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    Clinical Trial Results:
    A Phase 2 Multiple Dose, Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Recifercept in Children With Achondroplasia

    Summary
    EudraCT number
    2020-001189-13
    Trial protocol
    PT   DK   BE   IT  
    Global end of trial date
    27 Mar 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Oct 2023
    First version publication date
    07 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C4181005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04638153
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    27 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objectives: 1) to evaluate the safety and tolerability of recifercept doses and dosing regimes in subjects aged ≥2 to <11 years with achondroplasia; 2) to assess efficacy of recifercept to increase height growth in children with achondroplasia.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Dec 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Japan: 3
    Worldwide total number of subjects
    57
    EEA total number of subjects
    39
    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)
    3
    Children (2-11 years)
    54
    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
    -

    Pre-assignment
    Screening details
    A total of 63 subjects were screened with 58 subjects assigned to treatment. Of the 58 subjects assigned to treatment, 57 (98.3%) subjects were treated. One subject was assigned to treatment but not treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Recifercept 1 mg/kg QW
    Arm description
    Children subjects were enrolled and randomised to receive recifercept 1 mg/kg once weekly (QW) for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recifercept
    Investigational medicinal product code
    Other name
    PF-07256472
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Recifercept 1 mg/kg was administered once weekly.

    Arm title
    Recifercept 2 mg/kg BIW
    Arm description
    Children subjects were enrolled and randomised to receive recifercept 2 mg/kg twice weekly (BIW) for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recifercept
    Investigational medicinal product code
    Other name
    PF-07256472
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Recifercept 2 mg/kg was administered twice weekly.

    Arm title
    Recifercept 1.5 mg/kg QD
    Arm description
    Children subjects were enrolled and randomised to receive recifercept 1.5 mg/kg once daily (QD) for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recifercept
    Investigational medicinal product code
    Other name
    PF-07256472
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Recifercept 1.5 mg/kg was administered once daily.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This was a partially blinded study with open-label supplies. In order to minimize bias in measurement of the primary efficacy endpoint (height), the anthropometrist was blinded to dose assignment. There was no additional blinding.
    Number of subjects in period 1
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Started
    20
    19
    18
    Completed
    16
    17
    3
    Not completed
    4
    2
    15
         Study terminated by sponsor
    4
    2
    14
         Withdrawal by parent/guardian
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Recifercept 1 mg/kg QW
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 1 mg/kg once weekly (QW) for 12 months.

    Reporting group title
    Recifercept 2 mg/kg BIW
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 2 mg/kg twice weekly (BIW) for 12 months.

    Reporting group title
    Recifercept 1.5 mg/kg QD
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 1.5 mg/kg once daily (QD) for 12 months.

    Reporting group values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD Total
    Number of subjects
    20 19 18 57
    Age Categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    2 1 0 3
        Children (2-11 years)
    18 18 18 54
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    0 0 0 0
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    5.75 ± 2.84 5.16 ± 2.59 5.83 ± 2.31 -
    Gender Categorical
    Units: Subjects
        Female
    9 9 6 24
        Male
    11 10 12 33
    Race Categorical
    Units: Subjects
        White
    15 19 14 48
        Asian
    3 0 2 5
        Multiracial
    1 0 1 2
        Not Reported
    1 0 1 2
    Ethnicity Categorical
    Units: Subjects
        Hispanic or Latino
    3 0 2 5
        Not Hispanic or Latino
    16 19 15 50
        Not Reported
    1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    Recifercept 1 mg/kg QW
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 1 mg/kg once weekly (QW) for 12 months.

    Reporting group title
    Recifercept 2 mg/kg BIW
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 2 mg/kg twice weekly (BIW) for 12 months.

    Reporting group title
    Recifercept 1.5 mg/kg QD
    Reporting group description
    Children subjects were enrolled and randomised to receive recifercept 1.5 mg/kg once daily (QD) for 12 months.

    Primary: Number of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs)

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    End point title
    Number of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) [1]
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study intervention in a subject who received study intervention. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study intervention and up to 365 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to Recifercept was assessed by the investigator (Yes/No). Subjects with multiple occurrences of an AE within a category were counted once within the category. Analysis population included all subjects who received at least one dose of recifercept.
    End point type
    Primary
    End point timeframe
    The first dose up to 28 to 35 days after the last dose of study intervention (27 months).
    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: Analysis was planned only for the end point specified.
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Subjects
        Treatment-related AE
    7
    15
    14
        Treatment-related SAE
    0
    0
    0
    No statistical analyses for this end point

    Primary: Increase in Height Growth Above Expected in Reference Population

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    End point title
    Increase in Height Growth Above Expected in Reference Population
    End point description
    Height growth was defined as the ratio of observed change from baseline in standing height to the expected change from baseline in the reference population. Analysis population included all subjects (aged 2-10 years) who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Primary
    End point timeframe
    Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    18
    18
    18
    Units: Ratio
    arithmetic mean (standard deviation)
        Month 3 (n=15,17,17)
    1.1 ± 0.49
    71.4 ± 290.85
    130.0 ± 533.42
        Month 6 (n=16,16,15)
    0.9 ± 0.42
    1.1 ± 0.44
    1.0 ± 0.45
        Month 9 (n=16,16,11)
    1.0 ± 0.36
    1.0 ± 0.24
    1.0 ± 0.28
        Month 12 (n=7,9,2)
    0.9 ± 0.30
    1.1 ± 0.22
    0.8 ± 0.04
    Statistical analysis title
    Least-Square (LS) Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.6
    Statistical analysis title
    LS Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.1
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.9
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1 mg/kg QW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 1 mg/kg QW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.3
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1

