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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Boys With Duchenne Muscular Dystrophy

    Summary
    EudraCT number
    2014-002072-92
    Trial protocol
    GB   IT   PL   BG  
    Global end of trial date
    23 Nov 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    16 Dec 2020
    First version publication date
    07 Jun 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    correction to data

    Trial information

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    Trial identification
    Sponsor protocol code
    B5161002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02310763
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001763-PIP01-15
    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
    10 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to determine the safety and tolerability of multiple ascending repeat intravenous doses of domagrozumab (PF-06252616) in ambulatory boys with Duchenne Muscular dystrophy (DMD) and to demonstrate the efficacy of treatment with intravenous doses of domagrozumab based on an observed mean change from baseline on function (4 Stair Climb) as compared to placebo following 49 weeks of treatment.
    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 Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of subjects.
    Background therapy
    Subjects were required to be on a stable dose of glucocorticosteroids.
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 67
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    120
    EEA total number of subjects
    24
    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)
    105
    Adolescents (12-17 years)
    15
    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 162 subjects were screened, 121 subjects were enrolled in the study and assigned to 1 of 3 sequences. Only 120 subjects received the study treatment and 1 subject withdrew prior to dosing.

    Period 1
    Period 1 title
    Period 1 (Weeks 1 to 48)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence 1
    Arm description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Domagrozumab
    Investigational medicinal product code
    Other name
    PF-06252616
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.

    Arm title
    Sequence 2
    Arm description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Domagrozumab
    Investigational medicinal product code
    Other name
    PF-06252616
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.

    Arm title
    Sequence 3
    Arm description
    Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of administration.

    Number of subjects in period 1
    Sequence 1 Sequence 2 Sequence 3
    Started
    41
    39
    40
    Completed
    38
    37
    38
    Not completed
    3
    2
    2
         Unable to comply with study procedures
    -
    1
    1
         Adverse event, non-fatal
    1
    -
    -
         Consent withdrawn by subject
    1
    1
    1
         Lost to follow-up
    1
    -
    -
    Period 2
    Period 2 title
    Period 2 (Weeks 49 to 96)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence 1
    Arm description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Domagrozumab
    Investigational medicinal product code
    Other name
    PF-06252616
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.

    Arm title
    Sequence 2
    Arm description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of administration.

    Arm title
    Sequence 3
    Arm description
    Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
    Arm type
    Experimental

    Investigational medicinal product name
    Domagrozumab
    Investigational medicinal product code
    Other name
    PF-06252616
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.

    Number of subjects in period 2
    Sequence 1 Sequence 2 Sequence 3
    Started
    38
    37
    38
    Completed
    22
    21
    22
    Not completed
    16
    16
    16
         Study terminated by sponsor
    16
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence 1
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 2
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 3
    Reporting group description
    Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).

    Reporting group values
    Sequence 1 Sequence 2 Sequence 3 Total
    Number of subjects
    41 39 40 120
    Age Categorical
    Units: Subjects
        <=18 years
    41 39 40 120
        Between 18 and 65 years
    0 0 0 0
        >=65 years
    0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    8.3 ± 1.9 8.5 ± 1.5 9.3 ± 2.3 -
    Sex: Female, Male
    Units: Subjects
        Female
    0 0 0 0
        Male
    41 39 40 120
    Race/Ethnicity, Customized
    Units: Subjects
        White
    33 33 35 101
        Black
    1 0 1 2
        Asian
    6 5 4 15
        Other
    1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Sequence 1
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 2
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 3
    Reporting group description
    Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
    Reporting group title
    Sequence 1
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 2
    Reporting group description
    Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study.

    Reporting group title
    Sequence 3
    Reporting group description
    Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).

    Subject analysis set title
    Placebo (Period 1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects who received placebo from Week 1 to Week 48.

    Subject analysis set title
    Domagrozumab 5 mg/kg (Period 1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects who received domagrozumab at a dose of 5 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 1 to Week 16 (4 doses).

    Subject analysis set title
    Domagrozumab 20 mg/kg (Period 1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects who received domagrozumab at a dose of 20 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 17 to Week 32 (4 doses).

    Subject analysis set title
    Domagrozumab 40 mg/kg (Period 1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects who received domagrozumab at a dose of 40 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 33 to Week 48 (4 doses).

    Subject analysis set title
    Domagrozumab (Period 1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).

    Subject analysis set title
    NH Control Group (4SC, Week 49)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The natural history (NH) control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 4 stair climb (4SC) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) left ventricular ejection fraction (LVEF): >=55% or missing.

    Subject analysis set title
    NH Control Group (4SC, Week 97)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 4SC data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    NH Control Group (FVC, Week 49)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable forced vital capacity (FVC) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    NH Control Group (FVC, Week 97)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable FVC data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing

    Subject analysis set title
    NH Control Group (NSAA, Week 49)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable northstar ambulatory assessment (NSAA) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    NH Control Group (NSAA, Week 97)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable NSAA data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    NH Control Group (6MWD, Week 49)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH history control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 6 minute walk distance (6MWD) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    NH Control Group (6MWD, Week 97)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 6MWD data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.

    Subject analysis set title
    Placebo (4SC< 3.5 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC time <3.5 seconds.

    Subject analysis set title
    Domagrozumab (4SC< 3.5 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time <3.5 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).

    Subject analysis set title
    Placebo(4SC>=3.5 and <=8 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC time >=3.5 seconds and <=8 seconds.

    Subject analysis set title
    Domagrozumab (4SC>=3.5 and <=8 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time >=3.5 seconds and <=8 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).

    Subject analysis set title
    Placebo (4SC>8 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC >8 seconds.

    Subject analysis set title
    Domagrozumab (4SC>8 seconds, Period 1)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time >8 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).

    Subject analysis set title
    Domagrozumab 5 mg/kg (Sequence 3)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 5 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 49 to Week 64 (4 doses).

    Subject analysis set title
    Domagrozumab 20 mg/kg (Sequence 3)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 20 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 65 to Week 80 (4 doses).

    Subject analysis set title
    Domagrozumab 40 mg/kg (Sequence 3)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 40 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 81 to Week 96 (4 doses).

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) by Week 49

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs) by Week 49 [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Severe TEAEs were TEAEs that interfered significantly with subjects' usual function. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Study Day 1 to Week 49 visit
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        All-causalities TEAE
    38
    66
    57
    59
        Treatment-related TEAE
    14
    18
    14
    16
        All-causalities serious TEAE
    0
    1
    1
    1
        Treatment-related serious TEAE
    0
    0
    0
    1
        All-causalities severe TEAE
    2
    2
    3
    2
        Treatment-related severe TEAE
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects Who Discontinued From the Study Due to TEAEs by Week 49

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    End point title
    Number of Subjects Who Discontinued From the Study Due to TEAEs by Week 49 [2]
    End point description
    An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Study Day 1 to Week 49 visit
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        All-causalities TEAE
    0
    0
    0
    1
        Treatment-related TEAE
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49

