Growth Disorders
Conditions
Keywords
Insulin-like Growth Factor Deficiency, IGF-1, Short Stature
Brief summary
This is an extension study to Tercica study MS301 (NCT00125164) and is intended to collect long term safety and efficacy data on the continued use of recombinant human insulin-like growth factor-1 (rh IGF-1) in children and adolescents treated for primary IGF-1 deficiency (IGFD). The secondary objective is to use the data collected to learn more about the relationship of IGF-1 exposure to the promotion of normal growth and pubertal development.
Detailed description
Primary IGFD is a term that has been used to describe patients with intrinsic cellular defects in GH action. In this protocol, subjects that have completed one year of mecasermin treatment on Tercica protocol MS301 (NCT00125164) will be allowed to enroll in this extension study. All subjects were planned to receive treatment. This is a Phase IIIb open-label, multi-center, parallel dose, extension study conducted in approximately 40 centers across the United States.
Interventions
DRUGrh IGF-1 (mecasermin)
Patients from untreated arm for prior study MS301 (NCT00125164) were randomized to a dose of either 80 or 120 mcg/kg twice daily. For patients receiving active treatment in previous study MS 301 (NCT00125164), they started on a dose of 80 or 120 mcg/kg twice daily based on the dose reached at end of the previous study. Following a protocol amendment in May 2009, all patients were switched to once daily doses of 160 µg/kg, escalated to a targeted maximum dose of 240 µg/kg.
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
* Parents or legally authorized representatives must give signed informed consent before any trial related activities are conducted * Where required, assent of the subject will be appropriately documented prior to any study related activities * Completion of assessments at Visit 9 (Month 120 of Study MS301 \[NCT00125164\])
Exclusion criteria
* Incomplete participation in MS301 (NCT00125164) * Known or suspected allergy to the trial product (mecasermin, recombinant human IGF-1 injection) or its formulation * Development or presence of a chronic condition except as approved by the Medical Monitor * Pregnancy * Any social or medical condition that, in the opinion of the investigator, would be detrimental to either the subject or the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Height Velocity During BID Dosing Period | At Years 1, 2 and 3 in BID dosing period. | Height was measured standing, without shoes, as the average of 3 measurements by the same observer identical technique with a Harpenden or other wall-mounted stadiometer at baseline and each study visit up to 3 years. Height velocity (during any interval of time (annualised) is computed as (height on date 2 - height on date 1)/(age on date 2 - age on date 1) where height is expressed as centimetres so that height velocity is expressed as centimetres per year (cm/yr). Height velocity is presented for subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period | At baseline and Years 1, 2 and 3 in BID dosing period. | Height was measured standing, without shoes, as the average of 3 measurements by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer at baseline and each study visit up to 3 years. Height SD score was determined using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. The SD score was calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child. Mean change from baseline in height SD score is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]). |
| Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period | At baseline and Years 1, 2 and 3 in BID dosing period. | BMI SD score was calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. The SD score was calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child. Mean change from baseline in BMI SD score is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]). |
| Mean Change From Baseline in Bone Age During BID Dosing Period | At baseline and Years 1, 2 and 3 in BID dosing period. | Radiographs of the left hand and wrist were taken on an approximately annual basis for determination of bone (skeletal) age. The films were sent to a central facility for standardised evaluation. Mean change from baseline in bone age is presented for all subjects completing each year of BID treatment (i.e. Year1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]). |
| Mean Change From Baseline in Predicted Adult Height During BID Dosing Period | At baseline and Years 1, 2 and 3 in BID dosing period. | Predicted adult heights were estimated using the Roche-Wainer-Theissen method which takes into account changes in age, height and bone age. Mean change from baseline in predicted adult height is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]). |
Countries
France
Participant flow
Recruitment details
All subjects that completed study MS301 (NCT00125164) were eligible to enter this Phase 3b, open-label, extension study in prepubertal and pubertal male and female subjects with growth failure associated with primary insulin-like growth factor-1 deficiency (IGFD). This study (MS306) was terminated early by the sponsor on 01 December 2009.
Pre-assignment details
As subjects entered MS306 whilst MS301 was continuing, dosages were adjusted in MS306 after MS301 data became available. Baseline study data for MS306 were taken from the data collected for Visit 9 (Month 12) of study MS301.
Participants by arm
| Arm | Count |
|---|---|
| All rhIGF-1 Subjects All subjects entering MS306 began rhIGF-1 BID treatment. Each subject treated in MS301 had an MS306 starting dose that was based on their dose at the completion of MS301 (i.e. subcutaneous injections of rhIGF-1 at 40, 80, or 120 μg/kg BID). MS301 untreated control subjects were randomised in MS306 in a 1:1 ratio to a dose of either 80 or 120 μg/kg rhIGF-1 BID.
Following Protocol Amendment 1, the dosing regimen was changed and all subjects received either 80 or 120 μg/kg rhIGF-1 BID until the implementation of Protocol Amendment 2.
