Clinical Trial Results:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, Age 0 to < 60 Months
Summary
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EudraCT number |
2016-003826-18 |
Trial protocol |
GB |
Global end of trial date |
26 Jan 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Mar 2023
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First version publication date |
28 Mar 2023
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Other versions |
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Summary report(s) |
Secondary Endpoints_ITQOL Tables PK parameter Endpoints tables |
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 |
BMN 111-206
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03583697 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
BioMarin Pharmaceutical Inc
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Sponsor organisation address |
105 Digital Drive, Novato, CA, United States, 94949
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Public contact |
Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
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Scientific contact |
Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002033-PIP01-16 | ||
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 |
26 Jan 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Jan 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Jan 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of the study were to:
- Evaluate the safety and tolerability of Vosoritide in children aged 0 to < 60 months with ACH
- Evaluate the effect of Vosoritide on change from baseline in length/height Z-score
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Protection of trial subjects |
This clinical study was designed, implemented and reported in accordance with the protocol and also with the following:
• European Clinical Trial Directive 2001/20/EC and Good Clinical Practice (GCP) Directive 2005/28/EC, for studies conducted within any European country
• United States (US) Code of Federal Regulations (CFR) sections that address clinical research studies, and/or other national and local regulations, as applicable
• International Council on Harmonisation, Harmonised Tripartite Guideline: Guideline for GCP E6 (ICH E6)
• The ethical principles established by the Declaration of Helsinki
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Jun 2018
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
19 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 Kingdom: 8
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Country: Number of subjects enrolled |
United States: 41
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Country: Number of subjects enrolled |
Japan: 8
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Country: Number of subjects enrolled |
Australia: 18
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Worldwide total number of subjects |
75
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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) |
40
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Children (2-11 years) |
35
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Adolescents (12-17 years) |
0
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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 multi-center study conducted by 16 principal investigators at 16 study centers in four countries (United States, Australia, United Kingdom and Japan). | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 75 participants (full analysis set [FAS]) were enrolled into the study, of which 11 participants were enrolled to receive vosoritide (sentinel participants). 64 participants were randomized to receive vosoritide or placebo (32 randomized for vosoritide and 32 for placebo), which constituted the FAS (randomized). | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
Participants & site members were blinded to study treatment. The investigator and staff involved with the study also remained blinded to the treatment randomization code. In an emergency medical situation where participant management would be determined or significantly altered by knowing the treatment assignment, the investigator could be unblinded without prior written approval from the Medical Monitor.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sentinel | ||||||||||||||||||||||||
Arm description |
Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3) | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
BMN 111
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Investigational medicinal product code |
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Other name |
Vosoritide
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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 |
Cohort 1 Sentinel participants received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks.
Cohort 2 Sentinel participants Initially dosed with single daily subcutaneous injection of vosoritide 15 µg/kg/day and were adjusted to 30 µg/kg/day following the review of safety and PK data then adjusted to 15 µg/kg/day during the visit immediately preceding the 2-year birthday.
Cohort 3 Sentinel participants received a 30 μg/kg vosoritide single daily subcutaneous injection for 52 weeks.
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Arm title
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Randomized Vosoritide | ||||||||||||||||||||||||
Arm description |
Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
BMN 111
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Investigational medicinal product code |
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Other name |
Vosoritide
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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 |
Cohort 1: Participants received a vosoritide 15 μg/kg daily subcutaneous injection for 52 weeks.
Cohort 2: Participants received vosoritide 15 μg/kg to 30 μg/kg daily subcutaneous injection for 52 weeks.
Cohort 3: Participants received vosoritide 30 μg/kg daily subcutaneous injection for 52 weeks.
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Arm title
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Randomized Placebo | ||||||||||||||||||||||||
Arm description |
Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8) | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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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 |
Participants received a placebo single daily subcutaneous injection for 52 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Sentinel
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Reporting group description |
Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Randomized Vosoritide
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Reporting group description |
Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Randomized Placebo
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Reporting group description |
Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sentinel
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Reporting group description |
Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3) | ||
Reporting group title |
Randomized Vosoritide
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Reporting group description |
Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9) | ||
Reporting group title |
Randomized Placebo
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Reporting group description |
Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8) | ||
Subject analysis set title |
Cohort 1: Placebo
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months.