    Secondary: Change From Baseline in Pulse Rate at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Pulse Rate at Month 3, Month 6, Month 9, and Month 12
    End point description
    Pulse rate measurements were preceded by at least 5 minutes of rest for the subject in a quiet setting without distractions (eg, television, cell phones) where possible (with consideration of the age of the child). Pulse rate was summarized by treatment in accordance with the sponsor reporting standards. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: beats per minute (BPM)
    arithmetic mean (standard deviation)
        Baseline (n=20,19,18)
    96.40 ± 16.583
    97.58 ± 21.823
    94.50 ± 15.497
        Change at Month 3 (n=17,19,17)
    -1.47 ± 13.639
    -6.05 ± 20.871
    -2.94 ± 16.913
        Change at Month 6 (n=17,18,15)
    -2.65 ± 8.760
    -1.44 ± 15.659
    -2.20 ± 15.880
        Change at Month 9 (n=17,17,10)
    -4.35 ± 16.035
    -2.18 ± 17.746
    -15.20 ± 14.853
        Change at Month 12 (n=6,8,2)
    1.17 ± 15.484
    -0.75 ± 34.012
    -11.50 ± 37.477
    No statistical analyses for this end point

    Secondary: Change From Baseline in Respiratory Rate at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Respiratory Rate at Month 3, Month 6, Month 9, and Month 12
    End point description
    Respiratory rate was obtained with subject in the seated position, after having sat calmly for at least 5 minutes. Respiratory rate was summarized by treatment in accordance with the sponsor reporting standards. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: breaths/min
    arithmetic mean (standard deviation)
        Baseline (n=20,19,18)
    23.15 ± 4.603
    24.37 ± 3.905
    23.39 ± 5.863
        Change at Month 3 (n=17,19,17)
    0.47 ± 5.691
    -1.00 ± 2.809
    -1.53 ± 4.939
        Change at Month 6 (n=17,18,15)
    -1.12 ± 3.516
    -0.94 ± 4.221
    0.53 ± 4.502
        Change at Month 9 (n=17,17,10)
    -1.06 ± 3.473
    -0.94 ± 4.507
    -1.30 ± 6.945
        Change at Month 12 (n=7,8,2)
    2.00 ± 5.132
    -3.75 ± 4.979
    2.00 ± 15.556
    No statistical analyses for this end point

    Secondary: Change From Baseline in Blood Pressure at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Blood Pressure at Month 3, Month 6, Month 9, and Month 12
    End point description
    Blood pressure measurements were preceded by at least 5 minutes of rest for the subject in a quiet setting without distractions (eg, television, cell phones) where possible (with consideration of the age of the child). Supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) were summarized by treatment in accordance with the sponsor reporting standards. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (Supine DBP) (n=20,19,18)
    66.55 ± 9.870
    67.05 ± 9.897
    62.11 ± 13.244
        Change at Month 3 (Supine DBP) (n=17,19,17)
    -0.76 ± 12.179
    -4.47 ± 8.618
    -0.29 ± 12.849
        Change at Month 6 (Supine DBP) (n=17,18,15)
    -3.65 ± 14.845
    -0.83 ± 10.837
    5.27 ± 12.920
        Change at Month 9 (Supine DBP) (n=17,16,9)
    -3.41 ± 12.846
    -2.50 ± 11.408
    -2.44 ± 13.492
        Change at Month 12 (Supine DBP) (n=7,8,2)
    -3.14 ± 16.385
    -1.13 ± 13.953
    -4.50 ± 21.920
        Baseline (Supine SBP) (n=20,19,18)
    105.70 ± 10.732
    118.37 ± 22.056
    106.28 ± 14.199
        Change at Month 3 (Supine SBP) (n=17,19,17)
    10.47 ± 14.261
    -5.68 ± 21.445
    4.82 ± 15.134
        Change at Month 6 (Supine SBP) (n=17,18,15)
    1.88 ± 21.863
    3.94 ± 17.424
    5.73 ± 14.587
        Change at Month 9 (Supine SBP) (n=17,16,9)
    2.59 ± 15.732
    -2.94 ± 16.364
    2.33 ± 19.371
        Change at Month 12 (Supine SBP) (n=7,8,2)
    3.57 ± 27.700
    -11.75 ± 31.865
    -6.50 ± 4.950
    No statistical analyses for this end point

