X2)/SD, where X1 is the measured value, X2 the mean value for the relevant chronological age and sex, and SD the reference standard deviation for the relevant sex and age. Refer to SAP page 14 for the formula and to Appendix B (H SDS) and D (HV SDS) for the applied reference Table. In general, a negative SDS indicates that the value is below average or mean and a positive value means it is above the average or mean. The calculated mean change compared to baseline reflects the catch-up growth over time towards average normal growth starting from below average.
Time frame: Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 0.5 year | 0.51 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 2 years | 1.25 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 3 years | 1.50 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 4 years | 1.67 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 5 years | 1.82 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 6 years | 1.94 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 7 years | 2.07 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 8 years | 2.19 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 9 years | 2.18 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 10 years | 2.21 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 11 years | 2.38 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 12 years | 2.39 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 12.5 years | 3.01 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 3 months | 0.30 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 9 months | 0.68 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 1 year | 0.81 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 1.25 years | 0.93 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 1.5 years | 1.04 SDS |
| Omnitrope | Mean Change in Height Standard Deviation Score Over Time From Baseline | 1.75 years | 1.16 SDS |
Secondary
Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline
Mean change in Height velocity (HV) (cm/year) over time from baseline was reported.
Time frame: Baseline, 3 months, 1 year, 2 years, 5 years and 9 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | 3 months | 6.45 cm/year |
| Omnitrope | Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | 1 year | 4.71 cm/year |
| Omnitrope | Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | 2 years | 3.02 cm/year |
| Omnitrope | Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | 5 years | 1.37 cm/year |
| Omnitrope | Mean Change in Height Velocity (HV) (cm/Year) Over Time From Baseline | 9 years | 0.10 cm/year |
Secondary
Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline
SDS reflects the deviation of a measured value from the mean value of normally growing children of the same sex and chronological age, expressed in units of the standard deviation (SD) of normally growing children of the same sex and chronological age. SDS was calculated according to the formula SDS=(X1-X2)/SD, where X1 is the measured value, X2 the mean value for the relevant chronological age and sex, and SD the reference standard deviation for the relevant sex and age. Refer to SAP page 14 for the formula and to Appendix B (H SDS) and D (HV SDS) for the applied reference Table. In general, a negative SDS indicates that the value is below average or mean and a positive value means it is above the average or mean. The calculated mean change compared to baseline reflects the initial high increase in height velocity which remains positive over years, but is decreasing over time.
Time frame: Baseline, 3 months, 0.5 year, 9 months, 1 year, 1.25 years, 1.5 years, 1.75 years, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 12.5 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 2 years | 4.35 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 3 years | 3.62 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 4 years | 3.08 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 5 years | 2.99 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 6 years | 2.63 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 7 years | 2.43 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 9 years | 0.85 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 10 years | 0.62 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 11 years | 1.60 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 12 years | 1.34 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 12.5 years | 1.98 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 3 months | 8.41 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 0.5 year | 7.27 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 9 months | 6.69 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 1 year | 6.26 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 1.25 years | 5.29 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 1.5 years | 4.85 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 1.75 years | 4.59 SDS |
| Omnitrope | Mean Change in Height Velocity Standard Deviation Score (HV SDS) Over Time From Baseline | 8 years | 1.37 SDS |
Secondary
Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline
Mean change in IGFBP-3 levels (nmol/L) from baseline was reported.
Time frame: Baseline, 3 months, 1 year, 2 years, 5 years and 9 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | 3 months | 24.85 nmol/L |
| Omnitrope | Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | 1 year | 30.48 nmol/L |
| Omnitrope | Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | 2 years | 48.48 nmol/L |
| Omnitrope | Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | 5 years | 92.94 nmol/L |
| Omnitrope | Mean Change in IGFBP-3 Levels (Nmol/L) From Baseline | 9 years | 139.12 nmol/L |
Secondary
Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline
Mean change in serum IGF-1 level (nmol/L) from baseline was reported.
Time frame: Baseline, 3 months, 1 year, 2 years, 5 years and 9 years
Population: Full analysis set: FAS followed the ITT principle and comprised all patients who received at least 1 dose of study medication. Not all patients may have outcome data for all visits.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Omnitrope | Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | 3 months | 13.04 nmol/L |
| Omnitrope | Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | 1 year | 20.58 nmol/L |
| Omnitrope | Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | 2 years | 30.64 nmol/L |
| Omnitrope | Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | 5 years | 44.87 nmol/L |
| Omnitrope | Mean Change in Serum IGF-1 Level (Nmol/L) From Baseline | 9 years | 75.72 nmol/L |
Secondary
Number of Participants With the Development of Anti-rhGH Antibodies During Omnitrope Treatment
Number of participants with the development of anti-rhGH antibodies with positive test result were reported.
Time frame: throughout the study, approximately 13 years
Population: Safety analysis set: SAF comprised all patients who received at least 1 dose of study medication and had at least 1 post-baseline safety assessment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Omnitrope | Number of Participants With the Development of Anti-rhGH Antibodies During Omnitrope Treatment | 23 Participants |