Following Protocol Amendment 2, all subjects were first switched to receive subcutaneous injections of 160 μg/kg rhIGF-1 QD, followed by individual dose-escalation first to 200 μg/kg rhIGF-1 QD and subsequently to a targeted maximum dose of 240 μg/kg rhIGF-1 QD. Subjects were treated QD until the early termination of the study. | 114 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| BID Dosing Period | Adverse Event | 1 |
| BID Dosing Period | Lost to Follow-up | 7 |
| BID Dosing Period | Non-Compliance | 5 |
| BID Dosing Period | Other | 3 |
| BID Dosing Period | Sponsor's decision | 1 |
| BID Dosing Period | Withdrawal by Subject | 19 |
| QD Dosing Period | Lost to Follow-up | 2 |
| QD Dosing Period | Other | 1 |
| QD Dosing Period | Sponsor decision to terminate study | 74 |
| QD Dosing Period | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All rhIGF-1 Subjects |
|---|---|
| Age, Continuous | 8.5 years STANDARD_DEVIATION 2.4 |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 100 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 114 |
| other Total, other adverse events | 107 / 114 |
| serious Total, serious adverse events | 6 / 114 |
Outcome results
Primary
Height Velocity During BID Dosing Period
Height was measured standing, without shoes, as the average of 3 measurements by the same observer identical technique with a Harpenden or other wall-mounted stadiometer at baseline and each study visit up to 3 years. Height velocity (during any interval of time (annualised) is computed as (height on date 2 - height on date 1)/(age on date 2 - age on date 1) where height is expressed as centimetres so that height velocity is expressed as centimetres per year (cm/yr). Height velocity is presented for subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]).
Time frame: At Years 1, 2 and 3 in BID dosing period.
Population: The modified Intent-To-Treat (MITT) population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 120 μg/kg rhIGF-1 BID (MITT Population) | Height Velocity During BID Dosing Period | Year 1 | 7.7 cm/year | Standard Deviation 1.5 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Height Velocity During BID Dosing Period | Year 2 | 6.1 cm/year | Standard Deviation 1.4 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Height Velocity During BID Dosing Period | Year 3 | 5.9 cm/year | Standard Deviation 1.1 |
Secondary
Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period
BMI SD score was calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. The SD score was calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child. Mean change from baseline in BMI SD score is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]).
Time frame: At baseline and Years 1, 2 and 3 in BID dosing period.
Population: The MITT population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period | Year 3 | 0.4 SD score/year | Standard Deviation 0.5 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period | Year 1 | 0.3 SD score/year | Standard Deviation 0.5 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period | Year 2 | 0.2 SD score/year | Standard Deviation 0.5 |
Secondary
Mean Change From Baseline in Bone Age During BID Dosing Period
Radiographs of the left hand and wrist were taken on an approximately annual basis for determination of bone (skeletal) age. The films were sent to a central facility for standardised evaluation. Mean change from baseline in bone age is presented for all subjects completing each year of BID treatment (i.e. Year1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]).
Time frame: At baseline and Years 1, 2 and 3 in BID dosing period.
Population: The MITT population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Bone Age During BID Dosing Period | Year 2 | 2.3 Years | Standard Deviation 0.6 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Bone Age During BID Dosing Period | Year 3 | 3.4 Years | Standard Deviation 0.7 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Bone Age During BID Dosing Period | Year 1 | 1.2 Years | Standard Deviation 0.5 |
Secondary
Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period
Height was measured standing, without shoes, as the average of 3 measurements by the same observer using identical technique with a Harpenden or other wall-mounted stadiometer at baseline and each study visit up to 3 years. Height SD score was determined using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. The SD score was calculated as the patient value minus the mean divided by the standard deviation. The mean and the standard deviation vary depending on the age and sex of the child. Mean change from baseline in height SD score is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]).
Time frame: At baseline and Years 1, 2 and 3 in BID dosing period.
Population: The MITT population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period | Year 1 | 0.5 SD score/year | Standard Deviation 0.3 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period | Year 2 | 0.7 SD score/year | Standard Deviation 0.4 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period | Year 3 | 0.9 SD score/year | Standard Deviation 0.6 |
Secondary
Mean Change From Baseline in Predicted Adult Height During BID Dosing Period
Predicted adult heights were estimated using the Roche-Wainer-Theissen method which takes into account changes in age, height and bone age. Mean change from baseline in predicted adult height is presented for all subjects completing each year of BID treatment (i.e. Year 1 \[0-1 years\], Year 2 \[1-2 years\], Year 3 \[2-3 years\]).
Time frame: At baseline and Years 1, 2 and 3 in BID dosing period.
Population: The MITT population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Predicted Adult Height During BID Dosing Period | Year 1 | 2.7 cm | Standard Deviation 2 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Predicted Adult Height During BID Dosing Period | Year 2 | 3.9 cm | Standard Deviation 3.2 |
| 120 μg/kg rhIGF-1 BID (MITT Population) | Mean Change From Baseline in Predicted Adult Height During BID Dosing Period | Year 3 | 3.7 cm | Standard Deviation 3.4 |