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent
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Subject analysis set title |
Cohort 1: Vosoritide
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months. Vosoritide 15 μg/kg/day
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.
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Subject analysis set title |
Cohort 2: Placebo
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months).
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent
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Subject analysis set title |
Cohort 2: Vosoritide
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months). Vosoritide 15 μg/kg/day & 30 μg/kg/day
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent
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Subject analysis set title |
Cohort 3: Placebo
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 3 included participants stratified by age 0 to < 6 months.
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent
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Subject analysis set title |
Cohort 3: Vosoritide
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Cohort 3 included participants stratified by age 0 to < 6 months. Vosoritide 30 μg/kg/day
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent
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Subject analysis set title |
All Vosoritide
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.
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Subject analysis set title |
Placebo
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.
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End point title |
Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs) [1] | ||||||||||||||||||||||||||||||||||||
End point description |
A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study.
Serious adverse event (SAE)
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End point type |
Primary
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End point timeframe |
Up to Week 56 (Safety Follow-Up +/-7d)
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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: Only descriptive data was analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change from baseline in height Z-score at Week 52 [2] | ||||||||||||||||||||
End point description |
Standing Height/body length was converted to an age-and sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by comparison with reference data available for average stature children from the Centers for Disease Control and Prevention(CDC).
The primary efficacy analysis population was the subset of randomized participants in the FAS. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.
FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants).
FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
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End point type |
Primary
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End point timeframe |
Baseline to Week 52
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants. |
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Statistical analysis title |
Height Z-Score-Placebo Vs Vosoritide(FAS Random) | ||||||||||||||||||||
Statistical analysis description |
Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention.
Participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.
Difference in LS means were obtained from an analysis of covariance model.
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Comparison groups |
Randomized Vosoritide v Randomized Placebo
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Number of subjects included in analysis |
64
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.25
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.02 | ||||||||||||||||||||
upper limit |
0.53 | ||||||||||||||||||||
Notes [3] - Covariance model |
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Statistical analysis title |
Height Z-Score - Placebo Vs Vosoritide (FAS) | ||||||||||||||||||||
Statistical analysis description |
Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention.
Participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.
Difference in LS means were obtained from an analysis of covariance model.
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Comparison groups |
All Vosoritide v Placebo
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Number of subjects included in analysis |
75
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | ||||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.3
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.07 | ||||||||||||||||||||
upper limit |
0.54 | ||||||||||||||||||||
Notes [4] - Covariance model |
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End point title |
Change from baseline in height at Week 52 [5] | ||||||||||||||||||||
End point description |
FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants).
FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
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End point type |
Secondary
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End point timeframe |
Baseline to Week 52
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants. |
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Statistical analysis title |
Height-Placebo Vs Vosoritide(FAS Randomized) | ||||||||||||||||||||
Statistical analysis description |
Difference in LS means were obtained from an analysis of covariance model.
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Comparison groups |
Randomized Vosoritide v Randomized Placebo
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Number of subjects included in analysis |
64
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Analysis specification |
Pre-specified
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Analysis type |
other [6] | ||||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.77
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.02 | ||||||||||||||||||||
upper limit |
1.56 | ||||||||||||||||||||
Notes [6] - Covariance model. |
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Statistical analysis title |
Height - Placebo Vs Vosoritide (FAS) | ||||||||||||||||||||
Statistical analysis description |
Difference in LS means were obtained from an analysis of covariance model.