    Secondary: Change From Baseline in Temperature at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Temperature at Month 3, Month 6, Month 9, and Month 12
    End point description
    Temperature was obtained with subject in the seated position, after having sat calmly for at least 5 minutes. Temperature measurements were summarized by treatment in accordance with the sponsor reporting standards. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Degree Celsius (°C)
    arithmetic mean (standard deviation)
        Baseline (n=20,19,18)
    36.57 ± 0.441
    36.43 ± 0.519
    36.58 ± 0.466
        Change at Month 3 (n=17,19,17)
    -0.06 ± 0.362
    -0.04 ± 0.297
    0.11 ± 0.493
        Change at Month 6 (n=17,18,15)
    -0.08 ± 0.493
    -0.02 ± 0.298
    -0.03 ± 0.417
        Change at Month 9 (n=17,17,10)
    -0.16 ± 0.614
    -0.12 ± 0.437
    -0.20 ± 0.503
        Change at Month 12 (n=7,8,2)
    -0.21 ± 0.313
    -0.14 ± 0.316
    0.30 ± 0.141
    No statistical analyses for this end point

    Secondary: Number of Subjects With Abnormal Physical Examination Findings at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Number of Subjects With Abnormal Physical Examination Findings at Month 3, Month 6, Month 9, and Month 12
    End point description
    A physical examination included, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal systems and skin. Physical examination assessments were summarized by treatment in accordance with the sponsor reporting standards. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Subjects
        Abnormal Cardiovascular at Month 3 (n=17,19,17)
    0
    0
    0
        Abnormal Cardiovascular at Month 6 (n=17,19,15)
    0
    0
    0
        Abnormal Cardiovascular at Month 9 (n=16,17,9)
    0
    0
    0
        Abnormal Cardiovascular at Month 12 (n=16,16,3)
    0
    0
    0
        Abnormal Gastrointestinal at Month 3 (n=17,19,17)
    0
    0
    0
        Abnormal Gastrointestinal at Month 6 (n=17,19,15)
    0
    1
    0
        Abnormal Gastrointestinal at Month 9 (n=16,17,9)
    0
    2
    0
        Abnormal Gastrointestinal at Month 12 (n=16,16,3)
    0
    0
    0
        Abnormal Lungs at Month 3 (n=17,19,17)
    0
    0
    0
        Abnormal Lungs at Month 6 (n=17,19,15)
    0
    2
    0
        Abnormal Lungs at Month 9 (n=16,17,9)
    0
    0
    0
        Abnormal Lungs at Month 12 (n=16,16,3)
    1
    0
    0
        Abnormal Skin at Month 3 (n=17,19,17)
    2
    3
    1
        Abnormal Skin at Month 6 (n=17,19,15)
    1
    4
    2
        Abnormal Skin at Month 9 (n=16,17,9)
    3
    3
    2
        Abnormal Skin at Month 12 (n=16,16,3)
    2
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Abnormalities (Without Regard to Baseline Abnormality)

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    End point title
    Number of Subjects With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
    End point description
    Laboratory parameters included: hematology (corpuscular volume, corpuscular hemoglobin, corpuscular hemoglobin concentration, platelet, leukocytes, lymphocytes, neutrophils, eosinophils, and monocytes), and chemistry (bilirubin, alkaline phosphatase, albumin, urea nitrogen, urate, potassium, phosphate, bicarbonate). Clinical significance of laboratory parameters was determined at the investigator's discretion. Analysis population included all subjects who received at least one dose of recifercept.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Subjects
        Mean Corpuscular Volume<0.9xLLN
    0
    1
    2
        Mean Corpuscular Volume>1.1xULN
    1
    0
    0
        Mean Corpuscular Hemoglobin <0.9xLLN
    0
    1
    2
        Mean Corpuscular Hemoglobin Concentration<0.9xLLN
    0
    1
    1
        Platelets>1.75xULN
    0
    0
    1
        Leukocytes<0.6xLLN
    1
    0
    0
        Lymphocytes<0.8xLLN
    5
    9
    4
        Neutrophils<0.8xLLN
    1
    0
    0
        Neutrophils>1.2xULN
    1
    0
    1
        Eosinophils>1.2xULN
    1
    4
    3
        Monocytes >1.2xULN
    4
    1
    1
        Bilirubin>1.5xULN
    0
    1
    0
        Alkaline Phosphatase>3.0xULN
    1
    0
    0
        Albumin >1.2xULN
    2
    3
    1
        Urea Nitrogen>1.3xULN
    2
    5
    0
        Urate >1.2xULN
    2
    1
    0
        Potassium>1.1x ULN
    2
    4
    4
        Phosphate<0.8x LLN
    0
    0
    1
        Bicarbonate<0.9x LLN
    2
    2
    4
    No statistical analyses for this end point