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    End point title
    Number of Subjects With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49 [3]
    End point description
    An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Study Day 1 to Week 49 visit
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        All-causalities TEAE
    8
    4
    4
    0
        Treatment-related TEAE
    3
    0
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology [4]
    End point description
    Hematology evaluation included: hemoglobin, hematocrit, red blood cell (RBC) count, platelets, RBC morphology, white blood cell (WBC) count, absolute lymphocytes, absolute atypical lymphocytes, absolute total neutrophils, absolute total neutrophils count, absolute band cells, absolute basophils, absolute eosinophils, absolute monocytes and absolute myelocytes. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Hemoglobin <0.8*lower limit of normal (LLN)
    0
    0
    0
    0
        Hematocrit <0.8*LLN
    0
    0
    0
    0
        RBC count <0.8*LLN
    0
    0
    0
    0
        Platelets <0.5*LLN
    1
    1
    1
    1
        Platelets >1.75*upper limit of normal (ULN)
    0
    0
    0
    0
        RBC Morphology >0
    0
    0
    1
    1
        WBC count <0.6*LLN
    0
    0
    0
    0
        WBC count >1.5*ULN
    0
    1
    1
    0
        Absolute Lymphocytes <0.8*LLN
    0
    2
    2
    0
        Absolute lymphocytes >1.2*ULN
    1
    1
    0
    0
        Absolute atypical lymphocytes >0 (10*3/uL)
    99999
    1
    99999
    1
        Absolute total neutrophils <0.8*LLN
    1
    0
    0
    0
        Absolute total neutrophils >1.2*ULN
    13
    8
    5
    5
        Absolute total neutrophils count <1.35 (10*3/uL)
    2
    0
    2
    1
        Absolute total neutrophils count >8.15 (10*3/uL)
    20
    13
    12
    9
        Absolute band cells >0.27 (10*3/uL)
    0
    0
    0
    0
        Absolute basophils >1.2*ULN
    2
    1
    1
    2
        Absolute eosinophils >1.2*ULN
    6
    2
    6
    6
        Absolute monocytes >1.2*ULN
    1
    1
    2
    2
        Absolute myelocytes >0 (10*3/uL)
    99999
    99999
    99999
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation [5]
    End point description
    Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT). All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        aPTT >1.1*ULN
    1
    1
    1
    2
        PT >1.1*ULN
    13
    6
    3
    7
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function [6]
    End point description
    Liver function evaluation included: total/direct/indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, total protein, albumin and glutamate dehydrogenase. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Total bilirubin >1.5*ULN
    0
    0
    0
    0
        Direct bilirubin >1.5*ULN
    0
    99999
    99999
    0
        Indirect bilirubin >1.5*ULN
    0
    99999
    99999
    0
        AST >3*ULN
    39
    80
    76
    74
        ALT >3*ULN
    40
    80
    78
    75
        GGT >3*ULN
    0
    0
    0
    0
        Alkaline phosphatase >3*ULN
    0
    0
    0
    0
        Total protein <0.8*LLN
    0
    0
    0
    0
        Total protein >1.2*ULN
    0
    0
    0
    0
        Albumin <0.8*LLN
    0
    0
    0
    0
        Albumin >1.2*ULN
    0
    0
    0
    0
        Glutamate dehydrogenase >1.0*ULN
    8
    8
    6
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function [7]
    End point description
    Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        BUN >1.3*ULN
    0
    0
    0
    0
        Creatinine >1.3*ULN
    0
    0
    0
    0
        Uric acid >1.2*ULN
    0
    1
    3
    3
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes [8]
    End point description
    Electrolytes evaluation included: sodium, potassium, chloride, calcium, phosphate, bicarbonate, ferritin, transferrin saturation, iron, iron binding capacity and unsaturated iron binding capacity. Number of subjects with iron abnormalities was reported in different age groups. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Sodium <0.95*LLN
    0
    0
    0
    0
        Sodium >1.05*ULN
    0
    0
    0
    0
        Potassium <0.9*LLN
    0
    0
    0
    0
        Potassium >1.1*ULN
    0
    0
    0
    0
        Chloride <0.9*LLN
    0
    0
    0
    0
        Chloride >1.1*ULN
    0
    0
    0
    0
        Calcium <0.9*LLN
    0
    0
    0
    0
        Calcium >1.1*ULN
    0
    0
    0
    0
        Phosphate <0.8*LLN
    0
    0
    0
    0
        Phosphate >1.2*ULN
    0
    0
    0
    0
        Bicarbonate <0.9*LLN
    8
    2
    3
    4
        Bicarbonate >1.1*ULN
    1
    0
    0
    0
        Iron (1 Year<=Age<11 Years) <50 (ug/dL)
    19
    23
    14
    11
        Iron (1 Year<=Age<11 Years) >120 (ug/dL)
    12
    29
    33
    39
        Iron (11 Years<=Age<18 Years) <50 (ug/dL)
    2
    4
    2
    2
        Iron (11 Years<=Age<18 Years) >170 (ug/dL)
    0
    1
    1
    0
        Ferritin <15 (ug/L)
    20
    32
    38
    42
        Ferritin >140 (ug/L)
    1
    1
    0
    0
        Iron binding capacity <37.6 (ug/dL)
    0
    0
    0
    0
        Unsaturated iron binding capacity<130 (ug/dL)
    3
    7
    6
    10
        Unsaturated iron binding capacity >375 (ug/dL)
    1
    0
    0
    0
        Transferrin saturation <20%
    26
    34
    26
    20
        Transferrin saturation >50%
    4
    9
    19
    18
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones [9]
    End point description
    Hormone evaluations included free thyroxine (T4), thyroid stimulating hormone (TSH), lutenizing hormone (LH), follicle stimulating hormone (FSH), and androstenedione. Numbers of subjects with abnormalities of LH, FSH and androstenedione were reported in different age groups. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Free T4 <0.8*LLN
    0
    0
    0
    0
        Free T4 >1.2*ULN
    0
    0
    0
    0
        TSH <0.8*LLN
    0
    2
    0
    1
        TSH >1.2*ULN
    0
    0
    0
    0
        LH (15 Days<=Age<7 Years) <0.3 (mIU/mL)
    1
    2
    0
    99999
        LH (15 Days<=Age<7 Years) >2.8 (mIU/mL)
    0
    0
    0
    99999
        LH (7 Years<=Age<9 Years) <0.3 (mIU/mL)
    6
    23
    21
    14
        LH (7 Years<=Age<9 Years) >2.8 (mIU/mL)
    0
    0
    0
    0
        LH (9 Years<=Age<11 Years) <0.3 (mIU/mL)
    17
    17
    23
    27
        LH (9 Years<=Age<11 Years) >2.8 (mIU/mL)
    0
    0
    0
    0
        LH (11 Years<=Age<12 Years) <0.3 (mIU/mL)
    2
    2
    3
    1
        LH (11 Years<=Age<12 Years) >1.8 (mIU/mL)
    1
    1
    0
    0
        LH (12 Years<=Age<13 Years) <0.3 (mIU/mL)
    1
    1
    2
    2
        LH (12 Years<=Age<13 Years) >4.0 (mIU/mL)
    0
    0
    0
    0
        LH (13 Years<=Age<14 Years) <0.3 (mIU/mL)
    3
    1
    0
    1
        LH (13 Years<=Age<14 Years) >6.0 (mIU/mL)
    0
    1
    1
    1
        FSH (4 Years<=Age<7 Years) >6.70 (mIU/mL)
    0
    0
    0
    99999
        FSH (7 Years<=Age<9 Years) >4.10 (mIU/mL)
    0
    0
    0
    0
        FSH (9 Years<=Age<11 Years) >4.50 (mIU/mL)
    0
    0
    0
    0
        FSH (11 Years<=Age<12 Years) <0.40 (mIU/mL)
    0
    0
    0
    0
        FSH (11 Years<=Age<12 Years) >8.90 (mIU/mL)
    0
    0
    0
    0
        FSH (12 Years<=Age<13 Years) <0.50 (mIU/mL)
    0
    0
    0
    0
        FSH (12 Years<=Age<13 Years) >10.50 (mIU/mL)
    0
    0
    0
    0
        FSH (13 Years<=Age<14 Years) <0.70 (mIU/mL)
    0
    1
    0
    2
        FSH (13 Years<=Age<14 Years) >10.80 (mIU/mL)
    0
    0
    0
    0
        Androstenedione (1 Year<=Age<7 Years) <8 (ng/dL)
    1
    2
    1
    99999
        Androstenedione (1 Year<=Age<7Years) >50(ng/dL)
    0
    0
    0
    99999
        Androstenedione (7 Years<=Age<10Years)<3(ng/dL)
    5
    11
    10
    7
        Androstenedione(7Years<=Age<10Years) >31(ng/dL)
    1
    0
    4
    4
        Androstenedione(10Years<=Age<12Years) <7(ng/dL)
    13
    8
    8
    10
        Androstenedione (10Years<=Age<12Years)>41 (ng/dL)
    3
    0
    0
    0
        Androstenedione (12Years<=Age<14Years)<11 (ng/dL)
    3
    4
    2
    2
        Androstenedione(12 Years<=Age<14Years)>64 (ng/dL)
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry [10]
    End point description
    Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, and amylase. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Glucose <0.6*LLN
    0
    0
    0
    0
        Glucose >1.5*ULN
    0
    1
    0
    2
        CK >2.0*ULN
    40
    80
    78
    76
        Troponin I >3.0*ULN
    11
    12
    10
    13
        Amylase >1.5*ULN
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis [11]
    End point description
    Urinalysis included: urine pH, qualitative urine glucose, qualitative urine ketones, qualitative urine protein, qualitative blood/hemoglobin, urine nitrite, urine leukocytes, urine RBC, urine WBC, urine granular casts, urine hyaline casts, urine urate (uric acid) acidic crystal, urine calcium oxalate crystals, urine amorphous crystals, urine bacteria, urine microscopic exam. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    80
    78
    76
    Units: Subjects
        Qualitative urine glucose (dipstick) >=1
    1
    0
    0
    0
        Qualitative urine ketones (dipstick) >=1
    3
    3
    5
    6
        Qualitative urine protein (dipstick) >=1
    0
    1
    0
    0
        Qualitative urine blood/hemoglobin dipstick >=1
    0
    2
    1
    0
        Urine nitrite (dipstick) >=1
    0
    0
    0
    0
        Urine leukocytes (dipstick): +1
    0
    0
    1
    1
        Urine RBC >=20 (/high power field[HPF])
    0
    0
    0
    0
        Urine WBC >=20 (/HPF)
    0
    0
    0
    0
        Urine granular casts >1 (/low power field [LPF])
    1
    99999
    99999
    99999
        Urine hyaline casts >1 (/LPF)
    2
    99999
    99999
    99999
        Urine urate (uric acid) acidic crystal: Present
    4
    2
    2
    2
        Urine calcium oxalate crystals: Present
    19
    24
    23
    24
        Urine amorphous crystals: Present
    7
    7
    6
    11
        Urine bacteria >20 (/HPF)
    0
    0
    0
    0
        Urine microscopic exam: Positive
    31
    50
    49
    45
        Urine pH (dipstick) <4.5
    0
    0
    0
    0
        Urine pH (dipstick) >8
    0
    1
    1
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal