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Comparison groups |
All Vosoritide v Placebo
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Number of subjects included in analysis |
75
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Analysis specification |
Pre-specified
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Analysis type |
other [7] | ||||||||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.96
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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lower limit |
0.26 | ||||||||||||||||||||
upper limit |
1.66 | ||||||||||||||||||||
Notes [7] - Covariance model. |
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|||||||||||||||||||||
End point title |
Change from baseline in annualized growth velocity (AGV) at Week 52 [8] | ||||||||||||||||||||
End point description |
AGV was derived over 12-month intervals starting from the baseline visit. Annualized growth velocity (AGV) = Standing Height at Date 2 - Standing Height at Date 1/Interval Lenght (Days) x 365.25.
FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo
(32 participants).
FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
AGV - Placebo Vs Vosoritide(FAS Randomized) | ||||||||||||||||||||
Statistical analysis description |
Difference in LS means were obtained from an analysis of covariance model.
|
||||||||||||||||||||
Comparison groups |
Randomized Vosoritide v Randomized Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
64
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [9] | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.78
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.02 | ||||||||||||||||||||
upper limit |
1.54 | ||||||||||||||||||||
Notes [9] - Covariance model. |
|||||||||||||||||||||
Statistical analysis title |
AGV - Placebo Vs Vosoritide (FAS) | ||||||||||||||||||||
Statistical analysis description |
Difference in LS means were obtained from an analysis of covariance model.
|
||||||||||||||||||||
Comparison groups |
All Vosoritide v Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
75
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
0.92
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
0.24 | ||||||||||||||||||||
upper limit |
1.59 |
|
|||||||||||||||||||||
End point title |
Change from baseline in upper to lower body segment ratio at Week 52 [10] | ||||||||||||||||||||
End point description |
Upper to Lower Body ratio=Sitting Height / (Standing Height – Sitting Height). The ratio of derived sitting height and derived standing height was also calculated.
FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants).
FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants. |
|||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Upper-Lower Body Placebo Vs Vosoritide (FAS Rand) | ||||||||||||||||||||
Statistical analysis description |
Upper to lower body segment ratio.
Difference in LS means were obtained from an analysis of covariance model.
|
||||||||||||||||||||
Comparison groups |
Randomized Vosoritide v Randomized Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
64
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [11] | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.07
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.17 | ||||||||||||||||||||
upper limit |
0.04 | ||||||||||||||||||||
Notes [11] - Covariance model. |
|||||||||||||||||||||
Statistical analysis title |
Upper-Lower Body Ratio Placebo Vs Vosoritide (FAS) | ||||||||||||||||||||
Statistical analysis description |
Upper to lower body segment ratio.
Difference in LS means were obtained from an analysis of covariance model.
|
||||||||||||||||||||
Comparison groups |
All Vosoritide v Placebo
|
||||||||||||||||||||
Number of subjects included in analysis |
75
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
other [12] | ||||||||||||||||||||
Method |
|||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
-0.06
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||
lower limit |
-0.15 | ||||||||||||||||||||
upper limit |
0.03 | ||||||||||||||||||||
Notes [12] - Covariance model. |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm (Forearm) length, Lower Body Length, Upper Leg Length (Thigh), knee to heel length, and tibial length) at Week 52.
The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category.
Upper body length: (n=16, 19, 7, 12, 8, 11)
Head Circumference: (n=16, 19, 7, 11, 8, 11)
Arm Span: (n=16, 19, 7, 10, 8, 10)
Upper Arm Length: (n=16, 19, 7, 11, 8, 11)
Lower Arm (Forearm) Length : (n=16, 19, 7, 10, 8, 11)
Lower Body Length: (n=16, 19, 7, 12, 8, 11)
Upper Leg Length (Thigh): (n=16, 19, 7, 10, 8, 11)
Knee to Heel Length: (n=16, 19, 7, 11, 8, 11)
Tibial Length: (n=16, 19, 7, 11, 8, 11)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participant analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category.
