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    Clinical Trial Results:
    A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children with Achondroplasia

    Summary
    EudraCT number
    2013-004137-32
    Trial protocol
    GB   FR  
    Global end of trial date
    02 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jun 2019
    First version publication date
    27 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    111-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02055157
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc.
    Sponsor organisation address
    105 Digital Drive, Novato, CA, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002033-PIP01-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the initial 6-month phase is: To evaluate the safety and tolerability of daily Subcutaneous (SC) injections of BMN 111 administered for 6 months The primary objective of the study extension is: To evaluate the safety and tolerability of daily Subcutaneous (SC) injections of BMN 111 administered for up to 24 months
    Protection of trial subjects
    This clinical study was designed, conducted, recorded, and reported in compliance with the principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal regulations as well as “Guidance for Good Clinical Practice,” International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    France: 2
    Worldwide total number of subjects
    35
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    35
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 9 study centers in United States, Australia, United Kingdom and France.

    Pre-assignment
    Screening details
    Of the 35 subjects enrolled to study, 32 subjects completed the initial six months and 30 completed the eighteen months extension.

    Period 1
    Period 1 title
    Initial 6 months
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Cohorts 1
    Arm description
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Arm title
    Cohorts 2
    Arm description
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Arm title
    Cohorts 3
    Arm description
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

    Arm title
    Cohorts 4
    Arm description
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

    Number of subjects in period 1
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4
    Started
    8
    8
    10
    9
    Completed
    7
    7
    10
    8
    Not completed
    1
    1
    0
    1
         Consent withdrawn by subject
    1
    -
    -
    -
         Subject D/C due to PI decision
    -
    1
    -
    -
         Subject D/C due to AE
    -
    -
    -
    1
    Period 2
    Period 2 title
    18-month extension
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Cohorts 1
    Arm description
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, 7 subjects escalated to 7.5 μg/kg daily subcutaneous injection, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Arm title
    Cohorts 2
    Arm description
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Arm title
    Cohorts 3
    Arm description
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Arm title
    Cohorts 4
    Arm description
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 111
    Investigational medicinal product code
    Other name
    Vosoritide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Number of subjects in period 2
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4
    Started
    7
    7
    10
    8
    Completed
    6
    6
    10
    8
    Not completed
    1
    1
    0
    0
         Subject D/C due to growth plates closure
    -
    1
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohorts 1
    Reporting group description
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 2
    Reporting group description
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 3
    Reporting group description
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 4
    Reporting group description
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group values
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4 Total
    Number of subjects
    8 8 10 9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.3 ± 1.58 8.3 ± 2.19 8.0 ± 1.63 6.9 ± 1.17 -
    Gender categorical
    Units: Subjects
        Female
    5 3 6 5 19
        Male
    3 5 4 4 16
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    8 8 9 7 32
        Hispanic or Latino
    0 0 1 1 2
        Not Reported
    0 0 0 1 1
    Race
    Units: Subjects
        White
    7 6 5 6 24
        Asian
    0 1 3 3 7
        Black or African American
    1 0 1 0 2
        Other
    0 1 1 0 2
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    18.58 ± 2.223 22.50 ± 4.099 25.13 ± 5.736 19.59 ± 2.859 -
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    20.13 ± 2.089 21.78 ± 2.1 22.21 ± 2.694 20.44 ± 1.038 -

    End points

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    End points reporting groups
    Reporting group title
    Cohorts 1
    Reporting group description
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 2
    Reporting group description
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 3
    Reporting group description
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

    Reporting group title
    Cohorts 4
    Reporting group description
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.
    Reporting group title
    Cohorts 1
    Reporting group description
    BMN 111 at 2.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, 7 subjects escalated to 7.5 μg/kg daily subcutaneous injection, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Reporting group title
    Cohorts 2
    Reporting group description
    BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Reporting group title
    Cohorts 3
    Reporting group description
    BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Reporting group title
    Cohorts 4
    Reporting group description
    BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

    Subject analysis set title
    Cohort 3
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

    Subject analysis set title
    Cohort 4
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

