OPTIMA: Study to Define Optimal IGF-1 Monitoring in Children Treated With NutropinAq
Sponsor
Ipsen (Industry)
Overall Status
Completed
CT.gov ID
NCT00234533
Collaborator
(none)
251
45
1
49
5.6
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
251 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase IIIB, International, Single Group, Open Study to Define an Optimal Monitoring of IGF-1 in Children Treated With NutropinAq, Using a Novel Capillary Blood Collection Method
Study Start Date
:
Jun 1, 2004
Actual Primary Completion Date
:
Jul 1, 2008
Actual Study Completion Date
:
Jul 1, 2008
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: NutropinAq 10 mg/2 mL (30 IU) Patients received daily subcutaneous (s.c.) injections of NutropinAq 10 milligrams (mg)/2 milliliters (mL) for 6 months. The therapeutic daily doses administered were as follows: GHD patients: 0.025 - 0.035 mg/ kilogram (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. |
Drug: Somatropin (rDNA origin)
Daily subcutaneous injections, 0,025 - 0,05 mg/kg/day for 6 months.
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
- 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.
- 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.
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
N/A
to 18 Years
Sexes Eligible for Study:
All
Accepts 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dienst Kindergeneeskunde | Brussels | Belgium | B-1090 | |
| 2 | Dienst Kindergeneeskunde | Edegem | Belgium | B-2650 | |
| 3 | Klinika Deti a Dorostu | Praha | Czechia | 100 34 | |
| 4 | Aalborg Sygehus Nord, Borneafdelingen | Aalborg | Denmark | 9100 | |
| 5 | Sygeh. i Ringkjobing Amt, Borneafdeling | Herning | Denmark | 7400 | |
| 6 | Helsinki University Central Hospital | Helsinki | Finland | ||
| 7 | CHU - Hôtel Dieu | Angers | France | 49033 | |
| 8 | Cabinet Médical | Bordeaux | France | 33000 | |
| 9 | CHU Grenoble | Grenoble | France | 38043 | |
| 10 | Centre Hospitalier General | Le Havre | France | 76083 | |
| 11 | CHU Timone Enfants | Marseille | France | 13385 | |
| 12 | CHU de Montpellier | Montpellier | France | 34295 | |
| 13 | Hôpital Archet 2 | Nice | France | 06202 | |
| 14 | Hôpital Saint-Vincent de Paul | Paris | France | 75674 | |
| 15 | Groupe Hospitalier de Necker | Paris | France | 75743 | |
| 16 | Hôpital Charles Nicolle | Rouen | France | 76031 | |
| 17 | CHU Hautepierre | Strasbourg | France | 67100 | |
| 18 | Centre Hospitalier de Bigorre | Tarbes | France | 65013 | |
| 19 | Cabinet Médical | Toulouse | France | 31000 | |
| 20 | Hôpital des Enfants | Toulouse | France | 31059 | |
| 21 | Centre Pédiatrique Gatien de Clocheville | Tours | France | 37044 | |
| 22 | Universitätsklinikum Leipzig AöR | Leipzig | Germany | 04317 | |
| 23 | Universitätsklinikum Tübingen | Tübingen | Germany | 72076 | |
| 24 | General State Hospital of Nikaia | Athens | Greece | 18454 | |
| 25 | PA Kyriakou Children's Hospital | Athens | Greece | ||
| 26 | Azienda Policlinico - Università di Catania | Catania | Italy | 78-95123 | |
| 27 | Ospedale Policlinico | Chieti | Italy | 5-66013 | |
| 28 | Clinica Pediatrica II | Firenze | Italy | 13-50132 | |
| 29 | Il Università degli Studi di Napoli | Napoli | Italy | 4-80138 | |
| 30 | Clinica Pediatrica, Universita Federico II di Napoli | Napoli | Italy | ||
| 31 | Clinica Pediatrica | Novara | Italy | 18-28100 | |
| 32 | Clinica Pediatrica | Parma | Italy | 14-43100 | |
| 33 | Institutul de Endocrinologie C.I. Parhon | Bucuresti | Romania | Sector 1 | |
| 34 | Endocrinology Research Centre RAMS, Institute of Pediatric Endocrinology | Moscow | Russian Federation | ||
| 35 | Tushino Pediatric Hospital, RMAPE Department of Endocrinology for Childhood and Adolescent Age | Moscow | Russian Federation | ||
| 36 | Il Detska Klinika | Bratislava | Slovakia | 833 40 | |
| 37 | Hospital de Nens de Barcelona | Barcelona | Spain | 08009 | |
| 38 | Hospital General Universitario | Elche | Spain | 03203 | |
| 39 | Hospital Gregorio Marañón | Madrid | Spain | 28007 | |
| 40 | Hospital Parc Taulí | Sabadell | Spain | 08208 | |
| 41 | Hospital Clínico Universitario | Santiago de Compostela | Spain | 15706 | |
