Study to Define Optimal IGF-1 Monitoring in Children Treated With NutropinAq

Phase 3

Completed

Conditions: Dwarfism
Turner Syndrome
Pituitary Diseases
Renal Insufficiency, Chronic

Interventions: Drug: Somatropin (rDNA origin)

Registration Number: NCT00234533

Lead Sponsor: Ipsen

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 251

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NutropinAq 10 mg/2 mL (30 IU)	Somatropin (rDNA origin)	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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 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 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.
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.
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 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.
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 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.
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.
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.
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.

Trial Locations

Locations (42): Dienst Kindergeneeskunde
🇧🇪
Edegem, Belgium
University Hospital Wales
🇬🇧
Cardiff, Wales, United Kingdom
Centre Hospitalier General
🇫🇷
Le Havre, France
CHU de Montpellier
🇫🇷
Montpellier, France
Helsinki University Central Hospital
🇫🇮
Helsinki, Finland
CHU - Hôtel Dieu
🇫🇷
Angers, France
Hôpital Archet 2
🇫🇷
Nice, France
Cabinet Médical
🇫🇷
Toulouse, France
CHU Grenoble
🇫🇷
Grenoble, France
CHU Timone Enfants
🇫🇷
Marseille, France
Groupe Hospitalier de Necker
🇫🇷
Paris, France
Centre Hospitalier de Bigorre
🇫🇷
Tarbes, France
Centre Pédiatrique Gatien de Clocheville
🇫🇷
Tours, France
Universitätsklinikum Leipzig AöR
🇩🇪
Leipzig, Germany
Hospital Gregorio Marañón
🇪🇸
Madrid, Spain
Hospital Clínico Universitario
🇪🇸
Santiago de Compostela, Spain
Universitätsklinikum Tübingen
🇩🇪
Tübingen, Germany
General State Hospital of Nikaia
🇬🇷
Athens, Greece
PA Kyriakou Children's Hospital
🇬🇷
Athens, Greece
Azienda Policlinico - Università di Catania
🇮🇹
Catania, Italy
Il Università degli Studi di Napoli
🇮🇹
Napoli, Italy
Institutul de Endocrinologie C.I. Parhon
🇷🇴
Bucuresti, Romania
Clinica Pediatrica, Universita Federico II di Napoli
🇮🇹
Napoli, Italy
Endocrinology Research Centre RAMS, Institute of Pediatric Endocrinology
🇷🇺
Moscow, Russian Federation
Tushino Pediatric Hospital, RMAPE Department of Endocrinology for Childhood and Adolescent Age
🇷🇺
Moscow, Russian Federation
Clinica Pediatrica
🇮🇹
Parma, Italy
Il Detska Klinika
🇸🇰
Bratislava, Slovakia
Hospital de Nens de Barcelona
🇪🇸
Barcelona, Spain
Hospital General Universitario
🇪🇸
Elche, Spain
Hospital Parc Taulí
🇪🇸
Sabadell, Spain
Scientific-Research Institute of Endocrinology, Academy of Medical Science of Ukraine
🇺🇦
Kiev, Ukraine
Ukrainian Scientific practical Centre of Endocrine surgery, Endocrine Organs and Tissues Transplantation
🇺🇦
Kiev, Ukraine
Ospedale Policlinico
🇮🇹
Chieti, Italy
Clinica Pediatrica II
🇮🇹
Firenze, Italy
Hôpital Charles Nicolle
🇫🇷
Rouen, France
CHU Hautepierre
🇫🇷
Strasbourg, France
Hôpital Saint-Vincent de Paul
🇫🇷
Paris, France
Hôpital des Enfants
🇫🇷
Toulouse, France
Aalborg Sygehus Nord, Borneafdelingen
🇩🇰
Aalborg, Denmark
Klinika Deti a Dorostu
🇨🇿
Praha, Czechia
Sygeh. i Ringkjobing Amt, Borneafdeling
🇩🇰
Herning, Denmark
St George's Hospital
🇬🇧
London, England, United Kingdom