    Primary: Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

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    End point title
    Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs) [1]
    End point description
    Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period. SAE (Serious Adverse Event). AE (CTCAE) Grade: 1=Mild, 2=Moderate, 3=Severe or Undesirable, 4=Life Threatening or Debilitating.
    End point type
    Primary
    End point timeframe
    Up to Month 24 ± 14 Days
    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: Statistical Results were summarized by dose cohort and for all cohorts combined.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    8
    8
    10
    9
    Units: Number of subjects analysed
        Any Study Drug-Related AE—Grade 1
    7
    7
    9
    9
        Any Study Drug-Related AE—Grade 2
    0
    1
    0
    0
        Any Study Drug-Related AE—Grade 3
    0
    0
    0
    0
        Any Study Drug-Related AE—Grade 4
    0
    0
    0
    0
        Subjects with at Least 1 Reported TEAE
    8
    8
    10
    9
        At Least 1 Reported Study Drug-Related TEAE
    7
    8
    9
    9
        Subjects with at Least 1 Reported SAE
    1
    0
    1
    1
        At Least 1 Reported Study Drug-Related SAE
    0
    0
    0
    0
        Permanently Discontinued Study Drug due to TEAE
    0
    0
    0
    1
        Subjects Who Discontinued Study due to TEAE
    0
    0
    0
    0
        Subjects Who Died
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month

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    End point title
    Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Annualized Growth Velocity assessed by anthropometric measurements and measurement ratios. Anthropometric measurements included standing height, sitting height, weight, head circumference, upper and lower arm and leg, hand and foot. Ratios calculated of Upper arm to forearm length ratio, Upper leg to lower leg length ratio, Upper to lower body segment ratio. Weight was measured at Screening and at each in-clinic dosing visit.
    End point type
    Secondary
    End point timeframe
    At 6 month (Day 183)
    End point values
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4
    Number of subjects analysed
    8
    8
    10
    8
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline of Initial 6-Month Period (N = 8,8,10,8)
    3.755 ± 1.1094
    2.891 ± 1.3920
    4.044 ± 2.2751
    4.492 ± 1.1889
        Change from Baseline to Day 183 (N = 7,8,10,8)
    -0.371 ± 1.5920
    1.276 ± 1.4387
    2.014 ± 1.9990
    2.085 ± 2.1375
    No statistical analyses for this end point

    Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4

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    End point title
    Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (N= 10,8)
    4.044 ± 2.2751
    4.492 ± 1.1889
        Change from Baseline to Month 24 (N= 10,8)
    1.744 ± 1.7974
    1.538 ± 1.3387
    No statistical analyses for this end point

    Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers

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    End point title
    Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Mos (Months)
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 1 Cohorts 2
    Number of subjects analysed
    6
    6
    Units: cm/year
    arithmetic mean (standard deviation)
        Baseline (N = 6,6)
    3.629 ± 1.1586
    3.510 ± 0.8327
        Change from Baseline at >=12 Mos on 15μg/kg(N=3,6)
    1.846 ± 2.1466
    2.245 ± 0.9176
    No statistical analyses for this end point

    Secondary: Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment

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    End point title
    Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database.
    End point type
    Secondary
    End point timeframe
    At month 6 (Day 183)
    End point values
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4
    Number of subjects analysed
    8
    8
    10
    8
    Units: z score
    arithmetic mean (standard deviation)
        Baseline (n = 7,8,10,8)
    -6.056 ± 0.6331
    -5.145 ± 0.8530
    -4.613 ± 1.1355
    -5.193 ± 0.7486
        Change from Baseline to Day 183 (n = 7,8,10,8)
    -0.008 ± 0.1788
    0.078 ± 0.1440
    0.229 ± 0.1505
    0.265 ± 0.1869
    No statistical analyses for this end point

    Secondary: Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: z score
    arithmetic mean (standard deviation)
        Baseline (n = 10, 8)
    -4.613 ± 1.1355
    -5.193 ± 0.7486
        Change from Baseline to Month 24 (n = 10, 8)
    0.788 ± 0.2842
    0.896 ± 0.3010
    No statistical analyses for this end point

    Secondary: Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

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    End point title
    Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database. Mos (Months)
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 1 Cohorts 2
    Number of subjects analysed
    6
    6
    Units: z score
    arithmetic mean (standard deviation)
        Baseline (n = 6,6)
    -6.064 ± 0.6932
    -4.912 ± 0.7708
        Change from Baseline to >=12 Mos on 15ug/kg(n=3,6)
    0.520 ± 0.2950
    0.259 ± 0.1887
    No statistical analyses for this end point