    Secondary: Pre-Dose Serum Concentration (Ctrough) of Recifercept

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    End point title
    Pre-Dose Serum Concentration (Ctrough) of Recifercept
    End point description
    Ctrough was defined as pre-dose serum concentration during dosing and observed directly from data. Analysis population included all subjects who received at least one dose of recifercept and had at least one evaluable concentration. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day(s) 4, 8, 15, 29, 61, 91, 183, 273, 365
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: nanograms per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Day 4 (n=18,19,16)
    215.8 ± 63.28
    517.3 ± 174.18
    1785.2 ± 651.92
        Day 8 (n=19,19,18)
    95.3 ± 23.35
    614.6 ± 228.35
    2682.6 ± 912.79
        Day 15 (n=18,19,17)
    137.1 ± 39.26
    868.1 ± 341.98
    3199.4 ± 1311.65
        Day 29 (n=17,19,16)
    154.3 ± 46.91
    940.8 ± 415.45
    3804.4 ± 1573.91
        Day 61 (n=17,19,17)
    183.8 ± 75.76
    974.8 ± 604.47
    3431.4 ± 1477.48
        Day 91 (n=17,19,15)
    225.5 ± 90.91
    944.8 ± 466.38
    3702.3 ± 2074.64
        Day 183 (n=17,19,15)
    370.9 ± 424.80
    1078.9 ± 563.83
    5185.5 ± 3190.30
        Day 273 (n=15,16,9)
    278.2 ± 140.41
    1340.8 ± 695.10
    3879.6 ± 3027.59
        Day 365 (n=15,16,3)
    249.5 ± 174.54
    1320.4 ± 662.18
    6766.7 ± 3145.18
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) of Recifercept

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    End point title
    Number of Subjects With Positive Anti-Drug Antibodies (ADA) and Neutralizing Antibody (NAb) of Recifercept
    End point description
    The immunogenicity was measured by presence of ADA and NAb in subjects treated with recifercept and summarized by dose regimen. Analysis population included all subjects who received at least one dose of recifercept.
    End point type
    Secondary
    End point timeframe
    The first dose up to 28 to 35 days after the last dose of study intervention (27 months).
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Subjects
        Overall incidence of positive ADA
    16
    18
    17
        Overall incidence of positive NAb
    13
    16
    16
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sitting/Standing Height Ratio at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Sitting/Standing Height Ratio at Month 3, Month 6, Month 9, and Month 12
    End point description
    Sitting/standing height ratio was the ratio of sitting height to standing height. Analysis population included all subjects (aged 2-10 years) who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    18
    18
    18
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n=18,17,18)
    0.7 ± 0.02
    0.7 ± 0.02
    0.7 ± 0.02
        Change at Month 3 (n=15,17,17)
    0.0 ± 0.01
    -0.0 ± 0.01
    0.0 ± 0.01
        Change at Month 6 (n=16,16,15)
    0.0 ± 0.01
    -0.0 ± 0.01
    -0.0 ± 0.01
        Change at Month 9 (n=16,15,11)
    -0.0 ± 0.01
    -0.0 ± 0.01
    -0.0 ± 0.01
        Change at Month 12 (n=7,9,2)
    -0.0 ± 0.01
    -0.0 ± 0.01
    0.0 ± 0.00
    No statistical analyses for this end point

    Secondary: Change From Baseline in Arm Span to Standing Height/Length Difference at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Arm Span to Standing Height/Length Difference at Month 3, Month 6, Month 9, and Month 12
    End point description
    Arm span to standing height/length difference was the difference between arm span and standing height (for participants ≥2 years of age). Analysis population included all subjects (aged 2-10 years) who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    18
    18
    18
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=18,17,18)
    9.5 ± 3.93
    8.2 ± 3.24
    9.1 ± 3.27
        Change at Month 3 (n=15,17,17)
    0.5 ± 0.96
    0.0 ± 0.88
    -0.5 ± 1.62
        Change at Month 6 (n=16,16,15)
    0.2 ± 1.86
    0.7 ± 1.03
    -0.5 ± 1.93
        Change at Month 9 (n=16,16,11)
    0.6 ± 0.89
    0.7 ± 1.39
    0.1 ± 0.78
        Change at Month 12 (n=7,9,2)
    0.5 ± 1.22
    1.1 ± 1.75
    0.2 ± 0.71
    Statistical analysis title
    LS Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    1.2
    Statistical analysis title
    LS Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    1.8
    Statistical analysis title
    LS Mean Difference at Month 3
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.1
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    0.6
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1.9
    Statistical analysis title
    LS Mean Difference at Month 6
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.1
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 2 mg/kg BIW v Recifercept 1 mg/kg QW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.7
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 1.5 mg/kg QD
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    1.5
    Statistical analysis title
    LS Mean Difference at Month 9
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.2
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 2 mg/kg BIW treatment groups.
    Comparison groups
    Recifercept 1 mg/kg QW v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    1.5
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 1 mg/kg QW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 1 mg/kg QW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    2.8
    Statistical analysis title
    LS Mean Difference at Month 12
    Statistical analysis description
    The LS mean difference between Recifercept 2 mg/kg BIW and Recifercept 1.5 mg/kg QD treatment groups.
    Comparison groups
    Recifercept 1.5 mg/kg QD v Recifercept 2 mg/kg BIW
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    1.4

    Secondary: Change From Baseline in Knee Height : Lower Segment Ratio at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Knee Height : Lower Segment Ratio at Month 3, Month 6, Month 9, and Month 12
    End point description
    Knee height : lower segment ratio was the ratio of knee to heel length to the difference between standing height and sitting height. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n=18,16,18)
    0.81 ± 0.052
    0.84 ± 0.058
    0.80 ± 0.035
        Change at Month 3 (n=15,16,17)
    -0.00 ± 0.020
    -0.01 ± 0.052
    0.02 ± 0.035
        Change at Month 6 (n=16,15,14)
    -0.00 ± 0.028
    -0.02 ± 0.062
    0.00 ± 0.026
        Change at Month 9 (n=16,14,11)
    -0.00 ± 0.027
    -0.02 ± 0.065
    0.01 ± 0.026
        Change at Month 12 (n=7,8,2)
    0.00 ± 0.028
    -0.02 ± 0.081
    0.02 ± 0.023
    No statistical analyses for this end point