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    End point title
    Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal [12]
    End point description
    Number of subjects with blood detected in fecal samples is presented. All subjects who received at least 1 dose of investigational drug and had at least 1 fecal evaluation were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    79
    78
    74
    Units: Subjects
    2
    8
    2
    3
    No statistical analyses for this end point

    Primary: Categorical Summary of Liver Iron Accumulation by Week 49

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    End point title
    Categorical Summary of Liver Iron Accumulation by Week 49 [13]
    End point description
    Magnetic resonance imaging (MRI) of Liver was obtained to quantify liver iron accumulation for safety monitoring. MRIs were sent to an independent central radiology imaging facility for calculation of the average transverse relaxation rate (R2*) value which was used to monitor for iron accumulation in the liver. Number of subjects meeting the following criteria is presented as follows: 1) normal: R2*<=75Hz at 1.5T or <=139 Hz at 3.0T; 2) above normal: R2*>75Hz and <=190Hz at 1.5T or R2* >139Hz and <=369Hz at 3.0T; 3) mild overload: R2*>190Hz at 1.5T or R2*>360Hz at 3.0T. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Screening, Weeks 13, 29 and 45
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 Sequence 2 Sequence 3
    Number of subjects analysed
    41
    39
    40
    Units: Subjects
        Normal, Screening
    41
    39
    40
        Above normal, Screening
    0
    0
    0
        Mild overload, Screening
    0
    0
    0
        Normal, Week 13
    27
    24
    26
        Above normal, Week 13
    0
    0
    0
        Mild overload, Week 13
    0
    0
    0
        Normal, Week 29
    23
    21
    21
        Above normal, Week 29
    0
    0
    0
        Mild overload, Week 29
    0
    0
    0
        Normal, Week 45
    37
    37
    38
        Above normal, Week 45
    0
    0
    0
        Mild overload, Week 45
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Physical Examination Findings Reported as SAEs by Week 49

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    End point title
    Number of Subjects With Physical Examination Findings Reported as SAEs by Week 49 [14]
    End point description
    Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. A targeted nose and throat mucosal exam were also performed to monitor for any signs of mucosal telangiectasias. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which physical examination findings were reported as SAEs. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 Sequence 2 Sequence 3
    Number of subjects analysed
    41
    39
    40
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Summary of Tanner Stage Rating by Week 49

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    End point title
    Summary of Tanner Stage Rating by Week 49 [15]
    End point description
    Tanner staging was performed before the first dose of each dose escalation to monitor for signs of accelerated sexual development. The physical changes in pubertal development (pubic hair, penis and testes) were assessed using the system described by Marshall and Tanner. More details about the system can be referred to Tanner JM. Growth at Adolescence. Blackwell Scientific Publications 1962; 2nd edition. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Subjects
        Pubic hair, Stage 1, Baseline
    35
    70
        Pubic hair, Stage 2, Baseline
    4
    7
        Pubic hair, Stage 3, Baseline
    0
    1
        Pubic hair, Stage 4, Baseline
    1
    0
        Pubic hair, Stage 5, Baseline
    0
    0
        Pubic hair, Stage 1, Week 17
    30
    64
        Pubic hair, Stage 2, Week 17
    9
    11
        Pubic hair, Stage 3, Week 17
    0
    2
        Pubic hair, Stage 4, Week 17
    1
    0
        Pubic hair, Stage 5, Week 17
    0
    0
        Pubic hair, Stage 1, Week 33
    23
    60
        Pubic hair, Stage 2, Week 33
    11
    13
        Pubic hair, Stage 3, Week 33
    1
    1
        Pubic hair, Stage 4, Week 33
    1
    1
        Pubic hair, Stage 5, Week 33
    0
    0
        Pubic hair, Stage 1, Week 49
    21
    52
        Pubic hair, Stage 2, Week 49
    11
    15
        Pubic hair, Stage 3, Week 49
    3
    4
        Pubic hair, Stage 4, Week 49
    1
    1
        Pubic hair, Stage 5, Week 49
    1
    0
        Penis, Stage 1, Baseline
    30
    70
        Penis, Stage 2, Baseline
    9
    7
        Penis, Stage 3, Baseline
    0
    1
        Penis, Stage 4, Baseline
    1
    0
        Penis, Stage 5, Baseline
    0
    0
        Penis, Stage 1, Week 17
    29
    68
        Penis, Stage 2, Week 17
    10
    8
        Penis, Stage 3, Week 17
    0
    1
        Penis, Stage 4, Week 17
    1
    0
        Penis, Stage 5, Week 17
    0
    0
        Penis, Stage 1, Week 33
    22
    58
        Penis, Stage 2, Week 33
    11
    16
        Penis, Stage 3, Week 33
    3
    1
        Penis, Stage 4, Week 33
    0
    0
        Penis, Stage 5, Week 33
    0
    0
        Penis, Stage 1, Week 49
    21
    57
        Penis, Stage 2, Week 49
    9
    14
        Penis, Stage 3, Week 49
    5
    1
        Penis, Stage 4, Week 49
    2
    0
        Penis, Stage 5, Week 49
    0
    0
        Testes, Stage 1, Baseline
    34
    67
        Testes, Stage 2, Baseline
    4
    10
        Testes, Stage 3, Baseline
    1
    1
        Testes, Stage 4, Baseline
    1
    0
        Testes, Stage 5, Baseline
    0
    0
        Testes, Stage 1, Week 17
    29
    66
        Testes, Stage 2, Week 17
    10
    10
        Testes, Stage 3, Week 17
    0
    1
        Testes, Stage 4, Week 17
    1
    0
        Testes, Stage 5, Week 17
    0
    0
        Testes, Stage 1, Week 33
    24
    59
        Testes, Stage 2, Week 33
    9
    15
        Testes, Stage 3, Week 33
    1
    1
        Testes, Stage 4, Week 33
    2
    0
        Testes, Stage 5, Week 33
    0
    0
        Testes, Stage 1, Week 49
    19
    53
        Testes, Stage 2, Week 49
    11
    15
        Testes, Stage 3, Week 49
    4
    3
        Testes, Stage 4, Week 49
    3
    0
        Testes, Stage 5, Week 49
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Vital Signs Findings Reported as SAEs by Week 49

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    End point title
    Number of Subjects With Vital Signs Findings Reported as SAEs by Week 49 [16]
    End point description
    Vital signs evaluation included supine systolic and diastolic blood pressure (BP), pulse rate, and respiratory rate. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which vital signs findings were reported as SAEs. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49