    Secondary: Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

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    End point title
    Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database. Mos (Months)
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 1 Cohorts 2
    Number of subjects analysed
    6
    6
    Units: z score
    arithmetic mean (standard deviation)
        Baseline (n = 6,6)
    -2.615 ± 0.9648
    -1.436 ± 0.3942
        Change from Baseline to >=12 Mos on 15ug/kg(n=3,6)
    0.926 ± 0.2311
    0.173 ± 0.1287
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment

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    End point title
    Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 6 and month 24
    End point values
    Cohorts 1 Cohorts 2 Cohorts 3 Cohorts 4
    Number of subjects analysed
    8
    8
    10
    8
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n = 7,8,10,8)
    2.094 ± 0.0984
    2.027 ± 0.1793
    1.911 ± 0.2286
    1.962 ± 0.1822
        Change from Baseline to Day 183 (n = 7,8,10,8)
    -0.021 ± 0.0626
    0.003 ± 0.0510
    -0.024 ± 0.0369
    -0.030 ± 0.0811
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n= 10,8)
    1.911 ± 0.2286
    1.962 ± 0.1822
        Change from Baseline to Month 24 (n= 10,8)
    -0.067 ± 0.0451
    -0.121 ± 0.1058
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 [2]
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 6 (Day 183) and 24
    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 Results were summarized by dose cohort and for all cohorts combined.
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 10,8)
    1.130 ± 0.1190
    1.106 ± 0.0816
        Change from Baseline to Day 183 (n = 10,8)
    -0.048 ± 0.1002
    0.003 ± 0.0869
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 10,8)
    1.130 ± 0.1190
    1.106 ± 0.0816
        Change from Baseline to Month 24 (n = 10,8)
    0.037 ± 0.0673
    -0.027 ± 0.0504
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 [3]
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 6 (Day 183)
    Notes
    [3] - 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 Results were summarized by dose cohort and for all cohorts combined.
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 10,8)
    0.687 ± 0.0268
    0.691 ± 0.0847
        Change from Baseline to Day 183 (n = 10,8)
    0.007 ± 0.0411
    -0.006 ± 0.0810
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 10,8)
    0.687 ± 0.0268
    0.691 ± 0.0847
        Change from Baseline to Month 24 (n = 10, 8)
    0.010 ± 0.0503
    -0.033 ± 0.1065
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 [4]
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 6 (Day 183)
    Notes
    [4] - 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 Results were summarized by dose cohort and for all cohorts combined.
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n =10,8)
    1.107 ± 0.0607
    1.061 ± 0.1341
        Change from Baseline to Day 183 (n = 10,8)
    0.034 ± 0.1048
    0.015 ± 0.1571
    No statistical analyses for this end point

    Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 10,8)
    1.107 ± 0.0607
    1.061 ± 0.1341
        Change from Baseline to Month 24 (n = 10,8)
    0.014 ± 0.0888
    -0.012 ± 0.1477
    No statistical analyses for this end point

    Secondary: Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4

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    End point title
    Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4 [5]
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 6 (Day 183)
    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 Results were summarized by dose cohort and for all cohorts combined.
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 4,7)
    0.913 ± 0.0123
    0.893 ± 0.0284
        Change from Baseline to Day 183 (n= 4,7)
    0.007 ± 0.0063
    0.001 ± 0.0143
    No statistical analyses for this end point

    Secondary: Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4

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    End point title
    Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4
    End point description
    Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.
    End point type
    Secondary
    End point timeframe
    At month 24
    End point values
    Cohorts 3 Cohorts 4
    Number of subjects analysed
    10
    8
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n = 5,8)
    0.911 ± 0.0119
    0.900 ± 0.0315
        Change from Baseline to Month 24 (n = 5,8)
    0.000 ± 0.0123
    -0.006 ± 0.0290
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24