    Secondary: Change From Baseline in Occipito-Frontal Circumference at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Occipito-Frontal Circumference at Month 3, Month 6, Month 9, and Month 12
    End point description
    Occipito-frontal circumference data were summarized for each treatment arm. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=20,18,16)
    54.56 ± 2.877
    55.00 ± 2.179
    56.13 ± 1.949
        Change at Month 3 (n=16,18,15)
    0.19 ± 0.345
    0.19 ± 0.382
    0.30 ± 0.515
        Change at Month 6 (n=17,17,15)
    0.33 ± 0.396
    0.35 ± 0.506
    0.30 ± 0.437
        Change at Month 9 (n=17,17,11)
    0.46 ± 0.619
    0.35 ± 0.597
    0.54 ± 0.588
        Change at Month 12 (n=7,9,2)
    0.87 ± 1.106
    0.53 ± 0.557
    0.00 ± 0.424
    No statistical analyses for this end point

    Secondary: Change From Baseline in Occipito-Frontal to Occipito-Mid-Face Ratio at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Occipito-Frontal to Occipito-Mid-Face Ratio at Month 3, Month 6, Month 9, and Month 12
    End point description
    Occipito-Frontal to Occipito-Mid-Face Ratio were summarized for each treatment arm. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n=20,18,18)
    1.00 ± 0.053
    1.00 ± 0.055
    1.00 ± 0.058
        Change at Month 3 (n=16,18,17)
    0.01 ± 0.024
    0.00 ± 0.039
    -0.01 ± 0.034
        Change at Month 6 (n=17,17,15)
    -0.01 ± 0.056
    -0.00 ± 0.027
    -0.02 ± 0.039
        Change at Month 9 (n=17,17,11)
    -0.01 ± 0.042
    -0.01 ± 0.034
    -0.02 ± 0.031
        Change at Month 12 (n=7,9,2)
    -0.04 ± 0.034
    -0.01 ± 0.028
    0.00 ± 0.018
    No statistical analyses for this end point

    Secondary: Change From Baseline in Height Standard Deviation Score (Z-Score) at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Height Standard Deviation Score (Z-Score) at Month 3, Month 6, Month 9, and Month 12
    End point description
    Height Standard Deviation Score (SDS) (z-score) was calculated as the difference between mean observed standing height at each visit and mean value of reference population divided by standard deviation of reference population. Analysis population included all subjects (aged 2-10 years) who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    18
    18
    18
    Units: Units on scale
    arithmetic mean (standard deviation)
        Baseline (n=18,17,18)
    -0.2 ± 0.91
    0.1 ± 0.91
    0.2 ± 1.26
        Change at Month 3 (n=15,17,17)
    0.0 ± 0.13
    -0.0 ± 0.17
    -0.0 ± 0.26
        Change at Month 6 (n=16,16,15)
    -0.0 ± 0.21
    0.0 ± 0.21
    -0.0 ± 0.24
        Change at Month 9 (n=16,16,11)
    0.0 ± 0.26
    -0.0 ± 0.21
    0.0 ± 0.20
        Change at Month 12 (n=7,9,2)
    -0.0 ± 0.33
    0.1 ± 0.26
    -0.2 ± 0.17
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fixed Flexion Angles at Elbow at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Fixed Flexion Angles at Elbow at Month 3, Month 6, Month 9, and Month 12
    End point description
    Fixed flexion angles at elbow data were presented for each treatment arm. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: degrees (°)
    arithmetic mean (standard deviation)
        Baseline (n=20,18,16)
    -11.33 ± 20.002
    -18.31 ± 12.707
    -6.45 ± 17.628
        Change at Month 3 (n=16,18,14)
    2.23 ± 8.976
    4.29 ± 10.519
    1.09 ± 5.285
        Change at Month 6 (n=16,17,14)
    -0.02 ± 16.407
    2.80 ± 6.842
    0.83 ± 5.742
        Change at Month 9 (n=17,17,11)
    -0.03 ± 16.659
    4.83 ± 7.658
    0.77 ± 10.621
        Change at Month 12 (n=7,9,2)
    2.78 ± 34.075
    1.00 ± 7.016
    -0.08 ± 0.825
    No statistical analyses for this end point

