Treatment of Children and Adolescents With Growth Failure Associated With Primary IGF-1 Deficiency
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: All rhIGF-1 Subjects All subjects entering MS306 began recombinant human insulin-like growth factor-1 (rhIGF-1) twice a day (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 micrograms [μg]/ kilogram [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, 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 once a day (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. |
Drug: rh 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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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]).
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ipsen | Paris | France |
Sponsors and Collaborators
- Ipsen
Investigators
- Study Director: Sr Vice President, Clinical Development and Medical Affairs, Ipsen (formerly Tercica, Inc.)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MS306
- 2019-000844-81
Study Results
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 Detail | 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. |
| Arm/Group Title | All rhIGF-1 Subjects |
|---|---|
| Arm/Group Description | All subjects entering MS306 began recombinant human insulin-like growth factor-1 (rhIGF-1) twice a day (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 micrograms [μg]/ kilogram [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 once a day (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. |
| Period Title: BID Dosing Period | |
| STARTED | 114 |
| COMPLETED | 78 |
| NOT COMPLETED | 36 |
| Period Title: BID Dosing Period | |
| STARTED | 78 |
| COMPLETED | 0 |
| NOT COMPLETED | 78 |
Baseline Characteristics
| Arm/Group Title | All rhIGF-1 Subjects |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 114 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
8.5
(2.4)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
32
28.1%
|
| Male |
82
71.9%
|
| Race/Ethnicity, Customized (Number) [Number] | |
| Hispanic |
6
5.3%
|
| White |
100
87.7%
|
| Black |
1
0.9%
|
| Asian |
4
3.5%
|
| Native Hawaiian |
1
0.9%
|
| Other |
2
1.8%
|
Outcome Measures
| Title | Height Velocity During BID Dosing Period |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | 120 μg/kg rhIGF-1 BID (MITT Population) |
|---|---|
| Arm/Group Description | Subjects in the MITT population received 120 μg/kg rhIGF-1 BID and received the same dose throughout the BID phase of the study. |
| Measure Participants | 55 |
| Year 1 |
7.7
(1.5)
|
| Year 2 |
6.1
(1.4)
|
| Year 3 |
5.9
(1.1)
|
| Title | Mean Change From Baseline in Height Standard Deviation (SD) Score During BID Dosing Period |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | 120 μg/kg rhIGF-1 BID (MITT Population) |
|---|---|
| Arm/Group Description | Subjects in the MITT population received 120 μg/kg rhIGF-1 BID and received the same dose throughout the BID phase of the study. |
| Measure Participants | 55 |
| Year 1 |
0.5
(0.3)
|
| Year 2 |
0.7
(0.4)
|
| Year 3 |
0.9
(0.6)
|
| Title | Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | 120 μg/kg rhIGF-1 BID (MITT Population) |
|---|---|
| Arm/Group Description | Subjects in the MITT population received 120 μg/kg rhIGF-1 BID and received the same dose throughout the BID phase of the study. |
| Measure Participants | 55 |
| Year 1 |
0.3
(0.5)
|
| Year 2 |
0.2
(0.5)
|
| Year 3 |
0.4
(0.5)
|
| Title | Mean Change From Baseline in Bone Age During BID Dosing Period |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | 120 μg/kg rhIGF-1 BID (MITT Population) |
|---|---|
| Arm/Group Description | Subjects in the MITT population received 120 μg/kg rhIGF-1 BID and received the same dose throughout the BID phase of the study. |
| Measure Participants | 55 |
| Year 1 |
1.2
(0.5)
|
| Year 2 |
2.3
(0.6)
|
| Year 3 |
3.4
(0.7)
|
| Title | Mean Change From Baseline in Predicted Adult Height During BID Dosing Period |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | 120 μg/kg rhIGF-1 BID (MITT Population) |
