Dwarfism, Pituitary Diseases, Renal Insufficiency, Chronic, Turner Syndrome
Conditions
Keywords
growth, child development, growth hormone, inadequate growth hormone secretion, growth failure
Brief summary
The main purpose of this study is to establish an optimal monitoring regimen in NutropinAq treated children, using newly developed capillary blood spot IGF-1 measurement technology.
Interventions
Daily subcutaneous injections, 0,025 - 0,05 mg/kg/day for 6 months.
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* Children under 18 with growth failure associated with inadequate growth hormone secretion, or Turner syndrome or chronic renal insufficiency.
Exclusion criteria
* Children with closed epiphyses * Children with active neoplasm * Children with acute critical illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | At Weeks 21, 22 and 23 | Fingertip capillary blood was collected using filter paper cards for the assay of capillary blood spot IGF-I in line with the monitoring recommendations of the Lawson Wilkins Paediatric Endocrine Society (LWPES) for treatment with recombinant GH therapy in children. Capillary IGF-I assays were performed by the patient at home one day per week during Weeks 21, 22 and 23 only (same week day). The samples were scheduled in the evening prior to the injection of NutropinAq and between 7:00 and 9:00 the following morning. An extended window from 6:00 to 12:00 was allowed for defining protocol deviations. The number of capillary blood spot IGF-I measurements and the optimal timing of samples to assess the IGF-I status of NutropinAq treated patients was assessed. IGF-I measurements for the morning and evening sampling are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status | At Weeks 21, 22 and 23 | The influence of sex and prepubertal status on the IGF-I value as measured using the capillary blood spot method was analysed. Parameter estimates from the statistical model are presented as least squares means for the categories of sex (male and female) and prepubertal status (pubertal and prepubertal). The values reported represent average IGF-I levels as determined from the 6 measurements taken (i.e. morning and evening samples at Weeks 21, 22 and 23). |
| Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Up to Week 24 | A multivariate linear regression analysis of factors on within-subject coefficient of variation (WCV) using a stepwise forward-backward elimination was used to determine the effect of individual factors on IGF-I values as measured using the capillary blood spot method (p=0.15 for a variable to enter and remain in the model). The WCV was computed from the series of 6 measurements (2 samplings in each of Weeks 21, 22 and 23). The influence of disease condition and country clusters on the IGF-I value were assessed. Country clusters: cluster 1: France; cluster 2: Spain, Greece, Romania and Italy; cluster 3: UK, Belgium, Czech Republic, Denmark, Germany, Slovakia, Austria and Finland ; cluster 4: Russia ; cluster 5: Ukraine. Parameter estimates from the statistical model presented as least squares means for categories of disease condition (GHD and TS) and location (Clusters 1, 2, 3, 4 and 5) are presented. |
| Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | Up to Week 24 | A multivariate linear regression analysis of factors on WCV using a stepwise forward-backward elimination was used to determine the effect of individual factors on IGF-I values as measured using the capillary blood spot method (p=0.15 for a variable to enter and remain in the model). The WCV was computed from the series of 6 measurements (2 samplings in each of Weeks 21, 22 and 23). The influence of the time of the year (1st, 2nd, 3rd and 4th quarters), calculated age at enrolment and disease condition on the IGF-I value were assessed. Parameter estimates from the statistical model are presented as least squares means for the categories of time of the year (1st, 2nd, 3rd and 4th quarters), calculated age at enrolment and disease condition (GHD and TS). |
| Change From Baseline at Week 24 in the IGF-I Levels as Measured by Capillary Blood Spot Method and Serum IGF-I Assay | Baseline to Week 24 | 3 simultaneous IGF-I measurements were taken at Weeks 0 (baseline), 12 and 24 by serum and capillary assay to determine the precision profile of the capillary blood spot method versus the serum IGF-I assay. Change from baseline at Week 24 in the IGF-I measurements by capillary blood spot method and serum assay are presented. |
| Change From Baseline at Week 12 and Week 24 in Insulin-Like Growth Factor Binding Protein 3 (IGFBP3) Measurements | Baseline to Week 12 and Week 24 | The LWPES recommends that treatment for any indication with recombinant GH therapy in children be accompanied by regular monitoring of IGF-I and IGFBP3 concentrations. IGFBP3 binds circulating IGF-I and serum samples were taken at Visit 1 (Week 0), Visit 2 (Week 12) and Visit 3 (Week 24) in order to measure IGFBP3. Change from baseline (Visit 1) at Visits 2 and 3 in IGFBP3 is presented. |