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    End point title
    Number of Subjects With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49 [17]
    End point description
    Number of subjects with ECG data meeting the following criteria are presented: 1) corrected QT interval using Fridericia’s formula (QTcF interval) <450msec; 2) QTcF interval>=450 and <480msec; 3) QTcF interval >=480 and <500msec; 4) QTcF interval>=500msec; 5) QTcF interval increase from baseline<30msec; 6) QTcF interval increase from baseline >=30 and <60msec; 7) QTcF interval increase from baseline >=60msec. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab 5 mg/kg (Period 1) Domagrozumab 20 mg/kg (Period 1) Domagrozumab 40 mg/kg (Period 1)
    Number of subjects analysed
    40
    70
    67
    69
    Units: Subjects
        QTcF interval <450msec
    40
    70
    67
    68
        QTcF interval>=450 and <480msec
    0
    0
    0
    1
        QTcF interval >=480 and <500msec
    0
    0
    0
    0
        QTcF interval>=500msec
    0
    0
    0
    0
        QTcF interval increase <30msec
    40
    66
    65
    63
        QTcF interval increase >=30 and <60msec
    0
    4
    2
    6
        QTcF interval increase >=60msec
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49

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    End point title
    Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49
    End point description
    The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance image (MRI) or echocardiogram. The same method of cardiac imaging was used consistently within a single subject. Cardiac MRIs were read by a central imaging vendor and echocardiograms were read locally at each site. The LVEF values measured by cardiac MRI and echocardiogram are combined in the following presentation. The analysis of covariance (ANCOVA) model was used to analyze the change from baseline for domagrozumab compared to placebo on LVEF. The baseline result, age, use of angiotensin receptor blocker (ARB)/beta blocker/angiotensin converting enzyme (ACE) inhibitor and treatment were included as fixed effects in the model. All subjects who received at least 1 dose of investigational drug and had evaluable LVEF data at Week 49 were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    35
    72
    Units: Ratio of blood
        least squares mean (standard error)
    -0.063 ± 0.8464
    -1.356 ± 0.5620
    Statistical analysis title
    Statistical Comparison in LVEF by Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.2088 [19]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    1.293
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7343
         upper limit
    3.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.022
    Notes
    [18] - Least square mean difference was calculated by placebo minus domagrozumab.
    [19] - The significance level is 0.05.

    Primary: Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49

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    End point title
    Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49 [20]
    End point description
    Bone mineral density (BMD) was evaluated by Dual energy X-ray Absorptiometry (DXA). The height adjusted Z-score presented below is the number of standard deviations which compares the BMD of the subject to the average BMD matched for their age, sex and ethnicity. If the Z-score was -2 standard deviations or lower, the result was “below the expected range for age”. If the Z-score was above -2 standard deviations, the result was “within the expected range for age”. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Screening and Week 49
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 Sequence 2 Sequence 3
    Number of subjects analysed
    41
    39
    40
    Units: Standard deviations
    arithmetic mean (standard deviation)
        Screening
    -0.545151 ± 1.2845570
    -0.622784 ± 1.0778788
    -0.572650 ± 1.0283031
        Week 49
    -0.683750 ± 1.0673420
    -0.401631 ± 1.0758951
    -0.489513 ± 1.0057285
    No statistical analyses for this end point

    Primary: Bone Age to Chronological Age Ratio by Week 49

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    End point title
    Bone Age to Chronological Age Ratio by Week 49 [21]
    End point description
    Bone age assessment was evaluated by the ratio of the bone age to the chronological age using the X rays of the hand and wrist. Ratio of bone age to chronological age was calculated by bone age/chronological age at scan date. Chronological age at scan date was calculated by (scan date-date of birth+1)/365.25. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Screening, Weeks 17, 33 and 49
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Ratio
    arithmetic mean (standard deviation)
        Screening
    0.809 ± 0.1656
    0.762 ± 0.1650
        Week 17
    0.805 ± 0.1567
    0.749 ± 0.1654
        Week 33
    0.790 ± 0.1614
    0.750 ± 0.1589
        Week 49
    0.770 ± 0.1604
    0.761 ± 0.1778
    No statistical analyses for this end point

    Primary: Number of Subjects With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49

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    End point title
    Number of Subjects With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49 [22]
    End point description
    An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. The Columbia Suicide Severity Rating Scale (C-SSRS) was performed to identify the risk of suicide ideation or behavior. AEs of suicide ideation or behavior were determined by the investigator.
    End point type
    Primary
    End point timeframe
    Baseline to Week 49 visit
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Subjects
        Suicidal ideation
    0
    0
        Suicidal behavior
    0
    0
    No statistical analyses for this end point