| 42 | Scientific-Research Institute of Endocrinology, Academy of Medical Science of Ukraine | Kiev | Ukraine | ||
| 43 | Ukrainian Scientific practical Centre of Endocrine surgery, Endocrine Organs and Tissues Transplantation | Kiev | Ukraine | ||
| 44 | St George's Hospital | London | England | United Kingdom | SW17 0QT |
| 45 | University Hospital Wales | Cardiff | Wales | United Kingdom | 14 4XW |
Sponsors and Collaborators
- Ipsen
Investigators
- Study Director: Ipsen Medical Director, Ipsen
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Ipsen
ClinicalTrials.gov Identifier:
NCT00234533
Other Study ID Numbers:
- 2-79-58035-700
- 2004-000356-17
First Posted:
Oct 7, 2005
Last Update Posted:
Dec 9, 2019
Last Verified:
Nov 1, 2019
Keywords provided by Ipsen
Additional relevant MeSH terms:
Study Results
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 Detail | 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. |
| Arm/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | Patients received daily subcutaneous (s.c.) injections of NutropinAq 10 milligrams (mg)/ 2 milliliters (mL) for 6 months. The therapeutic daily doses administered were as follows: GHD patients: 0.025 - 0.035 mg/ kilogram (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. |
| Period Title: Overall Study | |
| STARTED | 251 |
| COMPLETED | 240 |
| NOT COMPLETED | 11 |
Baseline Characteristics
| Arm/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 244 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
9.9
(3.9)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
138
56.6%
|
| Male |
106
43.4%
|
| Birth height (centimeters (cm)) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [centimeters (cm)] |
48.49
(3.36)
|
| Birth weight (kg) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg] |
2.94
(0.60)
|
| Duration of gestation (weeks of amenorrhea) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [weeks of amenorrhea] |
38.7
(2.6)
|
| Genetic target height (cm) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [cm] |
166.26
(8.16)
|
| Calculated genetic target height Standard Deviation Score (SDS) (Standard Deviations (SD)) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Standard Deviations (SD)] |
-0.33
(0.95)
|
| Duration of previous Growth Hormone (GH) treatment (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
1.68
(1.56)
|
| Auxological Parameter - Height (cm) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [cm] |
122.95
(20.24)
|
| Auxological Parameter - Calculated height SDS (SD) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [SD] |
-2.68
(1.33)
|
| Auxological Parameter - Weight (kg) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [kg] |
27.97
(11.91)
|
| Auxological Parameter - Calculated weight SDS (SD) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [SD] |
-1.85
(1.88)
|
| Auxological Parameter - Annualised Growth Velocity (GV) (cm/year) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [cm/year] |
4.94
(2.56)
|
| Auxological Parameter - Calculated annualised GV SDS (SD) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [SD] |
-0.56
(2.67)
|
Outcome Measures
| Title | Insulin-Like Growth Factor I (IGF-I) Levels Measured Using the Timed Capillary Blood Spot Samples |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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/ kilogram 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. |
| Measure Participants | 244 |
| Week 21 Morning sampling |
223.54
(161.86)
|
| Week 21 Evening sampling |
212.97
(153.61)
|
| Week 22 Morning sampling |
238.02
(177.89)
|
| Week 22 Evening sampling |
226.90
(164.38)
|
| Week 23 Morning sampling |
241.58
(167.75)
|
| Week 23 Evening sampling |
235.47
(168.48)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Other | |
| Comments | An one-way Analysis of Covariance (ANOVA) was used to calculate the between patient variation and within patient variation and then the ICC and its confidence limitations. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | ICC |
| Estimated Value | 0.90 | |
| Confidence Interval |
(2-Sided) 95% 0.88 to 0.92 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | An ICC ≥ 0.8 was considered satisfactory and indicative that a single sample would be representative of the overall IGF-I status. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Other | |