| Change From Baseline at Week 24 in the Auxological Parameter Height | Baseline to Week 24 | The auxological parameter, height, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in measured height at Visit 3 (Week 24) for the overall ITT population is presented. |
| Change From Baseline at Week 24 in the Auxological Parameter Calculated Height SDS | Baseline to Week 24 | The auxological parameter, height, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Height SDS = (height - reference mean height (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in growth, therefore, a favorable outcome. Change from baseline in the calculated height SDS at Visit 3 (Week 24) for the overall ITT population is presented. |
| Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | At Weeks 21, 22 and 23 | The influence of daily and weekly timing on the IGF-I value as measured using the capillary blood spot method was analysed. A 3-way analyses of variance (ANOVA) was performed with patient, day and daily timing as factors after appropriate transformation to obtain normally distributed parameters. The interaction day\*time was tested and kept in the model only if p-value\<0.1. Parameter estimates from the statistical model are presented as least squares means for the categories of daily timing (Morning and Evening) and weekly timing (Week 21, Week 22 and Week 23). The values reported for Week 21, 22, and 23 represent the average IGF-I levels from the morning and evening samples at each week. The values reported for Evening represent the Evening IGF-I levels averaged across Weeks 21, 22, and 23, and similarly for the Morning values. |
| Change From Baseline at Week 24 in the Auxological Parameter Calculated Weight SDS | Baseline to Week 24 | The auxological parameter, weight, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Weight SDS = (weight - reference mean weight (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in weight, therefore, a favorable outcome. Change from baseline in the calculated weight SDS at Visit 3 (Week 24) for the overall ITT population is presented. |
| Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity | Baseline to Week 24 | The auxological parameter, annualised growth velocity, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in the measured annualised growth velocity at Visit 3 (Week 24) for the overall ITT population is presented. |
| Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity SDS | Baseline to Week 24 | The auxological parameter, annualised growth velocity, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Annualised GV SDS = (annualised GV - reference mean annualised GV (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in growth velocity, therefore, a favorable outcome. Change from baseline in the annualised growth velocity SDS at Visit 3 (Week 24) for the overall ITT population is presented. |
| Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | At Month 5 | The acceptability was evaluated by a questionnaire at Month 5. The users (parents and/or child) of NutropinAq pen and compliance aid booklet were asked to describe and rate the pen, cartridge, compliance aid booklet and their ease of use. The percentage of patients responding to each category for the assessment of the overall handling of the NutropinAq pen are presented. The categories are: Very easy, Easy, Moderately difficult, Difficult, Very difficult and Missing. |
| Posology of NutropinAq at Baseline (Visit 1) Summarised as Mean Dose | Visit 1 (Baseline) | It was intended that the posology (mg/kg/day) of NutropinAq would remain constant throughout the study. The mean posology adopted at Visit 1 is presented. |
| Extent of Exposure to NutropinAq Throughout the Study | Up to Week 24 | The extent of treatment exposure throughout the study is presented as the mean number of daily injections performed. |
| Change From Baseline at Week 24 in the Auxological Parameter Weight | Baseline to Week 24 | The auxological parameter, weight, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in measured weight at Visit 3 (Week 24) for the overall ITT population is presented. |
Countries
Belgium, Czechia, Denmark, Finland, France, Germany, Greece, Italy, Romania, Russia, Slovakia, Spain, Ukraine, United Kingdom
Participant flow
Recruitment details
251 children presenting growth failure associated with Growth Hormone Deficiency (GHD), Turner Syndrome (TS) or Chronic Renal Insufficiency (CRI) were screened (with informed consent) in 46 study centers across Europe. First patient enrolled: 7 June 2004; last subject completed: 22 July 2008
Pre-assignment details
Of the 251 children screened 3 did not receive study medication, 1 due to withdrawal of consent, 1 did not meet screening criteria for height and 1 was not included due to the investigator's decision.
