Short Children Born Small for Gestational Age (SGA)
Conditions
Keywords
Long-term, safety, follow-up, growth hormone treatment, short children, Small for Gestational Age, Somatropin
Brief summary
This study is performed as part of the Marketing Authorisation Holder's post-marketing pharmacovigilance plan 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
The purpose of this study is 1. to monitor short children born SGA who were treated with growth hormone in study EP00-401 for the development of diabetes for a further 10 years after termination of growth hormone treatment and 2. to report the incidence of anti-rhGH antibodies and of E. coli host cell peptide (HCP) antibodies (ABs) for 6 months after termination of GH treatment.
Interventions
OTHERBloodsampling
Bloodsampling
Sponsors
Sandoz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All patients who fulfilled the diagnosis SGA, participated in study EP00-401, and received at least one dose of study medication * Written informed consent of patient (for children who can read and/ or understand) and/or parent or legal guardian
Exclusion criteria
* Patients unwilling and/or parents/guardians who are not capable of ensuring compliance with the provisions of the study protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | baseline, 6 months, 1 year, 5 years | Supportive to Primary Endpoint. HOMA = homeostasis model assessment for Insulin resistance: Healthy Range: 1.0 (0.5-1.4). \< 1.0 means you are insulin-sensitive which is optimal. \>1.9 indicates early insulin resistance. \> 2.9 indicates significant insulin resistance. The quantitative insulin sensitivity check index (QUICKI) measures insulin sensitivity, which is the inverse of insulin resistance. The QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. Lower numbers reflect greater insulin resistance. |
| To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c) | baseline, 6 months, 1 year, 5 years | Supportive to Primary Endpoint |
| To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels | baseline, 6 months, 1 year, 5 years | Supportive to Primary Endpoint |
| Evaluate the Long-term Effect of Growth Hormone Treatment on the Development of Diabetes After End of Therapy. | 5 years | Number of participants diagnosed with Diabetes mellitus type 2 during the study, defined as fullfilment of these 3 criteria: * FPG ≥ 126 mg/dl (7.0 mmol/L) during blood sampling and/or during Oral Glucose Tolerance Test (OGTT) * 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/L) during an OGTT * Investigator documenting diagnosis of diabetes mellitus type 2 during OGTT |
| To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels | baseline, 6 months, 1 year, 5 years | Supportive to Primary Endpoint |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment. | baseline, 6 months, 1 year, 5 years | number of participants with positive results for anti-drug antibody (ADA). Percentages indicated are calculated based on the total number of patients (118 participants). |
| to Evaluate Final Height | baseline, 6 months, 1 year, 5 years | — |
| to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | baseline, 6 months, 1 year , 5 years | — |
Countries
Czechia, Georgia, Germany, Hungary, Poland, Romania
Participant flow
Recruitment details
130 participants signed informed consent. Of the 130 enrolled subjects, 11 subjects had no post-baseline visit, leading to exclusion from the SAF/FAS. Another subject was excluded as he received treatment with Omnitrope, which was not consistent with the protocol. Accordingly, 118 subjects comprised the SAF and in the FAS
Pre-assignment details
SAF : safety Analysis set FAS : full Analysis set
Participants by arm
| Arm | Count |
|---|---|
| Monitoring of Long-term Safety Long-term safety follow-up after the end of treatment with Omnitrope (single arm) | 118 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 33 |
| Overall Study | mainly due to premature termination | 93 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Monitoring of Long-term Safety |
|---|---|
| Age, Continuous | 14.79 years STANDARD_DEVIATION 2.848 |
| Race/Ethnicity, Customized Caucasian | 118 Participants |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 118 |
| other Total, other adverse events | 23 / 118 |
| serious Total, serious adverse events | 8 / 118 |
Outcome results
Primary
Evaluate the Long-term Effect of Growth Hormone Treatment on the Development of Diabetes After End of Therapy.