Upper Arm Length to Lower Arm (Forearm) Length Ratio: (n=16, 19, 7, 10, 8, 11)
Upper Leg Length(Thigh)-Knee to Heel Length Ratio: (n=16, 19, 7, 10, 8, 11)
Upper Leg Length (Thigh) to Tibial Length Ratio: (n=16, 19, 7, 10, 8, 11)
Arm Span to Standing Height Ratio: (n=16,19, 7, 10, 8, 10)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Change from baseline in body mass index (BMI) at Week 52 | ||||||||||||||||||||||||||||
End point description |
Body Mass Index (BMI): For height used for BMI calculation, participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.
There were no meaningful differences in BMI between treatment groups from baseline to Week 52 (change of <1 BMI score at Week 52 across all cohorts).
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in BMI Z-score at Week 52 | ||||||||||||
End point description |
BMI Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention. BMI Z-scores are derived only for participants aged 24 months or older, the change from baseline to Week 52 in BMI Z-score is summarized for Cohort 1 only as no participants in Cohort 2 or Cohort 3 were 24 months at baseline.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Change from baseline in weight Z-score at Week 52 | ||||||||||||||||||||||||||||
End point description |
Z-Scores were derived using age-sex specific reference data (means and SDs) for average stature children per the Centers for Disease Control and Prevention.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
# of participants analyzed reported in sequence:(n=C1 Placebo,C1 Vosoritide,C2 Placebo,C2 Vosoritide,C3 Placebo,C3 Vosoritide)incl sentinel for each category.
Overall Health Score:(n=12, 15, 5,10, 6, 10)
Physical Abilities Score:(n=14, 17, 7, 12, 7, 6)
Growth and Development Scores:(n=14, 17, 7, 12, 8, 10)
Pain Score:(n=14, 17, 7,12, 8, 10)
Temperament and mood Score:(n=14, 17, 7,12, 8, 10)
Behavior score:(n=13, 17, 5, 8, 0, 1) Ref PDF
Global behavior score:(n=13, 17, 5, 9, 0, 1) Ref PDF
Getting on with others score:(n=12, 17, 5, 8, 0,0) Ref PDF
Global health perceptions score:(n=13, 17, 7, 12, 8, 9)
Change in health score:(n=13, 16, 5, 6, 0, 1) Ref PDF
Parental impact emotional score:(n=14, 17, 7, 12, 8, 10)
Parental Impact Time Score:(n=14, 17, 7, 12, 8, 10)
Family Cohesion Score:(n=14, 16, 7, 12, 8, 10)
97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52 | ||||||||||||||||||||||||||||||||||||||||
End point description |
The Pediatric Functional Independence Measure-II (WeeFIM®-II) is designed to measure the functional independence of children between the ages of 6 months and 18 years who have physical or general developmental limitations (Msall 1994b). The WeeFIM-II is comprised of 3 domains that are rated by clinicians based on information obtained from parents/caregivers (self-care [score range 8 to 56], mobility [score range 8 to 35], and cognition [score range 8 to 35]) and provides a total score between 18 (worst) and 126 (Best).
The Wee-FIM-II is only validated in children ages 6 months to 18 years. Therefore results for Cohort 3 is not summarized.
The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) incl sentinel for each category.
WeeFIM-II Total Score: (n=14, 19, 6,11)
WeeFIM : Self-Care Score: (n=14, 19, 6, 11)
WeeFIM: Mobility Score: (n=14, 19, 6, 11)
WeeFIM: Cognitive Score: (n=14, 19, 6, 11)
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) for each category.
Motor Composite Score: (n=2, 4, 4, 9, 5,8)
Cognitive scaled score: (n=2, 4, 3, 8, 6,9)
Cognitive composite score: (n=2, 4, 3, 8, 6, 9)
Receptive communication language scaled score: (n=2, 4, 3, 9, 5,9)
Expressive communication language scaled score: (n=2, 4, 4, 8, 5, 8)
Language sum of scaled score: (n=2, 4, 4, 9, 6,9)
Language composite score: (n=2, 4, 4, 9, 5, 9)
Fine motor scaled score: (n=2, 4, 4, 9, 5, 8)
Gross motor scaled score: (n=2, 4, 4, 9, 5, 9)
BSID-III is performance-based clinician-reported outcome assessment for use in children from 1 to 42 months (1 month to 3.5 years). individually administered by the trained clinician to the participant/child. Each (sub)scale yields a total raw score, standardized according to the participant’s chronological age (scaled scores)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) vosoritide including sentinel and randomized participants for each category.