    Secondary: Change From Baseline in Polysomnography Index Parameters at Month 12

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    End point title
    Change From Baseline in Polysomnography Index Parameters at Month 12
    End point description
    Polysomnography refers to a systematic process used to collect physiologic parameters during sleep. Polysomnography index parameters included apnea-hypopnea index (AHI) (obstructive and total), desaturation index (ie, number of desaturations per hour >3% from baseline). Analysis population included all subjects who received at least one dose of recifercept and with a documented current diagnosis of sleep disordered breathing at enrollment. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    7
    4
    8
    Units: Unitis on a scale
    arithmetic mean (standard deviation)
        Baseline (AHI, obstructive) (n=7,4,8)
    3.79 ± 4.720
    1.20 ± 1.080
    6.23 ± 6.881
        Change at Month 12 (AHI, obstructive) (n=3,1,0)
    0.31 ± 9.902
    -1.90 ± 999999
    999999 ± 999999
        Baseline (AHI, total) (n=7,4,8)
    6.34 ± 5.837
    2.25 ± 2.872
    16.07 ± 26.299
        Change at Month 12 (AHI, total) (n=3,1,0)
    -1.03 ± 8.671
    -2.90 ± 999999
    999999 ± 999999
        Baseline (Desaturation Index) (n=7,4,8)
    4.90 ± 8.601
    2.18 ± 2.502
    13.53 ± 21.364
        Change at Month 12 (Desaturation Index) (n=3,1,0)
    -4.61 ± 14.598
    0.20 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Change From Baseline in Polysomnography Other Parameters at Month 12

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    End point title
    Change From Baseline in Polysomnography Other Parameters at Month 12
    End point description
    Polysomnography refers to a systematic process used to collect physiologic parameters during sleep. Polysomnography other parameters included percentage time spent <90% oxygen saturation (SaO2), percentage time spent with end-tidal (ET) carbon dioxide (CO2) >50 mm Hg, and SaO2 nadir. Analysis population included all subjects who received at least one dose of recifercept and with a documented diagnosis of sleep-disordered breathing at enrollment. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    7
    4
    8
    Units: percentage (%)
    arithmetic mean (standard deviation)
        Baseline of <90% SaO2 (n=6,4,8)
    16.43 ± 40.155
    24.79 ± 49.472
    0.72 ± 0.758
        Change at Month 12 of <90% SaO2 (n=2,1,0)
    -48.95 ± 69.933
    -99.00 ± 999999
    999999 ± 999999
        Baseline of ET CO2>50 mm Hg (n=4,4,8)
    7.02 ± 14.030
    9.50 ± 19.000
    7.37 ± 17.355
        Change at Month 12 of ET CO2>50 mm Hg (n=2,1,0)
    -14.03 ± 19.841
    -38.00 ± 999999
    999999 ± 999999
        Baseline of SaO2 nadir (n=7,4,8)
    92.29 ± 3.147
    94.25 ± 6.397
    91.06 ± 5.882
        Change at Month 12 of SaO2 nadir (n=3,1,0)
    -2.67 ± 7.095
    1.00 ± 999999
    999999 ± 999999
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI) at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Body Mass Index (BMI) at Month 3, Month 6, Month 9, and Month 12
    End point description
    Body Mass Index (BMI) = Weight (kg)/[(Standing Height (m))^2]. Standing height and weight were averaged over a visit before BMI was computed. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: kg/m^2
    arithmetic mean (standard deviation)
        Baseline (n=17,17,18)
    19.83 ± 1.022
    20.18 ± 1.318
    21.57 ± 2.566
        Change at Month 3 (n=15,17,17)
    0.10 ± 0.376
    -0.13 ± 0.400
    -0.01 ± 0.635
        Change at Month 6 (n=15,16,14)
    0.25 ± 0.547
    0.04 ± 0.500
    -0.21 ± 0.843
        Change at Month 9 (n=15,15,11)
    0.36 ± 0.565
    0.06 ± 0.593
    0.02 ± 0.996
        Change at Month 12 (n=6,9,2)
    0.12 ± 0.671
    -0.28 ± 0.569
    -0.50 ± 0.735
    No statistical analyses for this end point

    Secondary: Change From Baseline in Waist : Chest Circumference Ratio at Month 9 and Month 12

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    End point title
    Change From Baseline in Waist : Chest Circumference Ratio at Month 9 and Month 12
    End point description
    Waist : Chest Ratio = Waist Circumference / Chest Circumference. Waist and chest circumference were averaged over a visit before waist : chest circumference ratio was computed. Analysis population included all subjects who received at least one dose of recifercept. Here, “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    20
    19
    18
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n=19,17,16)
    0.93 ± 0.048
    0.94 ± 0.051
    0.97 ± 0.052
        Change at Month 9 (n=1,1,1)
    0.07 ± 999999
    0.00 ± 999999
    -0.01 ± 999999
        Change at Month 12 (n=6,9,2)
    0.05 ± 0.074
    0.00 ± 0.063
    -0.01 ± 0.007
    No statistical analyses for this end point

    Secondary: Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Component and Index Scores at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Component and Index Scores at Month 3, Month 6, Month 9, and Month 12
    End point description
    CHAQ (adapted for achondroplasia) is a 36-item measure of health status and physical function, which includes 8 components and 2 scale (pain and well being). Both a disability and discomfort index can be calculated. The CHAQ (adapted for achondroplasia) has a recall period of “over the past week”. A 5 point Likert Scale was utilized ranging from “without any difficulty” to “unable to do” and a “not applicable” option. Lower component and index scores indicate better health status/functioning. Analysis population included all subjects who received at least one dose of recifercept.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: Units on scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [2] - The results were not summarized due to the study early termination.
    [3] - The results were not summarized due to the study early termination.
    [4] - The results were not summarized due to the study early termination.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Quality of Life in Short Stature Youth (QoLISSY) Brief Total Score at Month 3, Month 6, Month 9, and Month 12