| Comments | An one-way ANOVA was used to calculate the between patient variation and within patient variation and then the ICC and its confidence limitations. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | ICC |
| Estimated Value | 0.92 | |
| Confidence Interval |
(2-Sided) 95% 0.90 to 0.93 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | An ICC ≥ 0.8 was considered satisfactory and indicative that a single sample would be representative of the overall IGF-I status. | |
| Title | Assessment of IGF-I Levels: Categorised by Weekly Timing (Weeks 21-23) and Daily Timing (Morning and Evening) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Week 21 |
218.3
|
| Week 22 |
232.4
|
| Week 23 |
238.5
|
| Evening |
225.1
|
| Morning |
234.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Fisher's F statistic (F) value |
| Estimated Value | 1.79 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the weekly timing on the IGF-I levels; F value = 1.79 and the significance probability value, PR>F = 0.1678. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the daily timing effect (morning versus evening) on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the daily timing on the IGF-I levels; F value = 1.06 and the significance probability value, PR>F = 0.3035 | |
| Title | Assessment of IGF-I Levels: Categorised by Sex and Prepubertal Status |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Female |
234.4
|
| Male |
172.1
|
| Pubertal |
238.9
|
| Prepubertal |
168.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the effect of the patient's sex (male versus female) on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 83.97 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the patient's sex on the IGF-I levels; F value = 83.97 and the significance probability value, PR>F = <0.0001. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 68.35 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the patient's pubertal status on the IGF-I levels; F value = 68.35 and the significance probability value, PR>F = <0.0001. | |
| Title | Multivariate Linear Regression Analyses to Assess Factors Affecting the Variability of IGF-I Levels: Categorised by Disease Condition and Location |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Disease condition: GHD |
0.058
(0.031)
|
| Disease condition: TS |
0.000
(0)
|
| Cluster 1 |
0.014
(0.045)
|
| Cluster 2 |
-0.070
(0.048)
|
| Cluster 3 |
-0.013
(0.046)
|
| Cluster 4 |
-0.059
(0.040)
|
| Cluster 5 |
0.000
(0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the disease condition (GHD versus TS) on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 10.73 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the disease condition on the IGF-I levels; F value = 10.73 and the significance probability value, PR>F = 0.0012. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the country cluster on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 2.20 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the country cluster on the IGF-I levels; F value = 2.20 and the significance probability value, PR>F = 0.0701. | |
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 175 |
| 1st quarter |
0.118
(0.034)
|
| 2nd quarter |
0.028
(0.033)
|
| 3rd quarter |
0.029
(0.038)
|
| 4th quarter |
0.000
(0)
|
| Calculated age at enrolment |
-0.007
(0.003)
|
| Disease condition: GHD |
0.051
(0.026)
|
| Disease condition: TS |
0.000
(0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the time of the year on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 3.65 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the time of the year on the IGF-I levels; F value = 3.65 and the significance probability value, PR>F = 0.0139. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the effect of the calculated age at enrolment on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 7.38 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the calculated age at enrolment on the IGF-I levels; F value = 7.38 and the significance probability value, PR>F = 0.0073. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | Analysis of the effect of the disease condition on the IGF-I value as measured by capillary blood spot method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | F value |