Emotionally Reactive Total: (n=15, 18, 4, 5)
Anxious/Depressed Total: (n=15, 18, 4, 5)
Withdrawn Total: (n=15, 18, 4, 5)
Somatic Complaints Total: (n=15, 18, 4, 5)
Sleep Problems Total: (n=15, 18, 4, 5)
Attention Problems Total: (n=15, 18, 4, 5)
Aggressive Behavior Total: (n=15, 18, 4, 5)
Total Problems Total: (n=15, 18, 4, 5)
The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale (0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often True). The time frame for item responses was the past 2 months. Raw scores, t-scores, and percentiles are calculated for all subscales and syndromes, with higher scores indicating higher problems.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in bilateral X-rays of lower extremities at Wee 52 | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category.
Left Femur Length: (n= 17, 14)
Right Femur Length: (n= 17, 14)
Left Fibula Length: (n= 40,,27)
Right Fibula Length: (n= 39, 27)
Left Tibia Length: (n= 40, 27)
Right Tibia Length: (n= 39, 27)
Left Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 38, 26)
Right Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 37, 26)
Left Lower Extremity: (n= 18, 14)
Right Lower Extremity: (n= 18, 14)
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52 | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All vosoritide , Placebo) for each category.
Left Tibia Bowing Angle : (n= 39, 27)
Right Tibia Bowing Angle : (n=38, 27)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52 | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo)
Left Femur Length (cm) to Tibia Length (cm) Ratio : (n= 17, 14)
Right Femur Length (cm) to Tibia Length (cm) Ratio: (n= 17, 14)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52 | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n= All vosoritide, Placebo)
Left Tibia Length (cm) to Fibula Length (cm) Ratio: (n=40, 27)
Right Tibia Length (cm) to Fibula Length (cm) Ratio: (n=39, 27)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category.
Anterior Height to Medial Height Ratio (L1): (n= 30, 23)
Anterior Height to Medial Height Ratio (L2): (n= 23, 13)
Anterior Height to Medial Height Ratio (L3): (n= 19, 11)
Anterior Height to Medial Height Ratio (L4): (n=26, 15)
Anterior Height to Medial Height Ratio (L5): (n=27, 12)
Anterior Height to Posterior Height Ratio (L1): (n= 40, 27)
Anterior Height to Posterior Height Ratio (L2): (n= 40, 27)
Anterior Height to Posterior Height Ratio (L3): (n= 40, 27)
Anterior Height to Posterior Height Ratio (L4): (n= 40, 27)
Anterior Height to Posterior Height Ratio (L5): (n= 40, 27)
Medial Height to Posterior Height Ratio (L1): (n= 30, 23)
Medial Height to Posterior Height Ratio (L2): (n= 23, 13)
Medial Height to Posterior Height Ratio (L3): (n= 19, 11)
Medial Height to Posterior Height Ratio (L4): (n= 26, 15)
Medial Height to Posterior Height Ratio (L5):(n= 27,12)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52 | |||||||||||||||||||||||||||
End point description |
||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52 | |||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
Sagittal Width (L1): (n=34, 26)
Sagittal Width (L2): (n=34, 26)
Sagittal Width (L3): (n=34, 26)
Sagittal Width (L4): (n=34, 26)
Sagittal Width (L5): (n=31, 25)
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Change from baseline in X-ray of Lumbar Spine Angles at Week 52 | |||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo)
Sacral Tilt: (n= 40, 27)
Lordosis Angle: (n= 40, 27)
Kyphosis Angle: (n= 39, 27)
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52 | |||||||||||||||||||||||||||
End point description |
||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume. | |||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
Volume of Face: (n=30, 21)
Volume of Sinus: (n=35, 24)
Volume of Calvarium: (n=34, 24)
Whole Brain Total Volume: (n=34, 24)
Ventricles Total Volume: (n=34, 25)
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level | ||||||||||||||||||
End point description |
|||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus | |||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo)
Ratio of face volume to calvarium: (n=29, 20)
Ratio of area of spinal cord to foramen magnum: (n=35, 25)
Ratio of face volume to sinus: (n=30, 21)
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC) | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
GE - Lunar Prodigy: Whole Body Less Head BMC: (n=8, 12)
Hologic - Discovery Horizon Whole Body Less Head BMC: (n=18, 8)
Dual Energy X-Ray Absorptiometry (DEXA)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD) | ||||||||||||||||||
End point description |
GE - Lunar Prodigy Whole Body Less Head BMD: (n=8,12)
Hologic - Discovery Horizon Whole Body Less Head BMD: (18, 8)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 of Whole Body BMC | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