    Primary: Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49

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    End point title
    Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline on 4SC for domagrozumab compared to placebo. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Seconds
    least squares mean (standard error)
        Week 17
    1.6896 ± 0.6776
    1.6051 ± 0.4814
        Week 33
    3.6407 ± 1.5837
    4.2244 ± 1.1209
        Week 49
    8.0122 ± 3.03
    8.2835 ± 2.1507
    Statistical analysis title
    Statistical Comparison on 4SC at Week 17
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.9191 [24]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0845
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7354
         upper limit
    1.5663
    Notes
    [23] - Mean difference was calculated by domagrozumab minus placebo.
    [24] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC at Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.7642 [26]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.5837
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2978
         upper limit
    4.4652
    Notes
    [25] - Mean difference was calculated by domagrozumab minus placebo.
    [26] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC at Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.9423 [28]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.2712
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.3799
         upper limit
    7.9223
    Notes
    [27] - Mean difference was calculated by domagrozumab minus placebo.
    [28] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Liters
    least squares mean (standard error)
        Week 17
    0.0578 ± 0.0327
    0.0578 ± 0.0250
        Week 33
    0.1008 ± 0.0385
    0.0749 ± 0.0286
        Week 49
    0.1513 ± 0.0367
    0.1092 ± 0.0278
    Statistical analysis title
    Statistical Comparison on FVC at Week 17
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.9993 [30]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0693
         upper limit
    0.0693
    Notes
    [29] - Mean difference was calculated by domagrozumab minus placebo.
    [30] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC at Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.5464 [32]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0259
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1107
         upper limit
    0.0589
    Notes
    [31] - Mean difference was calculated by domagrozumab minus placebo.
    [32] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC at Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.3041 [34]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1227
         upper limit
    0.0386
    Notes
    [33] - Mean difference was calculated by domagrozumab minus placebo.
    [34] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49
    End point description
    The NSAA was a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Units on a scale
    least squares mean (standard error)
        Week 17
    -1.9 ± 0.8
    -1.1 ± 0.6
        Week 33
    -4.5 ± 0.8
    -2.0 ± 0.6
        Week 49
    -5.2 ± 0.9
    -3.6 ± 0.7
    Statistical analysis title
    Statistical Comparison on NSAA at Week 17
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.3522 [36]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    2.5
    Notes
    [35] - Mean difference was calculated by domagrozumab minus placebo.
    [36] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on NSAA at Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    = 0.0061 [38]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    4.2
    Notes
    [37] - Mean difference was calculated by domagrozumab minus placebo.
    [38] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on NSAA at Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.1268 [40]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    3.8
    Notes
    [39] - Mean difference was calculated by domagrozumab minus placebo.
    [40] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49
    End point description
    ROM was evaluated by using goniometry to evaluate the loss of motion in the ankles. MMRM was used to analyze the change from baseline on ROM for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Degrees of passive dorsiflexion
    least squares mean (standard error)
        Left ankle, Week 17
    -1.0 ± 1.2
    -1.4 ± 0.9
        Left ankle, Week 33
    -1.9 ± 1.2
    -1.7 ± 0.9
        Left ankle, Week 49
    -2.3 ± 1.3
    -3.7 ± 1.0
        Right ankle, Week 17
    -2.1 ± 1.3
    -1.3 ± 1.0
        Right ankle, Week 33
    -4.1 ± 1.3
    -1.3 ± 0.9
        Right ankle, Week 49
    -3.6 ± 1.4
    -3.6 ± 1.1
    Statistical analysis title
    Statistical Comparison on ROM(Left ankle, Week 17)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    = 0.7337 [42]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    2.1
    Notes
    [41] - Mean difference was calculated by domagrozumab minus placebo.
    [42] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on ROM(Left ankle, Week 33)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    = 0.8893 [44]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    2.7
    Notes
    [43] - Mean difference was calculated by domagrozumab minus placebo.
    [44] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on ROM(Left ankle, Week 49)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.2939 [46]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    1.3
    Notes
    [45] - Mean difference was calculated by domagrozumab minus placebo.
    [46] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on ROM(Right ankle,Week 17)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    = 0.5995 [48]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    3.6
    Notes
    [47] - Mean difference was calculated by domagrozumab minus placebo.
    [48] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on ROM(Right ankle,Week 33)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.0385 [50]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    5.6
    Notes
    [49] - Mean difference was calculated by domagrozumab minus placebo.
    [50] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on ROM(Right ankle,Week 49)
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    P-value
    = 0.9927 [52]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    3.2
    Notes
    [51] - Mean difference was calculated by domagrozumab minus placebo.
    [52] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49
    End point description
    The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder(4 items), middle(9 items) and distal(8 items).Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model.Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Units on a scale
    least squares mean (standard error)
        Week 17
    -0.7 ± 0.6
    -1.0 ± 0.4
        Week 33
    -2.7 ± 1.1
    -0.9 ± 0.8
        Week 49
    -1.3 ± 0.5
    -1.4 ± 0.4
    Statistical analysis title
    Statistical Comparison in PUL at Week 17
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.6049 [54]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    1
    Notes
    [53] - Mean difference was calculated by domagrozumab minus placebo.
    [54] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison in PUL at Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    = 0.2065 [56]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    4.4
    Notes
    [55] - Mean difference was calculated by domagrozumab minus placebo.
    [56] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison in PUL at Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    P-value
    = 0.9391 [58]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    1.2
    Notes
    [57] - Mean difference was calculated by domagrozumab minus placebo.
    [58] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) score at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) score at Weeks 17, 33 and 49
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Meters
    least squares mean (standard error)
        Week 17
    -32.0 ± 9.1
    -30.2 ± 6.9
        Week 33
    -52.3 ± 9.9
    -43.4 ± 7.4
        Week 49
    -56.5 ± 12.7
    -58.0 ± 9.3
    Statistical analysis title
    Statistical Comparison on 6MWD at Week 17
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.8499 [60]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.7
         upper limit
    20.3
    Notes
    [59] - Mean difference was calculated by domagrozumab minus placebo.
    [60] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD at Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    P-value
    = 0.4008 [62]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    8.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12
         upper limit
    29.8
    Notes
    [61] - Mean difference was calculated by domagrozumab minus placebo.
    [62] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD at Week 49
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    P-value
    = 0.916 [64]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30
         upper limit
    27
    Notes
    [63] - Mean difference was calculated by domagrozumab minus placebo.
    [64] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49
    End point description
    Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Kilograms
    least squares mean (standard error)
        Left elbow extension, Week 17
    -0.182 ± 0.183
    -0.067 ± 0.141
        Left elbow extension, Week 33
    -0.213 ± 0.187
    -0.376 ± 0.141
        Left elbow extension, Week 49
    -0.353 ± 0.200
    -0.479 ± 0.150
        Right elbow extension, Week 17
    -0.064 ± 0.209
    -0.086 ± 0.158
        Right elbow extension, Week 33
    -0.052 ± 0.197
    -0.491 ± 0.148
        Right elbow extension, Week 49
    -0.396 ± 0.192
    -0.562 ± 0.145
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow extension at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    = 0.5726 [66]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.115
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.287
         upper limit
    0.517
    Notes
    [65] - Mean difference was calculated by domagrozumab minus placebo.
    [66] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow extension at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    = 0.4334 [68]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.574
         upper limit
    0.248
    Notes
    [67] - Mean difference was calculated by domagrozumab minus placebo.
    [68] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow extension at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    = 0.5767 [70]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.573
         upper limit
    0.321
    Notes
    [69] - Mean difference was calculated by domagrozumab minus placebo.
    [70] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow extension at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    P-value
    = 0.9274 [72]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.489
         upper limit
    0.446
    Notes
    [71] - Mean difference was calculated by domagrozumab minus placebo.
    [72] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow extension at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    = 0.0469 [74]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.439
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.872
         upper limit
    -0.006
    Notes
    [73] - Mean difference was calculated by domagrozumab minus placebo.
    [74] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow extension at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    = 0.4362 [76]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.587
         upper limit
    0.255
    Notes
    [75] - Mean difference was calculated by domagrozumab minus placebo.
    [76] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49
    End point description
    Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Kilograms
    least squares mean (standard error)
        Left elbow flexion, Week 17
    -0.096 ± 0.237
    -0.252 ± 0.181
        Left elbow flexion, Week 33
    -0.194 ± 0.244
    -0.497 ± 0.183
        Left elbow flexion, Week 49
    -0.573 ± 0.205
    -0.734 ± 0.159
        Right elbow flexion, Week 17
    -0.035 ± 0.220
    -0.118 ± 0.168
        Right elbow flexion, Week 33
    -0.057 ± 0.234
    -0.418 ± 0.175
        Right elbow flexion, Week 49
    -0.495 ± 0.199
    -0.684 ± 0.152
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow flexion at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    = 0.5557 [78]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.156
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.679
         upper limit
    0.367
    Notes
    [77] - Mean difference was calculated by domagrozumab minus placebo.
    [78] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow flexion at Week 33 was measured.
    Comparison groups
    Domagrozumab (Period 1) v Placebo (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [79]
    P-value
    = 0.2669 [80]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.303
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.841
         upper limit
    0.235
    Notes
    [79] - Mean difference was calculated by domagrozumab minus placebo.
    [80] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left elbow flexion at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [81]
    P-value
    = 0.4665 [82]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.161
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.598
         upper limit
    0.276
    Notes
    [81] - Mean difference was calculated by domagrozumab minus placebo.
    [82] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow flexion at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [83]
    P-value
    = 0.7335 [84]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.083
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.564
         upper limit
    0.399
    Notes
    [83] - Mean difference was calculated by domagrozumab minus placebo.
    [84] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow flexion, Week 33
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    = 0.1695 [86]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.361
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.877
         upper limit
    0.156
    Notes
    [85] - Mean difference was calculated by domagrozumab minus placebo.
    [86] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right elbow flexion at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    = 0.3783 [88]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.189
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.612
         upper limit
    0.234
    Notes
    [87] - Mean difference was calculated by domagrozumab minus placebo.
    [88] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49
    End point description
    Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Kilograms
    least squares mean (standard error)
        Left hip abduction, Week 17
    0.430 ± 0.321
    -0.156 ± 0.245
        Left hip abduction, Week 33
    -0.217 ± 0.318
    -0.171 ± 0.236
        Left hip abduction, Week 49
    -0.097 ± 0.334
    -0.475 ± 0.251
        Right hip abduction, Week 17
    0.535 ± 0.320
    -0.154 ± 0.247
        Right hip abduction, Week 33
    0.087 ± 0.340
    -0.249 ± 0.255
        Right hip abduction, Week 49
    0.056 ± 0.343
    -0.266 ± 0.260
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left hip abduction at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    = 0.1078 [90]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.586
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.303
         upper limit
    0.13
    Notes
    [89] - Mean difference was calculated by domagrozumab minus placebo.
    [90] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left hip abduction at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [91]
    P-value
    = 0.8967 [92]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.046
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.654
         upper limit
    0.746
    Notes
    [91] - Mean difference was calculated by domagrozumab minus placebo.
    [92] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Left hip abduction at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    = 0.3196 [94]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.378
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.128
         upper limit
    0.371
    Notes
    [93] - Mean difference was calculated by domagrozumab minus placebo.
    [94] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right hip abduction at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    = 0.0526 [96]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.689
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.386
         upper limit
    0.008
    Notes
    [95] - Mean difference was calculated by domagrozumab minus placebo.
    [96] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right hip abduction at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    = 0.3739 [98]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.336
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.082
         upper limit
    0.41
    Notes
    [97] - Mean difference was calculated by domagrozumab minus placebo.
    [98] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on Muscle Strength
    Statistical analysis description
    Right hip abduction at Week 49 was measured
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [99]
    P-value
    = 0.4019 [100]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.322
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.079
         upper limit
    0.436
    Notes
    [99] - Mean difference was calculated by domagrozumab minus placebo.
    [100] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49
    End point description
    Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Kilograms
    least squares mean (standard error)
        Left knee extension, Week 17
    -0.326 ± 0.336
    -0.434 ± 0.261
        Left knee extension, Week 33
    -0.713 ± 0.359
    -1.036 ± 0.272
        Left knee extension, Week 49
    -1.223 ± 0.369
    -1.110 ± 0.279
        Right knee extension, Week 17
    -0.213 ± 0.328
    -0.450 ± 0.253
        Right knee extension, Week 33
    -0.413 ± 0.380
    -0.880 ± 0.283
        Right knee extension, Week 49
    -0.976 ± 0.391
    -1.125 ± 0.292
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left knee extension at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [101]
    P-value
    = 0.7676 [102]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.107
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.825
         upper limit
    0.61
    Notes
    [101] - Mean difference was calculated by domagrozumab minus placebo.
    [102] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left knee extension at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [103]
    P-value
    = 0.4127 [104]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.322
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.098
         upper limit
    0.454
    Notes
    [103] - Mean difference was calculated by domagrozumab minus placebo.
    [104] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left knee extension at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [105]
    P-value
    = 0.7815 [106]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.693
         upper limit
    0.919
    Notes
    [105] - Mean difference was calculated by domagrozumab minus placebo.
    [106] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Right knee extension at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [107]
    P-value
    = 0.4975 [108]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.236
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.924
         upper limit
    0.451
    Notes
    [107] - Mean difference was calculated by domagrozumab minus placebo.
    [108] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Right knee extension at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [109]
    P-value
    = 0.2646 [110]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.467
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.294
         upper limit
    0.359
    Notes
    [109] - Mean difference was calculated by domagrozumab minus placebo.
    [110] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Right knee extension at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [111]
    P-value
    = 0.732 [112]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.149
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.008
         upper limit
    0.71
    Notes
    [111] - Mean difference was calculated by domagrozumab minus placebo.
    [112] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49