Participants by arm
| Arm | Count |
|---|---|
| NutropinAq 10 mg/2 ml (30 IU) Patients received daily s.c. injections of NutropinAq 10 mg/ 2 mL for 6 months. The therapeutic daily doses administered were as follows:
* GHD patients: 0.025 - 0.035 mg/kg bodyweight
* TS patients: up to 0.05 mg/kg bodyweight
* CRI patients: up to 0.05 mg/kg bodyweight
Patients visited the study clinic for a baseline visit and for 2 other visits every 3 months (Weeks 12 and 24). Additional home assessments were made at Weeks 21, 22 and 23.
The investigator determined the dose administered to each patient, and it was recommended to perform the injection in the evening. | 244 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Enrolled but not treated | 3 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Age, Continuous | 9.9 years STANDARD_DEVIATION 3.9 |
| Auxological Parameter - Annualised Growth Velocity (GV) | 4.94 cm/year STANDARD_DEVIATION 2.56 |
| Auxological Parameter - Calculated annualised GV SDS | -0.56 SD STANDARD_DEVIATION 2.67 |
| Auxological Parameter - Calculated height SDS | -2.68 SD STANDARD_DEVIATION 1.33 |
| Auxological Parameter - Calculated weight SDS | -1.85 SD STANDARD_DEVIATION 1.88 |
| Auxological Parameter - Height | 122.95 cm STANDARD_DEVIATION 20.24 |
| Auxological Parameter - Weight | 27.97 kg STANDARD_DEVIATION 11.91 |
| Birth height | 48.49 centimeters (cm) STANDARD_DEVIATION 3.36 |
| Birth weight | 2.94 kg STANDARD_DEVIATION 0.6 |
| Calculated genetic target height Standard Deviation Score (SDS) | -0.33 Standard Deviations (SD) STANDARD_DEVIATION 0.95 |
| Duration of gestation | 38.7 weeks of amenorrhea STANDARD_DEVIATION 2.6 |
| Duration of previous Growth Hormone (GH) treatment | 1.68 years STANDARD_DEVIATION 1.56 |
| Genetic target height | 166.26 cm STANDARD_DEVIATION 8.16 |
| Sex: Female, Male Female | 138 Participants |
| Sex: Female, Male Male | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 248 |
| other Total, other adverse events | 81 / 248 |
| serious Total, serious adverse events | 6 / 248 |
Outcome results
Primary
Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples
Fingertip capillary blood was collected using filter paper cards for the assay of capillary blood spot IGF-I in line with the monitoring recommendations of the Lawson Wilkins Paediatric Endocrine Society (LWPES) for treatment with recombinant GH therapy in children. Capillary IGF-I assays were performed by the patient at home one day per week during Weeks 21, 22 and 23 only (same week day). The samples were scheduled in the evening prior to the injection of NutropinAq and between 7:00 and 9:00 the following morning. An extended window from 6:00 to 12:00 was allowed for defining protocol deviations. The number of capillary blood spot IGF-I measurements and the optimal timing of samples to assess the IGF-I status of NutropinAq treated patients was assessed. IGF-I measurements for the morning and evening sampling are presented.