GE - Lunar Prodigy Whole Body BMC: (n=8, 12)
Hologic - Discovery Horizon Whole Body BMC: (n=18, 8)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 of Whole Body BMD | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
GE - Lunar Prodigy Whole Body BMD: (n=8, 12)
Hologic - Discovery Horizon Whole Body BMD: (n=18, 8)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
GE - Lunar Prodigy Lumbar Spine BMC: (n=9, 10)
Hologic - Discovery Horizon Lumbar Spine BMC: (n=27, 13)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD | ||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
GE - Lunar Prodigy Lumbar Spine BMD: (n=9, 10)
Hologic - Discovery Horizon Lumbar Spine BMD: (27, 13)
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Change from baseline to Week 52 in whole body BMD Z-score | |||||||||||||||
End point description |
Hologic - Discovery Horizon Whole Body BMD Z-Score
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline to Week 52
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline to Week 52 in Lumbar Spine BMD Z-Score | ||||||||||||
End point description |
Hologic - Discovery Horizon Lumbar Spine BMD Z-Score
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of participants with Incidence of Antibody Positivity at Scheduled Visits for : total antibody (TAb), Neutralizing antibodies (NAb), atrial natriuretic peptide (ANP), B-type Natriuretic Peptide (BNP) & C-type natriuretic peptide (CNP).
TAb Titer Positive, NAb Titer Positive, ANP Reactivity Positive, BNP Reactivity Positive & CNP Reactivity Positive.
Day 1 is the baseline assessment result taken prior to first dose of study drug.
Ever Positive = the number of participants with at least one positive sample result.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Biomarker: Bone Specific Alkaline Phosphatase (BSAP) overtime | |||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
Baseline: (n= 43, 32)
Day 8: (n=42, 27)
Change from baseline to Day 8: (n=42, 27)
Week 6: (n=41, 29)
Change from baseline to Week 6: (n=41, 29)
Week 20: (n=40, 28)
Change from baseline to Week 20: (n=40, 28)
Week 39: (n=34, 24)
Change from baseline to Week 39 : (n=34, 24)
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Baseline, Day 8, Week 6, Week 20, & Week 39.
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II) | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 52.
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Biomarker: Plasma cGMP Change from Pre-Dose to Maximum Post-Dose at Week 52 | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 52 Pre-Dose to Week 52 Maximum Post-Dose.
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change in Sleep Study Indices at Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
A sleep study was performed in a limited number of qualified sleep centers. A sleep-testing device was used to assess the presence and severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse rate, and airflow during overnight monitoring. Assessment of episodes of sleep apnea included but were not limited to the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.
PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞ excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.
The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52)
Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15)
Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF
Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3)
Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3,7)
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day1, Week 13, Week 26, Week 39, & Week 52.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Area under the plasma concentration-time curve from time 0 to nominal 120 minutes postdose (AUC 0- 120 min) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5), Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Maximum observed plasma concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participant analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16) Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Time to reach maximum concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52.
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Apparent clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.
PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.
The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52)
Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15)
Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF
Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3)
Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Apparent volume of distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.