|---|---|
| Arm/Group Description | Subjects in the MITT population received 120 μg/kg rhIGF-1 BID and received the same dose throughout the BID phase of the study. |
| Measure Participants | 55 |
| Year 1 |
2.7
(2.0)
|
| Year 2 |
3.9
(3.2)
|
| Year 3 |
3.7
(3.4)
|
Adverse Events
| Time Frame | Adverse events were collected for the overall study (including both the BID and QD dosing periods) from Day 1 until early termination of the study (up to 4 years, 3 months). | |
|---|---|---|
| Adverse Event Reporting Description | The safety population included all subjects who received at least one dose of study medication. | |
| Arm/Group Title | All rhIGF-1 Subjects | |
| Arm/Group Description | All subjects entering MS306 began recombinant human insulin-like growth factor-1 (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, 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. | |
All Cause Mortality |
||
| All rhIGF-1 Subjects | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/114 (0%) | |
Serious Adverse Events |
||
| All rhIGF-1 Subjects | ||
| Affected / at Risk (%) | # Events | |
| Total | 6/114 (5.3%) | |
| Hepatobiliary disorders | ||
| Cholelithiasis | 1/114 (0.9%) | 1 |
| Infections and infestations | ||
| Appendicitis | 1/114 (0.9%) | 1 |
| Otitis Externa | 1/114 (0.9%) | 1 |
| Pneumonia | 1/114 (0.9%) | 1 |
| Injury, poisoning and procedural complications | ||
| Forearm Fracture | 1/114 (0.9%) | 1 |
| Metabolism and nutrition disorders | ||
| Hypoglycaemia | 1/114 (0.9%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| All rhIGF-1 Subjects | ||
| Affected / at Risk (%) | # Events | |
| Total | 107/114 (93.9%) | |
| Blood and lymphatic system disorders | ||
| Lymphadenopathy | 8/114 (7%) | 8 |
| Ear and labyrinth disorders | ||
| Ear Pain | 7/114 (6.1%) | 9 |
| Gastrointestinal disorders | ||
| Abdominal Pain Upper | 20/114 (17.5%) | 27 |
| Diarrhoea | 13/114 (11.4%) | 13 |
| Vomiting | 23/114 (20.2%) | 44 |
| General disorders | ||
| Influenza Like Illness | 9/114 (7.9%) | 18 |
| Injection Site Bruising | 9/114 (7.9%) | 10 |
| Injection Site Hypertrophy | 16/114 (14%) | 30 |
| Pyrexia | 28/114 (24.6%) | 43 |
| Immune system disorders | ||
| Seasonal Allergy | 6/114 (5.3%) | 6 |
| Infections and infestations | ||
| Bronchitis | 8/114 (7%) | 9 |
| Ear Infection | 10/114 (8.8%) | 13 |
| Gastroenteritis | 9/114 (7.9%) | 14 |
| Gastroenteritis Viral | 20/114 (17.5%) | 23 |
| Influenza | 22/114 (19.3%) | 31 |
| Molluscum Contagiosum | 7/114 (6.1%) | 7 |
| Nasopharyngitis | 22/114 (19.3%) | 34 |
| Otitis Externa | 11/114 (9.6%) | 16 |
| Otitis Media | 20/114 (17.5%) | 28 |
| Pharyngitis Streptococcal | 23/114 (20.2%) | 32 |
| Sinusitis | 12/114 (10.5%) | 24 |
| Upper Respiratory Tract Infection | 38/114 (33.3%) | 79 |
| Viral Upper Respiratory Tract Infection | 8/114 (7%) | 10 |
| Injury, poisoning and procedural complications | ||
| Arthropod Bite | 7/114 (6.1%) | 7 |
| Investigations | ||
| Blood Glucose Decreased | 7/114 (6.1%) | 8 |
| Metabolism and nutrition disorders | ||
| Hypoglycaemia | 46/114 (40.4%) | 72 |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 9/114 (7.9%) | 15 |
| Pain In Extremity | 10/114 (8.8%) | 13 |
| Nervous system disorders | ||
| Dizziness | 6/114 (5.3%) | 7 |
| Headache | 35/114 (30.7%) | 86 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 21/114 (18.4%) | 27 |
| Nasal Congestion | 7/114 (6.1%) | 13 |
| Pharyngolaryngeal Pain | 14/114 (12.3%) | 21 |
| Rhinitis Allergic | 6/114 (5.3%) | 6 |
| Tonsillar Hypertrophy | 8/114 (7%) | 11 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Each investigator may publish or report data from their own subjects. The trial data in aggregate are the property of Tercica, Inc. and may not be published without permission of Tercica, Inc. Tercica, Inc. will be the final arbitrator of issues relating to the publication or presentation of the aggregate data.
Results Point of Contact
| Name/Title | Ipsen Medical Director |
|---|---|
| Organization | Ipsen |
| Phone | See email |
| clinical.trials@ipsen.com |
- MS306
- 2019-000844-81