Time frame: At Weeks 21, 22 and 23
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data. Only evaluable subjects with an assessment at the specified timepoint were included in each individual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 21 Morning sampling | 223.54 nanograms/milliliter (ng/mL) | Standard Deviation 161.86 |
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 21 Evening sampling | 212.97 nanograms/milliliter (ng/mL) | Standard Deviation 153.61 |
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 22 Morning sampling | 238.02 nanograms/milliliter (ng/mL) | Standard Deviation 177.89 |
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 22 Evening sampling | 226.90 nanograms/milliliter (ng/mL) | Standard Deviation 164.38 |
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 23 Morning sampling | 241.58 nanograms/milliliter (ng/mL) | Standard Deviation 167.75 |
| NutropinAq 10 mg/2 ml (30 IU) | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples | Week 23 Evening sampling | 235.47 nanograms/milliliter (ng/mL) | Standard Deviation 168.48 |
Comparison: An Intra-class Correlation Coefficient (ICC) for the evening series (defined as 12:00 to 24:00) was determined for the overall ITT population to confirm whether only one measurement would be sufficient to accurately represent the IGF-I measurement over Weeks 21, 22 and 23. The ICC expresses the relative magnitude of the 2 components of the total variability, i.e. the biological variability and random error, in a series of measurements on different patients.95% CI: [0.88, 0.92]
Comparison: An ICC for the morning series (defined as 06:00 to 12:00) was determined for the overall ITT population to confirm whether only one measurement would be sufficient to accurately represent the IGF-I measurement over Weeks 21, 22 and 23. The ICC expresses the relative magnitude of the 2 components of the total variability, i.e. the biological variability and random error, in a series of measurements on different patients.95% CI: [0.9, 0.93]
Secondary
Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status
The influence of sex and prepubertal status on the IGF-I value as measured using the capillary blood spot method was analysed. Parameter estimates from the statistical model are presented as least squares means for the categories of sex (male and female) and prepubertal status (pubertal and prepubertal). The values reported represent average IGF-I levels as determined from the 6 measurements taken (i.e. morning and evening samples at Weeks 21, 22 and 23).
Time frame: At Weeks 21, 22 and 23
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status | Male | 172.1 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status | Pubertal | 238.9 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status | Prepubertal | 168.4 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status | Female | 234.4 ng/mL |
Comparison: Analysis of the effect of the patient's sex (male versus female) on the IGF-I value as measured by capillary blood spot method.
Comparison: Analysis of the effect of the patient's pubertal status (pubertal versus prepubertal) on the IGF-I value as measured by capillary blood spot method.
Secondary
Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening)
The influence of daily and weekly timing on the IGF-I value as measured using the capillary blood spot method was analysed. A 3-way analyses of variance (ANOVA) was performed with patient, day and daily timing as factors after appropriate transformation to obtain normally distributed parameters. The interaction day\*time was tested and kept in the model only if p-value\<0.1. Parameter estimates from the statistical model are presented as least squares means for the categories of daily timing (Morning and Evening) and weekly timing (Week 21, Week 22 and Week 23). The values reported for Week 21, 22, and 23 represent the average IGF-I levels from the morning and evening samples at each week. The values reported for Evening represent the Evening IGF-I levels averaged across Weeks 21, 22, and 23, and similarly for the Morning values.
Time frame: At Weeks 21, 22 and 23
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | Week 21 | 218.3 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | Week 22 | 232.4 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | Week 23 | 238.5 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | Evening | 225.1 ng/mL |
| NutropinAq 10 mg/2 ml (30 IU) | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) | Morning | 234.4 ng/mL |
Comparison: Analysis of the weekly timing effect (Week 21 versus Week 22 versus Week 23) on the IGF-I value as measured by capillary blood spot method.
Comparison: Analysis of the daily timing effect (morning versus evening) on the IGF-I value as measured by capillary blood spot method.
Secondary
Change From Baseline at Week 12 and Week 24 in Insulin-Like Growth Factor Binding Protein 3 (IGFBP3) Measurements
The LWPES recommends that treatment for any indication with recombinant GH therapy in children be accompanied by regular monitoring of IGF-I and IGFBP3 concentrations. IGFBP3 binds circulating IGF-I and serum samples were taken at Visit 1 (Week 0), Visit 2 (Week 12) and Visit 3 (Week 24) in order to measure IGFBP3. Change from baseline (Visit 1) at Visits 2 and 3 in IGFBP3 is presented.