| Estimated Value | 3.86 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | For the effect of the disease condition on the IGF-I levels; F value = 3.86 and the significance probability value, PR>F = 0.0511 | |
| Title | Change From Baseline at Week 24 in the IGF-I Levels as Measured by Capillary Blood Spot Method and Serum IGF-I Assay |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| IGF-I Capillary blood spot method |
123.49
(127.40)
|
| Serum IGF-I assay |
215.41
(188.03)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|---|
| Comments | 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 presented | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean difference |
| Estimated Value | -164.79 | |
| Confidence Interval |
(2-Sided) 95% -483.35 to -153.77 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 159.28 |
|
| Estimation Comments | ||
| Title | Change From Baseline at Week 12 and Week 24 in Insulin-Like Growth Factor Binding Protein 3 (IGFBP3) Measurements |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Change from baseline to Visit 2 |
1112.4
(1321.4)
|
| Change from baseline to Visit 3 |
1285.2
(1350.9)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Height |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [cm] |
4.73
(1.69)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Calculated Height SDS |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [SD Score] |
0.45
(0.37)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Weight |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [kg] |
2.01
(1.87)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Calculated Weight SDS |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [SD Score] |
0.20
(0.56)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [cm/year] |
5.20
(4.72)
|
| Title | Change From Baseline at Week 24 in the Auxological Parameter Annualised Growth Velocity SDS |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Mean (Standard Deviation) [SD Score] |
5.10
(4.80)
|
| Title | Percentage of Patients Rating the Overall Handling of the Administration Device, NutropinAq Pen, to Assess the Acceptability and Tolerance of NutropinAq and Its Pen |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 244 |
| Very easy |
39.8
|
| Easy |
52.5
|
| Moderately difficult |
3.3
|
| Difficult |
0
|
| Very difficult |
0.4
|
| Missing |
4.1
|
| Title | Posology of NutropinAq at Baseline (Visit 1) Summarised as Mean Dose |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Population consisted of all patients who received at least one injection of treatment. |
| Arm/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 248 |
| Mean (Standard Deviation) [mg/kg/day] |
0.0382
(0.0092)
|
| Title | Extent of Exposure to NutropinAq Throughout the Study |
|---|---|
| Description | The extent of treatment exposure throughout the study is presented as the mean number of daily injections performed. |
| Time Frame | Up to Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Population consisted of all patients who received at least one injection of treatment. |
| Arm/Group Title | NutropinAq 10 mg/2 ml (30 IU) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 248 |
| Mean (Standard Deviation) [days] |
159.7
(35.8)
|
Adverse Events
| Time Frame | From baseline (Week 0) up to Week 24. | |
|---|---|---|
| Adverse Event Reporting Description | Treatment emergent adverse events are presented for the Safety Population which consisted of all patients who received at least 1 injection of treatment. | |
| Arm/Group Title | NutropinAq 10 mg/2 ml (30 IU) | |
| Arm/Group Description | 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. | |
All Cause Mortality |
||
| NutropinAq 10 mg/2 ml (30 IU) | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/248 (0%) | |
Serious Adverse Events |
||
| NutropinAq 10 mg/2 ml (30 IU) | ||
| Affected / at Risk (%) | # Events | |
| Total | 6/248 (2.4%) | |
| Congenital, familial and genetic disorders | ||
| Retinitis Pigmentosa | 1/248 (0.4%) | 1 |
| Infections and infestations | ||
