Clinical Trial Results:
RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-1 (rhIGF-1) TREATMENT OF CHILDREN AND ADOLESCENTS WITH GROWTH FAILURE ASSOCIATED WITH PRIMARY IGF-1 DEFICIENCY: AN OPEN-LABEL, MULTI-CENTER, EXTENSION STUDY
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Summary
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EudraCT number |
2019-000844-81 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
19 Jan 2010
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Sep 2019
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First version publication date |
22 Sep 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MS306
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00330668 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ipsen Pharma
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Sponsor organisation address |
65 Quai Georges Gorse, Boulogne Billancourt, France, 92100
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Public contact |
Medical Director, Ipsen Pharma, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Ipsen Pharma, clinical.trials@ipsen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Dec 2009
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Jan 2010
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this extension study (following on from Study MS301) was to collect safety and efficacy data on the continued use of recombinant human insulin-like growth factor-1 (rhIGF-1) in children and adolescents treated for primary IGF-1 deficiency (IGFD) (height Standard Deviation [SD] score and IGF-1 SD Score <–2 and normal stimulated growth hormone [GH]).
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Protection of trial subjects |
The study was conducted in accordance with Good Clinical Practice as set out in the International Conference on Harmonization E6 document and the United States Code of Federal Regulations, the ethical principles that have their origins in the Declaration of Helsinki, and all applicable local and national regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Oct 2005
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 114
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Worldwide total number of subjects |
114
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
104
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Adolescents (12-17 years) |
10
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a Phase 3b, open-label, multi-centre, extension study in prepubertal and pubertal male and female subjects with growth failure associated with primary IGFD. All subjects that completed study MS301 (EudraCT 2019-001020-36) were eligible to enter this study, MS306. The study was terminated early by the sponsor on 01 December 2009. | ||||||||||||||||||||
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Pre-assignment
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Screening 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. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Twice a Day (BID) Dosing Period
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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All rhIGF-1 BID Subjects | ||||||||||||||||||||
Arm 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. 40, 80 or 120 micrograms [μg]/ kilogram [kg] rhIGF-1 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. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
rhIGF-1
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Investigational medicinal product code |
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Other name |
Mecasermin, Increlex®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received subcutaneous injections of rhIGF-1 at 40, 80, or 120 μg/kg BID.
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Period 2
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Period 2 title |
Once a Day (QD) Dosing Period
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Is this the baseline period? |
No | ||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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All rhIGF-1 QD Subjects | ||||||||||||||||||||
Arm description |
Following Protocol Amendment 2, all subjects were first switched to receive 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. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
rhIGF-1
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Investigational medicinal product code |
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Other name |
Mecasermin, Increlex®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received subcutaneous injections of 160 μg/kg rhIGF-1 QD, followed by individual dose-escalation to 200 μg/kg rhIGF-1 QD and then to a targeted maximum dose of 240 μg/kg rhIGF-1 QD.
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Baseline characteristics reporting groups
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Reporting group title |
Twice a Day (BID) Dosing Period
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All rhIGF-1 BID Subjects
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Reporting 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. 40, 80 or 120 micrograms [μg]/ kilogram [kg] rhIGF-1 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. | ||
Reporting group title |
All rhIGF-1 QD Subjects
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Reporting group description |
Following Protocol Amendment 2, all subjects were first switched to receive 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. | ||
Subject analysis set title |
Modified Intent-To-Treat (MITT) Population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Subjects in the Intent-To-Treat (ITT) population (i.e. treated subjects having at least one baseline and at least 1 post baseline assessment of the primary efficacy endpoint of the original protocol before amendments) and who were randomised to receive 120 μg/kg rhIGF-1 BID in either MS301 or MS306, were included in the MITT population.
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End point title |
Height Velocity During BID Dosing Period [1] | ||||||||||||||
End point 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 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]).
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End point type |
Primary
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End point timeframe |
At Years 1, 2 and 3 in BID dosing period.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No comparative analyses were planned for this endpoint. |
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| Notes [2] - Year 1: n=54, Year 2: n=44, Year 3: n=16 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Mean Change From Baseline in Height SD Score During BID Dosing Period | ||||||||||||||
End point 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 calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. 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]).
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End point type |
Secondary
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End point timeframe |
At baseline and Years 1, 2 and 3 in BID dosing period.
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| Notes [3] - Year 1: n=54, Year 2: n=44, Year 3: n=16 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Mean Change From Baseline in Body Mass Index (BMI) SD Score During BID Dosing Period | ||||||||||||||
End point description |
BMI SD score was calculated using the National Center for Health Statistics 2000 data as provided by the Center for Disease Control. 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]).
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End point type |
Secondary
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End point timeframe |
At baseline and Years 1, 2 and 3 in BID dosing period.
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| Notes [4] - Year 1: n=54, Year 2: n=44, Year 3: n=16 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Mean Change From Baseline in Bone Age During BID Dosing Period | ||||||||||||||
End point 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. Year 1 [0-1 years], Year 2 [1-2 years], Year 3 [2-3 years]).
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End point type |
Secondary
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End point timeframe |
At baseline and Years 1, 2 and 3 in BID dosing period.
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| Notes [5] - Year 1: n=53, Year 2: n=38, Year 3: n=12 |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Mean Change From Baseline in Predicted Adult Height During BID Dosing Period | ||||||||||||||
End point 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]).
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End point type |
Secondary
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End point timeframe |
At baseline and Years 1, 2 and 3 in BID dosing period.
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| Notes [6] - Year 1: n=53, Year 2: n=38, Year 3: n=12 |
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
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).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
Safety Population
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Reporting group description |
The safety population included all subjects who received at least one dose of study medication. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Nov 2005 |
Provision was made for subjects completing MS301 on 120 μg/kg rhIGF-1 BID to continue at this dose during MS306. Subjects randomised to receive 40 μg/kg rhIGF-1 BID during MS301 would commence MS306 on 80 μg/kg rhIGF-1, followed by a dose escalation to 120 μg/kg rhIGF-1 BID at Week 3. Subjects in the untreated cohort of MS301 would commence at 80 or 120 μg/kg rhIGF-1 BID. Subjects originally randomised to 80 or 120 μg/kg rhIGF-1 BID during MS301 but who then completed that study on <80 μg/kg rhIGF-1 BID following a dose-reduction, were considered by the Investigator and Medical Monitor on an individual basis and assigned to a MS306 dose accordingly. Pregnancy testing was introduced for female subjects with Tanner Stage 2 breast development. Additional covariates were added to the primary analysis (pre-treatment height velocity, age at the beginning of the second year of treatment and sex). Fundoscopic examinations were introduced at all visits. Anti-IGF-1 antibody evaluation (previously planned only at Visit 1 and End of Study) would take place annually. |
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08 May 2009 |
All subjects were switched from BID to QD dosing, using a dose escalation procedure with a targeted maximum dose of 240 μg/kg rhIGF-1 QD. Subjects underwent mandatory dose reduction if their IGF-1 SDS for estimated 24 hour mean IGF-1 concentration was >+3 on two occasions. The urinalysis test, thyroid function test and fasting blood tests for lipids, glucose and insulin were all discontinued. Non-fasting capillary blood glucose was conducted at each and every visit. All clinical visits were to occur in the morning. The maximum duration of QD treatment was limited to 1 year. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The study was terminated by the sponsor due to an unacceptably high incidence of hypoglycaemia observed in approximately 50% of the subjects receiving 200 μg/kg rhIGF-1 or greater QD. | |||