Time frame: Baseline to Week 12 and Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data. Evaluable subjects with data available at each timepoint are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 12 and Week 24 in Insulin-Like Growth Factor Binding Protein 3 (IGFBP3) Measurements | Change from baseline to Visit 2 | 1112.4 ng/mL | Standard Deviation 1321.4 |
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 12 and Week 24 in Insulin-Like Growth Factor Binding Protein 3 (IGFBP3) Measurements | Change from baseline to Visit 3 | 1285.2 ng/mL | Standard Deviation 1350.9 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity
The auxological parameter, annualised growth velocity, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in the measured annualised growth velocity at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity | 5.20 cm/year | Standard Deviation 4.72 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity SDS
The auxological parameter, annualised growth velocity, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Annualised GV SDS = (annualised GV - reference mean annualised GV (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in growth velocity, therefore, a favorable outcome. Change from baseline in the annualised growth velocity SDS at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity SDS | 5.10 SD Score | Standard Deviation 4.8 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Calculated Height SDS
The auxological parameter, height, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Height SDS = (height - reference mean height (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in growth, therefore, a favorable outcome. Change from baseline in the calculated height SDS at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Calculated Height SDS | 0.45 SD Score | Standard Deviation 0.37 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Calculated Weight SDS
The auxological parameter, weight, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). The French growth charts were used for the calculation of SDS parameters: the charts provide for each age range and sex a mean parameter and SD value, from which the SDS parameter can be derived assuming a normal distribution. For example: Weight SDS = (weight - reference mean weight (age, sex)) / reference SD (age, sex). The SDS indicates the number of standard deviations away from the mean. A SDS of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A positive change in SDS indicates an improvement in weight, therefore, a favorable outcome. Change from baseline in the calculated weight SDS at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Calculated Weight SDS | 0.20 SD Score | Standard Deviation 0.56 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Height
The auxological parameter, height, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in measured height at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Height | 4.73 cm | Standard Deviation 1.69 |
Secondary
Change From Baseline at Week 24 in the Auxological Parameter Weight
The auxological parameter, weight, was measured at Visit 1 (Baseline measurement), Visit 2 (Week 12) and Visit 3 (Week 24). Change from baseline in measured weight at Visit 3 (Week 24) for the overall ITT population is presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the Auxological Parameter Weight | 2.01 kg | Standard Deviation 1.87 |
Secondary
Change From Baseline at Week 24 in the IGF-I Levels as Measured by Capillary Blood Spot Method and Serum IGF-I Assay
3 simultaneous IGF-I measurements were taken at Weeks 0 (baseline), 12 and 24 by serum and capillary assay to determine the precision profile of the capillary blood spot method versus the serum IGF-I assay. Change from baseline at Week 24 in the IGF-I measurements by capillary blood spot method and serum assay are presented.
Time frame: Baseline to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data. Evaluable subjects with data available at Week 24 are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the IGF-I Levels as Measured by Capillary Blood Spot Method and Serum IGF-I Assay | IGF-I Capillary blood spot method | 123.49 ng/mL | Standard Deviation 127.4 |
| NutropinAq 10 mg/2 ml (30 IU) | Change From Baseline at Week 24 in the IGF-I Levels as Measured by Capillary Blood Spot Method and Serum IGF-I Assay | Serum IGF-I assay | 215.41 ng/mL | Standard Deviation 188.03 |
Comparison: The Bland and Altman method was used to compare the results of each of the three simultaneous random capillary and serum measurements were compared. The difference between the capillary blood spot method and the serum IGF-I measurements is presented95% CI: [-483.35, -153.77]
Secondary
Extent of Exposure to NutropinAq Throughout the Study
The extent of treatment exposure throughout the study is presented as the mean number of daily injections performed.
Time frame: Up to Week 24
Population: The Safety Population consisted of all patients who received at least one injection of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Extent of Exposure to NutropinAq Throughout the Study | 159.7 days | Standard Deviation 35.8 |
Secondary
Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location
A multivariate linear regression analysis of factors on within-subject coefficient of variation (WCV) using a stepwise forward-backward elimination was used to determine the effect of individual factors on IGF-I values as measured using the capillary blood spot method (p=0.15 for a variable to enter and remain in the model). The WCV was computed from the series of 6 measurements (2 samplings in each of Weeks 21, 22 and 23). The influence of disease condition and country clusters on the IGF-I value were assessed. Country clusters: cluster 1: France; cluster 2: Spain, Greece, Romania and Italy; cluster 3: UK, Belgium, Czech Republic, Denmark, Germany, Slovakia, Austria and Finland ; cluster 4: Russia ; cluster 5: Ukraine. Parameter estimates from the statistical model presented as least squares means for categories of disease condition (GHD and TS) and location (Clusters 1, 2, 3, 4 and 5) are presented.