| Bronchopneumonia | 1/248 (0.4%) | 1 |
| Gastroenteritis | 1/248 (0.4%) | 1 |
| Pyelonephritis acute | 1/248 (0.4%) | 1 |
| Injury, poisoning and procedural complications | ||
| Accidental overdose | 1/248 (0.4%) | 1 |
| Femur fracture | 1/248 (0.4%) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Pain in extremity | 1/248 (0.4%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| NutropinAq 10 mg/2 ml (30 IU) | ||
| Affected / at Risk (%) | # Events | |
| Total | 81/248 (32.7%) | |
| Blood and lymphatic system disorders | ||
| Lymphadenopathy | 1/248 (0.4%) | 1 |
| Cardiac disorders | ||
| Tachycardia | 1/248 (0.4%) | 1 |
| Ear and labyrinth disorders | ||
| Auricular swelling | 1/248 (0.4%) | 1 |
| Endocrine disorders | ||
| Hypothyroidism | 2/248 (0.8%) | 2 |
| Thyroiditis acute | 1/248 (0.4%) | 1 |
| Eye disorders | ||
| Conjunctivitis allergic | 1/248 (0.4%) | 1 |
| Gastrointestinal disorders | ||
| Abdominal pain | 4/248 (1.6%) | 4 |
| Abdominal pain upper | 4/248 (1.6%) | 5 |
| Aptyalism | 1/248 (0.4%) | 1 |
| Diarrhoea | 3/248 (1.2%) | 4 |
| Gastritis | 1/248 (0.4%) | 1 |
| Gastrooesophageal reflux disease | 1/248 (0.4%) | 1 |
| Nausea | 3/248 (1.2%) | 3 |
| Stomatitis | 1/248 (0.4%) | 1 |
| Vomiting | 5/248 (2%) | 8 |
| General disorders | ||
| Asthenia | 2/248 (0.8%) | 3 |
| Face oedema | 1/248 (0.4%) | 1 |
| Feeling cold | 1/248 (0.4%) | 1 |
| Hyperthermia | 1/248 (0.4%) | 1 |
| Injection site bruising | 2/248 (0.8%) | 2 |
| Injection site oedema | 1/248 (0.4%) | 1 |
| Injection site pain | 1/248 (0.4%) | 1 |
| Malaise | 1/248 (0.4%) | 1 |
| Oedema peripheral | 1/248 (0.4%) | 1 |
| Pyrexia | 9/248 (3.6%) | 10 |
| Infections and infestations | ||
| Acute sinusitis | 1/248 (0.4%) | 1 |
| Bronchitis | 1/248 (0.4%) | 1 |
| Bronchitis acute | 3/248 (1.2%) | 3 |
| Bronchopneumonia | 1/248 (0.4%) | 1 |
| Cellulitis | 1/248 (0.4%) | 1 |
| Ear infection | 1/248 (0.4%) | 2 |
| Enterovirus infection | 1/248 (0.4%) | 1 |
| Gastroenteritis | 1/248 (0.4%) | 1 |
| Gastroenteritis viral | 1/248 (0.4%) | 1 |
| Influenza | 3/248 (1.2%) | 4 |
| Lower respiratory tract infection | 2/248 (0.8%) | 3 |
| Nasopharyngitis | 3/248 (1.2%) | 3 |
| Otitis media | 5/248 (2%) | 6 |
| Rhinitis | 6/248 (2.4%) | 6 |
| Scarlet fever | 1/248 (0.4%) | 1 |
| Tonsillitis | 2/248 (0.8%) | 2 |
| Tonsillitis bacterial | 1/248 (0.4%) | 2 |
| Upper respiratory tract infection | 7/248 (2.8%) | 10 |
| Viral infection | 1/248 (0.4%) | 1 |
| Viral upper respiratory tract infection | 1/248 (0.4%) | 1 |
| Injury, poisoning and procedural complications | ||
| Arthropod bite | 1/248 (0.4%) | 1 |
| Arthropod sting | 1/248 (0.4%) | 1 |
| Foot fracture | 1/248 (0.4%) | 1 |
| Hand fracture | 2/248 (0.8%) | 2 |
| Wound complication | 1/248 (0.4%) | 1 |
| Investigations | ||
| Insulin-like Growth Factor increased | 13/248 (5.2%) | 13 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 1/248 (0.4%) | 2 |
| Hyperglycaemia | 1/248 (0.4%) | 1 |
| Polydipsia | 1/248 (0.4%) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 3/248 (1.2%) | 3 |
| Back pain | 3/248 (1.2%) | 3 |
| Pain in extremity | 2/248 (0.8%) | 3 |
| Pubic pain | 1/248 (0.4%) | 1 |
| Scoliosis | 1/248 (0.4%) | 1 |
| Nervous system disorders | ||
| Headache | 14/248 (5.6%) | 27 |
| Migraine | 1/248 (0.4%) | 1 |
| Renal and urinary disorders | ||
| Polyuria | 1/248 (0.4%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Allergic bronchitis | 1/248 (0.4%) | 1 |
| Cough | 1/248 (0.4%) | 1 |
| Epistaxis | 1/248 (0.4%) | 1 |
| Pharyngolaryngeal pain | 1/248 (0.4%) | 1 |
| Skin and subcutaneous tissue disorders | ||
| Alopecia | 1/248 (0.4%) | 1 |
| Dermatitis allergic | 1/248 (0.4%) | 1 |
| Dry skin | 1/248 (0.4%) | 1 |
| Eczema | 1/248 (0.4%) | 1 |
| Rash | 2/248 (0.8%) | 2 |
| Swelling face | 1/248 (0.4%) | 1 |
| Vascular disorders | ||
| Wound haemorrhage | 1/248 (0.4%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Medical Director, Pediatric Endocrinology |
|---|---|
| Organization | Ipsen |
| Phone | |
| clinical.trials@ipsen.com |
Responsible Party:
Ipsen
ClinicalTrials.gov Identifier:
NCT00234533
Other Study ID Numbers:
- 2-79-58035-700
- 2004-000356-17
First Posted:
Oct 7, 2005
Last Update Posted:
Dec 9, 2019
Last Verified:
Nov 1, 2019