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    End point title
    Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24
    End point description
    Pharmacokinetic Parameter Tmax is the time to reach Cmax (maximum observed plasma concentration) PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose for month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: min
        median (full range (min-max))
    15.5 (6.00 to 32.0)
    17.0 (15.0 to 30.0)
    30.0 (15.0 to 88.0)
    30.0 (15.0 to 60.0)
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24
    End point description
    Pharmacokinetic Parameter Cmax is the maximum observed plasma concentration. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: pg/mL
        arithmetic mean (standard deviation)
    21800 ± 35500
    4450 ± 2330
    8730 ± 4800
    20500 ± 12700
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24

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    End point title
    Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24
    End point description
    Pharmacokinetic parameter (AUC(0-t)) is the Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: pg-min/mL
        arithmetic mean (standard deviation)
    602000 ± 526000
    180000 ± 104000
    609000 ± 457000
    1730000 ± 936000
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24

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    End point title
    Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24
    End point description
    Pharmacokinetic parameter (AUC0-∞) is the Area under the plasma concentration-time curve from time 0 to infinity. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: pg-min/mL
        arithmetic mean (standard deviation)
    720000 ± 539000
    382000 ± 0.00
    643000 ± 470000
    1720000 ± 1000000
    No statistical analyses for this end point

    Secondary: Apparent clearance of BMN 111 (CL/F) at month 24

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    End point title
    Apparent clearance of BMN 111 (CL/F) at month 24
    End point description
    Pharmacokinetic parameter (CL/F) is the Apparent clearance of BMN 111. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: mL/min/kg
        arithmetic mean (standard deviation)
    33.0 ± 23.2
    39.3 ± 0.00
    31.9 ± 14.8
    26.7 ± 21.9
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution of BMN 111 (Vz/F) at month 24

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    End point title
    Apparent volume of distribution of BMN 111 (Vz/F) at month 24
    End point description
    Pharmacokinetic parameter (Vz/F) is the Apparent volume of BMN 111. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: mL/kg
        arithmetic mean (standard deviation)
    1060 ± 629
    1220 ± 0.00
    1210 ± 428
    1180 ± 472
    No statistical analyses for this end point

    Secondary: Elimination half-life (t1/2) of BMN 111 at month 24

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    End point title
    Elimination half-life (t1/2) of BMN 111 at month 24
    End point description
    Pharmacokinetic parameter (t1/2) is the Elimination half-life PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    10
    8
    Units: min
        arithmetic mean (standard deviation)
    23.5 ± 2.56
    21.5 ± 0.00
    29.0 ± 8.05
    38.4 ± 14.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AbdominalUp to Month 24 � 14 Days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Entire Study Period - Cohort 1
    Reporting group description
    -

    Reporting group title
    Entire Study Period - Cohort 2
    Reporting group description
    -

    Reporting group title
    Entire Study Period - Cohort 3
    Reporting group description
    -

    Reporting group title
    Entire Study Period - Cohort 4
    Reporting group description
    -