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    End point title
    Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49
    End point description
    Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 17, 33 and 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    80
    Units: Kilograms
    least squares mean (standard error)
        Left shoulder abduction, Week 17
    -0.099 ± 0.213
    -0.143 ± 0.163
        Left shoulder abduction, Week 33
    -0.123 ± 0.226
    -0.278 ± 0.166
        Left shoulder abduction, Week 49
    -0.296 ± 0.238
    -0.319 ± 0.177
        Right shoulder abduction, Week 17
    0.079 ± 0.217
    -0.157 ± 0.165
        Right shoulder abduction, Week 33
    0.421 ± 0.251
    -0.336 ± 0.185
        Right shoulder abduction, Week 49
    0.140 ± 0.313
    -0.300 ± 0.229
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left shoulder abduction at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [113]
    P-value
    = 0.8569 [114]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.044
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.525
         upper limit
    0.437
    Notes
    [113] - Mean difference was calculated by domagrozumab minus placebo.
    [114] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left shoulder abduction at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [115]
    P-value
    = 0.5495 [116]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.154
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.663
         upper limit
    0.355
    Notes
    [115] - Mean difference was calculated by domagrozumab minus placebo.
    [116] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Left shoulder abduction at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [117]
    P-value
    = 0.934 [118]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.566
         upper limit
    0.521
    Notes
    [117] - Mean difference was calculated by domagrozumab minus placebo.
    [118] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Right shoulder abduction at Week 17 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [119]
    P-value
    = 0.3279 [120]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.236
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.711
         upper limit
    0.239
    Notes
    [119] - Mean difference was calculated by domagrozumab minus placebo.
    [120] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength
    Statistical analysis description
    Right shoulder abduction at Week 33 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [121]
    P-value
    = 0.0086 [122]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.757
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.318
         upper limit
    -0.196
    Notes
    [121] - Mean difference was calculated by domagrozumab minus placebo.
    [122] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparion on Muscle Strength abduction
    Statistical analysis description
    Right shoulder abduction at Week 49 was measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority [123]
    P-value
    = 0.2328 [124]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.439
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.165
         upper limit
    0.286
    Notes
    [123] - Mean difference was calculated by domagrozumab minus placebo.
    [124] - The significance level is 0.05.

    Secondary: Change From Baseline to Weeks 49 on 4SC for Subjects in Sequence 3 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Weeks 49 on 4SC for Subjects in Sequence 3 Compared to the Natural History Control Group [125]
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for the natural history control group compared to placebo group (Sequence 3). The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 4SC data at Week 49.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    Notes
    [125] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 3 NH Control Group (4SC, Week 49)
    Number of subjects analysed
    32
    58
    Units: Seconds
        least squares mean (standard error)
    3.464 ± 1.232
    3.253 ± 0.91
    Statistical analysis title
    Comparison on 4SC Between Sequence 3 and NH group
    Comparison groups
    Sequence 3 v NH Control Group (4SC, Week 49)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [126]
    P-value
    = 0.8908 [127]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.211
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8353
         upper limit
    3.2573
    Notes
    [126] - Mean difference was calculated by Sequence 3 minus NH control group.
    [127] - The significance level is 0.05.

    Secondary: Change From Baseline to Weeks 97 on 4SC for Subjects in Sequence 1 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Weeks 97 on 4SC for Subjects in Sequence 1 Compared to the Natural History Control Group [128]
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for domagrozumab compared to the natural history control group. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 4SC data at Week 97.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    Notes
    [128] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 NH Control Group (4SC, Week 97)
    Number of subjects analysed
    18
    77
    Units: Seconds
        least squares mean (standard error)
    4.205 ± 1.011
    3.386 ± 0.531
    Statistical analysis title
    Comparison on 4SC Between Sequence 1 and NH group
    Comparison groups
    Sequence 1 v NH Control Group (4SC, Week 97)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [129]
    P-value
    = 0.4748 [130]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.819
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4514
         upper limit
    3.0895
    Notes
    [129] - Mean difference was calculated by Sequence 1 minus NH control group.
    [130] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 49 on FVC for Subjects in Sequence 3 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Week 49 on FVC for Subjects in Sequence 3 Compared to the Natural History Control Group [131]
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for the natural history control group compared to placebo group (Sequence 3). The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to match the natural history control group with the placebo group. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable FVC data at Week 49.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    Notes
    [131] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 3 NH Control Group (FVC, Week 49)
    Number of subjects analysed
    38
    49
    Units: Liters
        least squares mean (standard error)
    0.1358 ± 0.0328
    0.1261 ± 0.0294
    Statistical analysis title
    Comparison on FVC Between Sequence 3 and NH group
    Comparison groups
    Sequence 3 v NH Control Group (FVC, Week 49)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [132]
    P-value
    = 0.807 [133]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0097
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0692
         upper limit
    0.0887
    Notes
    [132] - Mean difference was calculated by Sequence 3 minus NH control group.
    [133] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 97 on FVC for Subjects in Sequence 1 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Week 97 on FVC for Subjects in Sequence 1 Compared to the Natural History Control Group [134]
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to the natural history control group. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable FVC data at Week 97.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    Notes
    [134] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 NH Control Group (FVC, Week 97)
    Number of subjects analysed
    22
    86
    Units: Liters
        least squares mean (standard error)
    0.2528 ± 0.0508
    0.2022 ± 0.0292
    Statistical analysis title
    Comparison on FVC Between Sequence 1 and NH Group
    Comparison groups
    Sequence 1 v NH Control Group (FVC, Week 97)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority [135]
    P-value
    = 0.3643 [136]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0506
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.0594
         upper limit
    0.1607
    Notes
    [135] - Mean difference was calculated by Sequence 1 minus NH control group.
    [136] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 49 on NSAA for Subjects in Sequence 3 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Week 49 on NSAA for Subjects in Sequence 3 Compared to the Natural History Control Group [137]
    End point description
    The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance.The total score could range from 0 to 34 (fully-independent function).MMRM was used to analyze the change from baseline for natural history control group compared to placebo group (Sequence 3).The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model.Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.This MMRM was established to assess the appropriateness on using natural history control group as a comparator.This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable NSAA data at Week 49.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    Notes
    [137] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 3 NH Control Group (NSAA, Week 49)
    Number of subjects analysed
    37
    18
    Units: Units on a scale
        least squares mean (standard error)
    -4.8 ± 1.2
    -2.0 ± 1.4
    Statistical analysis title
    Comparison on NSAA Between Sequence 3 and NH Group
    Comparison groups
    Sequence 3 v NH Control Group (NSAA, Week 49)
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [138]
    P-value
    = 0.0483 [139]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    0
    Notes
    [138] - Mean difference was calculated by Sequence 3 minus NH control group.
    [139] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 97 on NSAA for Subjects in Sequence 1 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Week 97 on NSAA for Subjects in Sequence 1 Compared to the Natural History Control Group [140]
    End point description
    The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance.The total score ranged from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline for domagrozumab compared to natural history control group.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable NSAA data at Week 97.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    Notes
    [140] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 NH Control Group (NSAA, Week 97)
    Number of subjects analysed
    21
    15
    Units: Units on a scale
        least squares mean (standard error)
    -4.5 ± 1.2
    -0.6 ± 1.3
    Statistical analysis title
    Comparison on NSAA Between Sequence 1 and NH Group
    Comparison groups
    Sequence 1 v NH Control Group (NSAA, Week 97)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority [141]
    P-value
    = 0.0146 [142]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7
         upper limit
    -0.8
    Notes
    [141] - Mean difference was calculated by Sequence 1 minus NH control group.
    [142] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 49 on 6MWD for Subjects in Sequence 3 Compared to Natural History Control Group