PK parameters for another participant on Day 1 obtained from extrapolation. V/F excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.
The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52)
Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15)
Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF
Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3)
Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
|
||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52.
|
||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||
End point title |
PK parameter: Elimination half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52 | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.
PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.
The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52)
Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15)
Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF
Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3)
Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)
|
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End point type |
Secondary
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End point timeframe |
At Day 01, Week 13, Week 26, Week 39, & Week 52.
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No statistical analyses for this end point |
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End point title |
Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM | |||||||||||||||||||||||||||||||||||||||
End point description |
The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category.
Baseline: (n= 42, 32)
Day 8: (n=42, 24)
Change from baseline to Day 8: (n=41, 24)
Week 6: (n=41, 29)
Change from baseline to Week 6: (n=40, 29)
Week 20: (n=42, 29)
Change from baseline to Week 20: (n=41, 29)
Week 39: (n=33, 22)
Change from baseline to Week 39 : (n=32, 22)
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End point type |
Secondary
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End point timeframe |
At Baseline, Day 8, Week 6, Week 20, & Week 39.
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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 |
Up to Week 56 Safety Follow-Up.
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Adverse event reporting additional description |
The Safety Population was a subset of the FAS who received at least one dose of vosoritide or placebo in the study.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vosoritide
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 Aug 2018 |
• The lower age range of participating participants who have a >= 6-month period of pretreatment growth assessment in 111-901 immediately before study entry was revised from >= 3 months to >= 6 months.
• Language updated to state that no two sentinel participants would be dosed on the same day for any cohort.
• Echocardiogram would be performed at the Week 56Safety Follow-up and Early Termination visits
• Use of residual plasma samples for cGMP PD biomarker assessment in all age groups was added to procedures.
• An anti-vosoritide immunogenicity assessment was added at Week 3.
• Bone metabolism urine biomarkers, vosoritide pharmacodynamic urine biomarkers, and urine chemistry assessments were added at Week 39.
• The sleep study scheduled at the Week 26 visit was removed.
• DXA scans would no longer include tibia scans.
• If the 111-901 visit at which the participant entered 111-206 and the 111-206 Screening visit were on the same day, the procedures common to both visits were performed one time only.
• On days when PK samples were being drawn, ECG would be performed within a 5-minute window prior to the 30-minute PK assessment.
• Exclusion criterion #6 was revised from “…as determined by the Investigator based on the following assessments…) to (…as determined by theInvestigator and informed by the following assessments…). The determination about whether presence of cervicomedullary compression is likely to require surgical intervention will be informed by physical exam, polysomnography, and MRI.
• Exclusion criterion #15 was revised to include cervicomedullary decompression surgery (Cohorts 2 and 3 only).
• Inclusion/exclusion criteria was added for Cohort 3 participants enrolling in the observational period.
• A table of restricted medications, including growth hormone, was added. For participants enrolled in Cohort 3 (0 to < 6 months old), the collection period for all AEs was to begin after informed consent is obtained.
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08 Feb 2019 |
The following exploratory objectives were revised to secondary objectives.
• Evaluate the effect of vosoritide on growth parameters and body proportions, including change from baseline in upper:lower segment ratio
• Evaluate the effect of vosoritide on sleep apnea
• Evaluate the effect of vosoritide on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal dimensions
• Describe the incidence of surgical interventions, including cervical decompression, adenotonsellectomy, and typanostomy
The secondary imaging assessment procedures, excluding the MRI assessment, were moved to the secondary safety variables section. The hip imaging assessment was removed, the X-ray assessment was modified to include long bone growth, and the DXA assessment would no longer include the forearm. Also, the paragraph discussing the possibility of
non-radiological methods of assessment for participants in Cohort 3 was deleted.
The screening baseline hip assessment with pelvis X-ray was removed from the Schedule of Events.
Footnotes were changed to modify procedures and to add early termination visits (ETV) for anthropomorphic measurements, DXA, and X-rays.
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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. | |||
None reported |