    Serious adverse events
    Entire Study Period - Cohort 1 Entire Study Period - Cohort 2 Entire Study Period - Cohort 3 Entire Study Period - Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Thyroglossal cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Entire Study Period - Cohort 1 Entire Study Period - Cohort 2 Entire Study Period - Cohort 3 Entire Study Period - Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    8 / 8 (100.00%)
    9 / 10 (90.00%)
    9 / 9 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 8 (62.50%)
    5 / 8 (62.50%)
    4 / 10 (40.00%)
    2 / 9 (22.22%)
         occurrences all number
    8
    13
    4
    5
    Haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pallor
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Surgical and medical procedures
    Ear tube insertion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Tooth extraction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    6 / 8 (75.00%)
    7 / 8 (87.50%)
    8 / 10 (80.00%)
    9 / 9 (100.00%)
         occurrences all number
    1035
    1051
    1398
    1869
    Injection site erythema
         subjects affected / exposed
    5 / 8 (62.50%)
    7 / 8 (87.50%)
    9 / 10 (90.00%)
    9 / 9 (100.00%)
         occurrences all number
    76
    1231
    465
    1935
    Injection site swelling
         subjects affected / exposed
    5 / 8 (62.50%)
    4 / 8 (50.00%)
    5 / 10 (50.00%)
    2 / 9 (22.22%)
         occurrences all number
    32
    4
    431
    28
    Injection site urticaria
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    4 / 9 (44.44%)
         occurrences all number
    105
    3
    145
    10
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    3
    60
    Pyrexia
         subjects affected / exposed
    5 / 8 (62.50%)
    3 / 8 (37.50%)
    5 / 10 (50.00%)
    2 / 9 (22.22%)
         occurrences all number
    5
    3
    7
    3
    Injection site bruising
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    11
    2
    0
    2
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    2
    Injection site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Application site erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cyst
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site discolouration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Injection site induration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Medical device site reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Seasonal allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 8 (62.50%)
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    4 / 9 (44.44%)
         occurrences all number
    8
    2
    5
    10
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    8
    6
    0
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    0 / 10 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    5
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Sneezing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Snoring
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Emotional disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Irritability
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Enuresis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Frustration tolerance decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aggression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    3
    Eosinophil count increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood immunoglobulin E increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory rate increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep study abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    5
    6
    1
    Fall
         subjects affected / exposed
    4 / 8 (50.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    4
    0
    2
    3
    Contusion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    2
    1
    0
    Procedural anxiety
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    2
    Thermal burn
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Meniscus injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Thyroglossal cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    3 / 9 (33.33%)
         occurrences all number
    15
    8
    13
    8
    Dizziness
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Presyncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Sinus headache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 8 (50.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    6
    2
    3
    Ear swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tympanic membrane hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Eye discharge
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Hypermetropia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    6
    5
    6
    5
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    3
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    1
    1
    3
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    3
    1
    Dental caries
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Malpositioned teeth
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Toothache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    4
    2
    1
    Dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    1
    Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rash generalised
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Acne
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Skin striae
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    4 / 9 (44.44%)
         occurrences all number
    2
    1
    1
    8
    Arthralgia
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    0
    2
    2
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    1
    Groin pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 8 (50.00%)
    5 / 10 (50.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    11
    12
    9
    Ear infection
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    2 / 10 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    4
    12
    3
    7
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    4
    7
    5
    Otitis media
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    1
    3
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    7
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    0
    2
    Viral infection
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    2
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    2
    Otitis externa
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Acute sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Atypical pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Croup infectious
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Eye abscess
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Incision site infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Onychomycosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Rash pustular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scarlet fever
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Varicella
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2014
    Amendment 1 established an optional, open-label extension phase of approximately 18 months to commence at the end of the initial phase of the study, making a total study duration of approximately 25 months, including a 1-month safety follow-up visit. The rationale for extending this Phase 2 study was to assess the long-term safety and tolerability of BMN 111 in children with ACH; and to assess longer-term effects of BMN 111 on the growth in these children.
    08 May 2015
    Amendment 2 established higher doses in 2 additional cohorts in the initial 6 months of the study. Cohort 4 and 5 daily doses of 30 μg/kg and up to 60 μg/kg BMN 111, respectively, were selected with the intent to achieve exposures expected to result in further increases in growth velocity in children with ACH with an acceptable safety profile. In addition, baseline hip assessments and hip monitoring to screen for effects on hip joints and/or mobility were added for all cohorts.
    26 Oct 2015
    Amendment 3 added a thyroid function test at the Month 24 visit to assess any changes over the course of the open-label extension phase of 111-202. This amendment also specified that the assessment at Month 24 would serve as the baseline/screening assessments for entry into 111-205 and waived the safety follow-up visit at Month 25 if a subject enrolled in 111-205 at the Month 24/Study Completion Visit. These changes ensured uninterrupted transition of subjects who complete 111-202 into 111-205.
    22 Aug 2016
    Amendment 4 removed Cohort 5 based on the 6-month data from Cohort 4. Preliminary PK data from Cohort 4 (30 μg/kg daily) showed a greater than dose proportional increase in BMN 111 exposure, with mean plasma maximum observed plasma concentration (Cmax) and area under the time-concentration curve from zero to the last quantifiable concentration (AUC0-t) values at the target exposure previously expected to require daily doses up to 60 μg/kg. A marginal improvement was observed in both absolute AGV and change from baseline AGV in Cohort 4 (BMN 111 daily at 30 μg/kg) after 6 months of BMN 111 treatment when compared with Cohort 3 (BMN 111 daily at 15 μg/kg). Given this observation, higher doses of BMN 111 were not expected to demonstrate an improved benefit/risk profile. Thus, Cohort 5 (with daily dosing up to 60 μg/kg) was not pursued.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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