Number of participants diagnosed with Diabetes mellitus type 2 during the study, defined as fullfilment of these 3 criteria: * FPG ≥ 126 mg/dl (7.0 mmol/L) during blood sampling and/or during Oral Glucose Tolerance Test (OGTT) * 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/L) during an OGTT * Investigator documenting diagnosis of diabetes mellitus type 2 during OGTT
Time frame: 5 years
Population: full Analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Monitoring of Long-term Safety | Evaluate the Long-term Effect of Growth Hormone Treatment on the Development of Diabetes After End of Therapy. | 0 Participants |
Primary
To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels
Supportive to Primary Endpoint
Time frame: baseline, 6 months, 1 year, 5 years
Population: full Analysis set with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels | baseline | 70.87 pmol/L | Standard Deviation 38.477 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels | 6 months | -2.34 pmol/L | Standard Deviation 38.267 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels | 1 year | -7.48 pmol/L | Standard Deviation 34.676 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Insulin Levels | 5 years | 3.40 pmol/L | Standard Deviation 52.526 |
Primary
To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels
Supportive to Primary Endpoint
Time frame: baseline, 6 months, 1 year, 5 years
Population: safety Analysis set with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels | FPG baseline | 4.69 mmol/L | Standard Deviation 0.492 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels | FPG 6 months | -0.13 mmol/L | Standard Deviation 0.567 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels | FPG 1 year | -0.14 mmol/L | Standard Deviation 0.457 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Fasting Plasma Glucose (FPG) Levels | FPG 5 years | -0.37 mmol/L | Standard Deviation 0.856 |
Primary
To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c)
Supportive to Primary Endpoint
Time frame: baseline, 6 months, 1 year, 5 years
Population: full Analysis set with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c) | baseline | 5.280 percentage | Standard Deviation 0.3569 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c) | 6 months | -0.057 percentage | Standard Deviation 0.3621 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c) | 1 year | -0.108 percentage | Standard Deviation 0.2931 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through Glucose Glycolsylated Hemoglobin (HbA1c) | 5 years | -0.308 percentage | Standard Deviation 0.6036 |
Primary
To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores
Supportive to Primary Endpoint. HOMA = homeostasis model assessment for Insulin resistance: Healthy Range: 1.0 (0.5-1.4). \< 1.0 means you are insulin-sensitive which is optimal. \>1.9 indicates early insulin resistance. \> 2.9 indicates significant insulin resistance. The quantitative insulin sensitivity check index (QUICKI) measures insulin sensitivity, which is the inverse of insulin resistance. The QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. Lower numbers reflect greater insulin resistance.
Time frame: baseline, 6 months, 1 year, 5 years
Population: safety Analysis set with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | HOMA score baseline | 2.082 score on a scale | Standard Deviation 1.0336 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | HOMA score 6 months | -0.073 score on a scale | Standard Deviation 1.1447 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | HOMA score 1 year | -0.206 score on a scale | Standard Deviation 1.017 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | HOMA score 5 years | 0.094 score on a scale | Standard Deviation 1.8835 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | QUICKI score baseline | 0.354 score on a scale | Standard Deviation 0.0459 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | QUICKI score 6 months | 0.004 score on a scale | Standard Deviation 0.035 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | QUICKI score 1 year | 0.012 score on a scale | Standard Deviation 0.0413 |
| Monitoring of Long-term Safety | To Evaluate the Long Term Effects of rhGH on Carbohydrate Metabolism Through HOMA and QUICKI Scores | QUICKI score 5 years | 0.022 score on a scale | Standard Deviation 0.0703 |
Secondary
to Evaluate Final Height
Time frame: baseline, 6 months, 1 year, 5 years
Population: Full Analysis set with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | to Evaluate Final Height | 6 months | 152.41 cm | Standard Deviation 16.894 |
| Monitoring of Long-term Safety | to Evaluate Final Height | 1 year | 152.43 cm | Standard Deviation 16.698 |
| Monitoring of Long-term Safety | to Evaluate Final Height | 5 years | 150.42 cm | Standard Deviation 12.938 |
| Monitoring of Long-term Safety | to Evaluate Final Height | baseline | 152.63 cm | Standard Deviation 16.362 |
Secondary
to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment
Time frame: baseline, 6 months, 1 year , 5 years
Population: full Analysis set, with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGF-1 baseline | 67.42 nmol/L | Standard Deviation 31.137 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGF-1 6 months | 48.42 nmol/L | Standard Deviation 20.002 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGF-1 1 year | 46.28 nmol/L | Standard Deviation 21.555 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGF-1 5 years | 44.60 nmol/L | Standard Deviation 16.035 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGFBP-3 baseline | 211.12 nmol/L | Standard Deviation 49.523 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGFBP-3 6 months | 187.79 nmol/L | Standard Deviation 42.999 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGFBP-3 1 year | 186.59 nmol/L | Standard Deviation 47.246 |
| Monitoring of Long-term Safety | to Evaluate IGF-I and IGFBP-3 Levels After End of Growth Hormone Treatment | IGFBP-3 5 years | 180.00 nmol/L | Standard Deviation 26.47 |
Secondary
To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment.
number of participants with positive results for anti-drug antibody (ADA). Percentages indicated are calculated based on the total number of patients (118 participants).
Time frame: baseline, 6 months, 1 year, 5 years
Population: safety Analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Monitoring of Long-term Safety | To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment. | baseline | 0 Participants |
| Monitoring of Long-term Safety | To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment. | 6 months | 1 Participants |
| Monitoring of Long-term Safety | To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment. | 1 year | 0 Participants |
| Monitoring of Long-term Safety | To Evaluate the Incidence of Anti-rhGH Antibodies After Termination of Growth Hormone Treatment. | 5 years | 0 Participants |