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    End point title
    Change From Baseline in Quality of Life in Short Stature Youth (QoLISSY) Brief Total Score at Month 3, Month 6, Month 9, and Month 12
    End point description
    QoLISSY Brief measures health-related quality of life (HRQoL) in children 4-18 years old from the subject and parent perspectives. The 9 items on the QoLISSY Brief were selected from the full QoLISSY physical, social and emotional HRQoL dimensions. The QoLISSY Brief questions ask the subject or caregiver about their status currently. Intended for children or caregivers of children, the instrument uses a 5-point Likert Scale ranging from 'not at all/never' to 'extremely/always'. The QoLISSY Brief total score is the 0-100 transformed sum of the 9 item scores, with higher scores representing better quality of life. Analysis population included all subjects who received at least one dose of recifercept.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, Month 6, Month 9, and Month 12
    End point values
    Recifercept 1 mg/kg QW Recifercept 2 mg/kg BIW Recifercept 1.5 mg/kg QD
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: Units on scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [5] - The results were not summarized due to the study early termination.
    [6] - The results were not summarized due to the study early termination.
    [7] - The results were not summarized due to the study early termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The first dose up to 28 to 35 days after the last dose of study intervention (27 months).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Recifercept 1 mg/kg QW
    Reporting group description
    -

    Reporting group title
    Recifercept 1.5 mg/kg QD
    Reporting group description
    -

    Reporting group title
    Recifercept 2 mg/kg BIW
    Reporting group description
    -