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    End point title
    Change From Baseline to Week 49 on 6MWD for Subjects in Sequence 3 Compared to Natural History Control Group [143]
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for the natural history control group compared to placebo group (Sequence 3). The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 6MWD data at Week 49.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    Notes
    [143] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 3 NH Control Group (6MWD, Week 49)
    Number of subjects analysed
    30
    17
    Units: Meters
        least squares mean (standard error)
    -80.8 ± 19.3
    -49.2 ± 22.2
    Statistical analysis title
    Comparison on 6MWD Between Sequence 3 and NH Group
    Comparison groups
    Sequence 3 v NH Control Group (6MWD, Week 49)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [144]
    P-value
    = 0.1669 [145]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -31.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -76.9
         upper limit
    13.6
    Notes
    [144] - Mean difference was calculated by Sequence 3 minus NH control group.
    [145] - The significance level is 0.05.

    Secondary: Change From Baseline to Week 97 on 6MWD for Subjects in Sequence 1 Compared to the Natural History Control Group

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    End point title
    Change From Baseline to Week 97 on 6MWD for Subjects in Sequence 1 Compared to the Natural History Control Group [146]
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to the natural history control group. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 6MWD data at Week 97.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 97
    Notes
    [146] - 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: No statistical analysis was planned for this endpoint
    End point values
    Sequence 1 NH Control Group (6MWD, Week 97)
    Number of subjects analysed
    17
    12
    Units: Meters
        least squares mean (standard error)
    -97.6 ± 20.7
    -31.3 ± 24.8
    Statistical analysis title
    Comparion on 6MWD Between Sequence 1 and NH Group
    Comparison groups
    Sequence 1 v NH Control Group (6MWD, Week 97)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    superiority [147]
    P-value
    = 0.0267 [148]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -66.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -124.5
         upper limit
    -8.1
    Notes
    [147] - Mean difference was calculated by Sequence 1 minus NH control group.
    [148] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    39
    74
    Units: Seconds
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.2329 ± 0.1513
    0.1637 ± 0.092
        Baseline 4SC>=3.5 and <=8 seconds
    0.7644 ± 0.4108
    0.9758 ± 0.3283
        Baseline 4SC>8 seconds
    7.7149 ± 4.8455
    5.071 ± 3.0969
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [149]
    P-value
    = 0.7033 [150]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0692
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4345
         upper limit
    0.2961
    Notes
    [149] - Mean difference was calculated by domagrozumab minus placebo.
    [150] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [151]
    P-value
    = 0.6893 [152]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.2114
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8472
         upper limit
    1.27
    Notes
    [151] - Mean difference was calculated by domagrozumab minus placebo.
    [152] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [153]
    P-value
    = 0.6469 [154]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -2.6439
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.4292
         upper limit
    9.1414
    Notes
    [153] - Mean difference was calculated by domagrozumab minus placebo.
    [154] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 33
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    33
    70
    Units: Seconds
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.435 ± 0.1852
    0.1062 ± 0.1061
        Baseline 4SC>=3.5 and <=8 seconds
    2.2085 ± 0.8933
    2.5542 ± 0.7234
        Baseline 4SC>8 seconds
    3.7436 ± 8.1156
    12.0329 ± 3.6174
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority [155]
    P-value
    = 0.1353 [156]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.3289
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7649
         upper limit
    0.1072
    Notes
    [155] - Mean difference was calculated by domagrozumab minus placebo.
    [156] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority [157]
    P-value
    = 0.7648 [158]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.3457
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9614
         upper limit
    2.6528
    Notes
    [157] - Mean difference was calculated by domagrozumab minus placebo.
    [158] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    superiority [159]
    P-value
    = 0.3562 [160]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    8.2893
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.6409
         upper limit
    26.2194
    Notes
    [159] - Mean difference was calculated by domagrozumab minus placebo.
    [160] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets
    End point description
    The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    32
    63
    Units: Seconds
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    1.0056 ± 0.294
    0.4474 ± 0.1816
        Baseline 4SC>=3.5 and <= 8 seconds
    3.526 ± 1.1574
    3.6204 ± 0.9391
        Baseline 4SC>8 seconds
    30.3411 ± 9.7373
    19.053 ± 4.1965
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [161]
    P-value
    = 0.1163 [162]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.5582
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2615
         upper limit
    0.1451
    Notes
    [161] - Mean difference was calculated by domagrozumab minus placebo.
    [162] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [163]
    P-value
    = 0.2947 [164]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -11.2881
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.8328
         upper limit
    10.2566
    Notes
    [163] - Mean difference was calculated by domagrozumab minus placebo.
    [164] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 4SC in Subsets
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [165]
    P-value
    = 0.9503 [166]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0944
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.0798
         upper limit
    3.2686
    Notes
    [165] - Mean difference was calculated by domagrozumab minus placebo.
    [166] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    78
    Units: Liters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.0562 ± 0.0603
    0.0722 ± 0.0368
        Baseline 4SC>=3.5 and <=8 seconds
    0.0543 ± 0.0352
    0.0411 ± 0.0276
        Baseline 4SC>8 seconds
    -0.0168 ± 0.0800
    0.0721 ± 0.0534
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [167]
    P-value
    = 0.8229 [168]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.127
         upper limit
    0.1588
    Notes
    [167] - Mean difference was calculated by domagrozumab minus placebo.
    [168] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [169]
    P-value
    = 0.7709 [170]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0132
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1036
         upper limit
    0.0772
    Notes
    [169] - Mean difference was calculated by domagrozumab minus placebo.
    [170] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [171]
    P-value
    = 0.3746 [172]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0889
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1219
         upper limit
    0.2996
    Notes
    [171] - Mean difference was calculated by domagrozumab minus placebo.
    [172] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 33
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    37
    76
    Units: Liters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.1971 ± 0.0659
    0.1036 ± 0.0389
        Baseline 4SC>=3.5 and <=8 seconds
    0.0585 ± 0.0476
    0.0468 ± 0.0376
        Baseline 4SC>8 seconds
    0.0332 ± 0.1053
    0.0895 ± 0.0703
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [173]
    P-value
    = 0.2294 [174]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0934
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2481
         upper limit
    0.0613
    Notes
    [173] - Mean difference was calculated by domagrozumab minus placebo.
    [174] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [175]
    P-value
    = 0.8485 [176]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0117
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1339
         upper limit
    0.1105
    Notes
    [175] - Mean difference was calculated by domagrozumab minus placebo.
    [176] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [177]
    P-value
    = 0.6645 [178]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.0562
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2187
         upper limit
    0.3312
    Notes
    [177] - Mean difference was calculated by domagrozumab minus placebo.
    [178] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets
    End point description
    FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    38
    74
    Units: Liters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.2199 ± 0.0675
    0.1186 ± 0.0418
        Baseline 4SC>=3.5 and <=8 seconds
    0.1364 ± 0.0376
    0.1006 ± 0.0297
        Baseline 4SC>8 seconds
    0.0052 ± 0.0936
    0.1091 ± 0.0634
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [179]
    P-value
    = 0.2101 [180]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2622
         upper limit
    0.0597
    Notes
    [179] - Mean difference was calculated by domagrozumab minus placebo.
    [180] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds wrere analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [181]
    P-value
    = 0.4603 [182]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.0359
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1326
         upper limit
    0.0608
    Notes
    [181] - Mean difference was calculated by domagrozumab minus placebo.
    [182] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on FVC in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [183]
    P-value
    = 0.3739 [184]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.1039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1386
         upper limit
    0.3463
    Notes
    [183] - Mean difference was calculated by domagrozumab minus placebo.
    [184] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets
    End point description
    The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    38
    77
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -0.4 ± 1.8
    -0.7 ± 1.1
        Baseline 4SC>=3.5 and <=8 seconds
    -1.3 ± 0.8
    -0.1 ± 0.6
        Baseline 4SC>8 seconds
    -3.2 ± 0.9
    -1.9 ± 0.6
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [185]
    P-value
    = 0.8925 [186]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    3.9
    Notes
    [185] - Mean difference was calculated by domagrozumab minus placebo.
    [186] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [187]
    P-value
    = 0.2107 [188]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    3.2
    Notes
    [187] - Mean difference was calculated by domagrozumab minus placebo.
    [188] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [189]
    P-value
    = 0.2298 [190]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    3.5
    Notes
    [189] - Mean difference was calculated by domagrozumab minus placebo.
    [190] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets

    Close Top of page
    End point title
    Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets
    End point description
    The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 33
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    38
    75
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -3.9 ± 1.5
    -0.4 ± 0.9
        Baseline 4SC>=3.5 and <=8 seconds
    -3.5 ± 1.0
    -2.0 ± 0.8
        Baseline 4SC>8 seconds
    -5.6 ± 1.3
    -2.7 ± 0.9
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [191]
    P-value
    = 0.0554 [192]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    7.1
    Notes
    [191] - Mean difference was calculated by domagrozumab minus placebo.
    [192] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [193]
    P-value
    = 0.2027 [194]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    4
    Notes
    [193] - Mean difference was calculated by domagrozumab minus placebo.
    [194] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [195]
    P-value
    = 0.0926 [196]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    6.3
    Notes
    [195] - Mean difference was calculated by domagrozumab minus placebo.
    [196] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets

    Close Top of page
    End point title
    Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets
    End point description
    The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    37
    73
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -3.8 ± 1.8
    -1.8 ± 1.1
        Baseline 4SC>=3.5 and <= 8 seconds
    -4.2 ± 1.1
    -3.7 ± 0.9
        Baseline 4SC>8 seconds
    -8.4 ± 1.4
    -4.4 ± 0.9
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [197]
    P-value
    = 0.3597 [198]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    6.3
    Notes
    [197] - Mean difference was calculated by domagrozumab minus placebo.
    [198] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [199]
    P-value
    = 0.7345 [200]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    3.3
    Notes
    [199] - Mean difference was calculated by domagrozumab minus placebo.
    [200] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on NSAA in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [201]
    P-value
    = 0.032 [202]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    7.7
    Notes
    [201] - Mean difference was calculated by domagrozumab minus placebo.
    [202] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets
    End point description
    The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline .The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    40
    78
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -1.1 ± 1.1
    0.2 ± 0.7
        Baseline 4SC>=3.5 and <=8 seconds
    0.2 ± 0.7
    -1.0 ± 0.5
        Baseline 4SC>8 seconds
    0.4 ± 1.7
    -0.5 ± 1.2
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were measured.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [203]
    P-value
    = 0.3345 [204]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    3.8
    Notes
    [203] - Mean difference was calculated by domagrozumab minus placebo.
    [204] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [205]
    P-value
    = 0.14 [206]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    0.4
    Notes
    [205] - Mean difference was calculated by domagrozumab minus placebo.
    [206] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were anlyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority [207]
    P-value
    = 0.6764 [208]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    3.6
    Notes
    [207] - Mean difference was calculated by domagrozumab minus placebo.
    [208] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets

    Close Top of page
    End point title
    Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets
    End point description
    The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 33
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    37
    76
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -6.4 ± 3.3
    0.1 ± 2.0
        Baseline 4SC>=3.5 and <= 8 seconds
    0 ± 0.6
    -0.3 ± 0.5
        Baseline 4SC>8 seconds
    -1.0 ± 1.9
    -2.0 ± 1.2
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [209]
    P-value
    = 0.097 [210]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    14.2
    Notes
    [209] - Mean difference was calculated by domagrozumab minus placebo.
    [210] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [211]
    P-value
    = 0.6919 [212]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    1.3
    Notes
    [211] - Mean difference was calculated by domagrozumab minus placebo.
    [212] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [213]
    P-value
    = 0.6736 [214]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.8
         upper limit
    3.9
    Notes
    [213] - Mean difference was calculated by domagrozumab minus placebo.
    [214] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets

    Close Top of page
    End point title
    Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets
    End point description
    The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder(4 items), middle(9 items) and distal(8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    38
    75
    Units: Units on a scale
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    0.3 ± 0.6
    0.3 ± 0.4
        Baseline 4SC>=3.5 and <=8 seconds
    -0.9 ± 0.7
    -1.0 ± 0.5
        Baseline 4SC>8 seconds
    -2.6 ± 1.7
    -3.5 ± 1.1
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [215]
    P-value
    = 0.9582 [216]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    1.5
    Notes
    [215] - Mean difference was calculated by domagrozumab minus placebo.
    [216] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [217]
    P-value
    = 0.8629 [218]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    1.5
    Notes
    [217] - Mean difference was calculated by domagrozumab minus placebo.
    [218] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on PUL in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [219]
    P-value
    = 0.6746 [220]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    3.7
    Notes
    [219] - Mean difference was calculated by domagrozumab minus placebo.
    [220] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    36
    74
    Units: Meters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -6.9 ± 15.4
    -12.7 ± 9.3
        Baseline 4SC>=3.5 and <=8 seconds
    -21.0 ± 8.8
    -22.4 ± 7.0
        Baseline 4SC>8 seconds
    -34.0 ± 28.3
    -20.9 ± 16.3
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [221]
    P-value
    = 0.7483 [222]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.4
         upper limit
    30.7
    Notes
    [221] - Mean difference was calculated by domagrozumab minus placebo.
    [222] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [223]
    P-value
    = 0.9053 [224]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.9
         upper limit
    21.2
    Notes
    [223] - Mean difference was calculated by domagrozumab minus placebo.
    [224] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority [225]
    P-value
    = 0.6896 [226]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    13.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -53.4
         upper limit
    79.7
    Notes
    [225] - Mean difference was calculated by domagrozumab minus placebo.
    [226] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 33
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    31
    70
    Units: Meters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -12.0 ± 13.2
    -15.7 ± 7.8
        Baseline 4SC>=3.5 and <=8 seconds
    -45.7 ± 10.9
    -38.4 ± 8.6
        Baseline 4SC>8 seconds
    -71.9 ± 40.6
    -55.6 ± 17.5
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [227]
    P-value
    = 0.8117 [228]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.8
         upper limit
    27.5
    Notes
    [227] - Mean difference was calculated by domagrozumab minus placebo.
    [228] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [229]
    P-value
    = 0.6018 [230]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.6
         upper limit
    35.2
    Notes
    [229] - Mean difference was calculated by domagrozumab minus placebo.
    [230] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [231]
    P-value
    = 0.7152 [232]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    16.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -73.4
         upper limit
    106
    Notes
    [231] - Mean difference was calculated by domagrozumab minus placebo.
    [232] - The significance level is 0.05.

    Secondary: Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets

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    End point title
    Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets
    End point description
    6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    Placebo (Period 1) Domagrozumab (Period 1)
    Number of subjects analysed
    30
    61
    Units: Meters
    least squares mean (standard error)
        Baseline 4SC<3.5 seconds
    -33.5 ± 16.4
    -26.5 ± 10.1
        Baseline 4SC>=3.5 and <=8 seconds
    -42.0 ± 16.7
    -57.8 ± 13.4
        Baseline 4SC>8 seconds
    -75.1 ± 47.6
    -71.2 ± 18.9
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC<3.5 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority [233]
    P-value
    = 0.719 [234]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.1
         upper limit
    46.1
    Notes
    [233] - Mean difference was calculated by domagrozumab minus placebo.
    [234] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority [235]
    P-value
    = 0.4634 [236]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -15.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -58.9
         upper limit
    27.3
    Notes
    [235] - Mean difference was calculated by domagrozumab minus placebo.
    [236] - The significance level is 0.05.
    Statistical analysis title
    Statistical Comparison on 6MWD in Subset
    Statistical analysis description
    Subjects with baseline 4SC>8 seconds were analyzed.
    Comparison groups
    Placebo (Period 1) v Domagrozumab (Period 1)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority [237]
    P-value
    = 0.94 [238]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -100.7
         upper limit