Time frame: Up to Week 24
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data. Only evaluable subjects within each of the individual subgroups are presented for each category. As there was only 1 patient with CRI, no analysis was performed for this disease condition.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Disease condition: GHD | 0.058 Regression coefficient | Standard Error 0.031 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Cluster 1 | 0.014 Regression coefficient | Standard Error 0.045 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Cluster 2 | -0.070 Regression coefficient | Standard Error 0.048 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Cluster 3 | -0.013 Regression coefficient | Standard Error 0.046 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Disease condition: TS | 0.000 Regression coefficient | Standard Error 0 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Cluster 4 | -0.059 Regression coefficient | Standard Error 0.04 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location | Cluster 5 | 0.000 Regression coefficient | Standard Error 0 |
Comparison: Analysis of the disease condition (GHD versus TS) on the IGF-I value as measured by capillary blood spot method.
Comparison: Analysis of the country cluster on the IGF-I value as measured by capillary blood spot method.
Secondary
Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition
A multivariate linear regression analysis of factors on WCV using a stepwise forward-backward elimination was used to determine the effect of individual factors on IGF-I values as measured using the capillary blood spot method (p=0.15 for a variable to enter and remain in the model). The WCV was computed from the series of 6 measurements (2 samplings in each of Weeks 21, 22 and 23). The influence of the time of the year (1st, 2nd, 3rd and 4th quarters), calculated age at enrolment and disease condition on the IGF-I value were assessed. Parameter estimates from the statistical model are presented as least squares means for the categories of time of the year (1st, 2nd, 3rd and 4th quarters), calculated age at enrolment and disease condition (GHD and TS).
Time frame: Up to Week 24
Population: The Per Protocol Population consisted of all patients in the ITT Population for whom no major protocol violations/deviations occurred. Only evaluable subjects within each of the individual subgroups are presented for each category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | Disease condition: TS | 0.000 Regression coefficient | Standard Error 0 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | 3rd quarter | 0.029 Regression coefficient | Standard Error 0.038 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | 4th quarter | 0.000 Regression coefficient | Standard Error 0 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | Calculated age at enrolment | -0.007 Regression coefficient | Standard Error 0.003 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | Disease condition: GHD | 0.051 Regression coefficient | Standard Error 0.026 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | 2nd quarter | 0.028 Regression coefficient | Standard Error 0.033 |
| NutropinAq 10 mg/2 ml (30 IU) | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Time of Year, Calculated Age at Enrolment and Disease Condition | 1st quarter | 0.118 Regression coefficient | Standard Error 0.034 |
Comparison: Analysis of the time of the year on the IGF-I value as measured by capillary blood spot method.
Comparison: Analysis of the effect of the calculated age at enrolment on the IGF-I value as measured by capillary blood spot method.
Comparison: Analysis of the effect of the disease condition on the IGF-I value as measured by capillary blood spot method.
Secondary
Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen
The acceptability was evaluated by a questionnaire at Month 5. The users (parents and/or child) of NutropinAq pen and compliance aid booklet were asked to describe and rate the pen, cartridge, compliance aid booklet and their ease of use. The percentage of patients responding to each category for the assessment of the overall handling of the NutropinAq pen are presented. The categories are: Very easy, Easy, Moderately difficult, Difficult, Very difficult and Missing.
Time frame: At Month 5
Population: The ITT Population consisted of all treated patients (enrolled patients who received at least one injection of treatment) and who provided any follow-up data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Very easy | 39.8 Percentage of patients |
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Easy | 52.5 Percentage of patients |
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Moderately difficult | 3.3 Percentage of patients |
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Difficult | 0 Percentage of patients |
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Very difficult | 0.4 Percentage of patients |
| NutropinAq 10 mg/2 ml (30 IU) | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen | Missing | 4.1 Percentage of patients |
Secondary
Posology of NutropinAq at Baseline (Visit 1) Summarised as Mean Dose
It was intended that the posology (mg/kg/day) of NutropinAq would remain constant throughout the study. The mean posology adopted at Visit 1 is presented.
Time frame: Visit 1 (Baseline)
Population: The Safety Population consisted of all patients who received at least one injection of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NutropinAq 10 mg/2 ml (30 IU) | Posology of NutropinAq at Baseline (Visit 1) Summarised as Mean Dose | 0.0382 mg/kg/day | Standard Deviation 0.0092 |