    Serious adverse events
    Recifercept 1 mg/kg QW Recifercept 1.5 mg/kg QD Recifercept 2 mg/kg BIW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Recifercept 1 mg/kg QW Recifercept 1.5 mg/kg QD Recifercept 2 mg/kg BIW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    16 / 18 (88.89%)
    19 / 19 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin papilloma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hyperaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    5
    0
    Haematoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    3
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    4
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site induration
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    5
    Injection site mass
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    3
    Injection site oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Injection site pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Injection site rash
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 18 (11.11%)
    4 / 19 (21.05%)
         occurrences all number
    7
    5
    12
    Injection site reaction
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    3 / 19 (15.79%)
         occurrences all number
    0
    3
    5
    Injection site swelling
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    1 / 19 (5.26%)
         occurrences all number
    1
    4
    1
    Injection site haematoma
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site erythema
         subjects affected / exposed
    4 / 20 (20.00%)
    4 / 18 (22.22%)
    5 / 19 (26.32%)
         occurrences all number
    30
    11
    17
    Injection site bruising
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    0 / 19 (0.00%)
         occurrences all number
    5
    3
    0
    Injection site pruritus
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 18 (11.11%)
    3 / 19 (15.79%)
         occurrences all number
    3
    9
    8
    Injection site urticaria
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    3
    0
    Injection site warmth
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 18 (22.22%)
    3 / 19 (15.79%)
         occurrences all number
    4
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Tonsillar inflammation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    2
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Cough
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    2
    4
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Antisocial behaviour
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood albumin increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Blood creatinine decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Blood phosphorus increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    2
    Blood urea increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Haematocrit increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Haemoglobin increased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 18 (22.22%)
    7 / 19 (36.84%)
         occurrences all number
    3
    4
    7
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Bite
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Burns second degree
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Fall
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Head injury
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Post procedural discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hand fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    5
    8
    3
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Tension headache
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dyskinesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Eosinophilia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    0
    3
    3
    Monocytosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Ear pain
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 18 (16.67%)
    2 / 19 (10.53%)
         occurrences all number
    2
    3
    2
    Otorrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Anal pruritus
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    4
    1
    2
    Toothache
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Dental caries
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Drug eruption
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dermatitis atopic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cafe au lait spots
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Acanthosis nigricans
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    4
    Neurodermatitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin swelling
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Erythema
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    1 / 19 (5.26%)
         occurrences all number
    0
    3
    1
    Eczema
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Ecchymosis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    4
    1
    2
    Back pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    3 / 19 (15.79%)
         occurrences all number
    3
    2
    5
    Myalgia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 18 (11.11%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    2
    Ear infection
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    4
    1
    3
    COVID-19
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    4
    0
    Bronchitis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    3
    0
    Herpangina
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Gastrointestinal infection
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Varicella
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    3 / 19 (15.79%)
         occurrences all number
    3
    2
    5
    Skin candida
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    2
    Otitis media bacterial
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 20 (25.00%)
    2 / 18 (11.11%)
    5 / 19 (26.32%)
         occurrences all number
    6
    2
    7
    Influenza
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    Impetigo
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    3
    Suspected COVID-19
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Viral rash
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2020
    The following changes were made due to regulatory requests from different countries which the sponsor classified as substantial. Section 1.3: Additional ECG at close to Cmax (Day 4) and additional pharmacokinetic & immunogenicity sample at Month 9 were added. Clarify that monitoring after first 5 doses be done by appropriately trained individuals with access to facilities necessary to manage hypersensitivity MRI at baseline was added and only applicable for those without scan in last 12 months. Section 4.1: Clarify age range to align with inclusion criteria. Section 4.2: Clarify language around baseline MRI. Section 5.1: Provide clear demarcation between main and exploratory cohorts. Section 5.2: Exclude those with evidence of significant renal or hepatic impairment, or with history of hypersensitivity to study intervention or excipients. Section 6.1.1: To clarify that only parent/caregiver/ healthcare professional should administer the study medication. Section 6.6: Clarify age of those in block A. Section 6.6.1: There will be a planned eDMC review after block A prior to progressing to block B. Change SUSAR to SAR. Clarify that the primary efficacy analysis will be done on treatment naïve subjects enrolled to each cohort. Section 7.1: To clarify the role of the investigator in stopping study intervention as a result of adverse events or need for prohibited treatments. Section 8.2.4: Add D4 ECG. Section 8.3.1: Confirm that investigator should enquire about both AEs and SAEs at follow-up visit. Section 9.4.2: Clarify the analysis to be performed as ANOVA not ANCOVA. Sections 9.4.2 & 9.4.3: Clarify the analysis to be performed (removal of stratification). Section 9.6: Describe control of familywise error rate. Section 10.4.2: Confirm that WOCBP cannot enroll in the study since subjects must be Tanner stage 1 at enrolment. Section 10.5: Clarify that LFTs are measured in routine safety assessments.
    14 Apr 2021
    The changes in this amendment were made due to eDMC recommendations and additional regulatory requests from different countries. Section 1.2: Block B enrollment of high dose subjects was reduced from n=8 to n=3 and enrollment using a sentinel approach. In addition, Block B 2-6yrs old at low & medium doses was expanded from n=3 to n=8 per dose with enrollment also using a sentinel approach. Sections 4.1 & 6.6: Block B to Block C progression rules were revised in line with the sentinel approach from n=3 per dose to n=2 per dose. The number of high dose children included in the safety review will stay the same (n=3). Appendix 2: Addition of Phosphate to chemistry panel and collection of time since last food intake. Section 1.3: Addition of Hematology & Chemistry Labs at Month 9. Section 2.2.1: Final data from study C4181002 added. Summary safety & PK data from Block A added. Section 5.2: Criterion No. 6 CrCL GFR formula ‘bedside’ Schwartz was added. Section 6.2.1: Clarification of what should be considered adequate training for caregivers for home drug administration was added. Section 6.4.1: Clarified instructions for caregivers regarding injection site reactions during home dosing is documented in the caregiver dosing diary. Sections 8.6, 8.7.2, and 8.7.7: Confirmation this section is not applicable in Denmark.
    23 Mar 2022
    The changes in this amendment were made due to eDMC recommendations, regulatory requests from different countries and addition of a PK cohort. Section 1.2: Update to expand recruitment of those aged 2-<6y in block C at the high dose (1.5 mg/kg daily) from a total of n=3 to n=8 (ie, move all 5 subjects from block D). Section 6.6.1: Update to a sentinel dosing approach for recruiting those aged 2-<6 years in block C such that n=2 at high dose will be dosed followed by a 2-week delay before further dosing occurs in that age group. Section 1.3: Added footnote for blood chemistry that subjects are required to fast for >4 hours prior to blood sampling. Section 8.2.5 & Appendix 2: Subjects are required to fast for >4 hours prior to blood sampling. Section 2.2.1: Updated clinical safety as of September 2021, to include number of subjects per Block and AEs. Section 4.1: Updated to include a PK cohort that will include 12 subjects who will randomly receive 1 dose of Phase 2 (process 1c) followed by 1 dose of proposed Phase 3 (process 2) recifercept formulation or vice versa in a cross-over study, at select sites only. PK analysis following each dose will be conducted to evaluate the two formulations. Single dose of 3 mg/kg will be used for the PK study cohort. Dose of the cohort could be changed due to emerging safety and efficacy data in the study. Section 4.3: Updated to include a PK cohort of 12 subjects. The tentative dose for the PK study cohort is 3 mg/kg. The dose selected for the PK cohort could be changed after evaluating the entirety of the safety, PK and efficacy data collected in the program before initiating the cohort. The dose selected will not exceed the highest dose found to be safe and tolerated. Section 8.0: Updated to include the PK cohort, as the total blood volume collected for individual subjects is approximately 67 mL in this cohort. Sections 1.2, 1.3, 8.5, 9.2, 9.3, and 9.4: Updated to include PK cohort.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Nov 2022
    Following the results of an interim analysis in this study (C4181005) and the temporary halt decision of 20 October 2022, Pfizer Inc. made the decision to terminate this study as of 18 November 2022 (date of decision of the global study termination by the sponsor). The decision to terminate this study was due to not meeting the pre specified 6 month efficacy criteria at the tested doses and not due to any safety concerns.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The additional PK cohort for 2 formulations was not completed as the study was early terminated prior to enrolling any subjects in the PK cohort. No data was collected for additional PK cohort.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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