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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis

    Summary
    EudraCT number
    2019-000968-18
    Trial protocol
    DK   GB   PL   DE   HU   CZ   BE   ES   IT  
    Global end of trial date
    26 Oct 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Nov 2022
    First version publication date
    06 Nov 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MG0003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03971422
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SRL
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, 1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstrate the clinical efficacy of rozanolixizumab in participants with generalized myasthenia gravis (MG)
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    03 Jun 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Georgia: 13
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    200
    EEA total number of subjects
    84
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    151
    From 65 to 84 years
    47
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll study participants in Jun 2019 and concluded in Oct 2021. Two participants randomized to RLZ ~7mg/kg, were administered RLZ ~10mg/kg at baseline visit. So, these two participants were included in RLZ ~7 mg/kg group in randomized set, but in RLZ ~10 mg/kg group in safety set.

    Pre-assignment
    Screening details
    Participant Flow refers to the Randomized Set which consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of the actual treatment received.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received placebo subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received placebo at pre-specified time points.

    Arm title
    Rozanolixizumab ~7 mg/kg
    Arm description
    Participants received rozanolixizumab (RLZ) equivalent to approximately 7 milligrams/kilogram (mg/kg) subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).
    Arm type
    Experimental

    Investigational medicinal product name
    Rozanolixizumab
    Investigational medicinal product code
    UCB7665
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received rozanolixizumab equivalent to approximately 7 mg at pre-specified time points.

    Arm title
    Rozanolixizumab ~10 mg/kg
    Arm description
    Participants received rozanolixizumab equivalent to approximately 10 mg/kg subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).
    Arm type
    Experimental

    Investigational medicinal product name
    Rozanolixizumab
    Investigational medicinal product code
    UCB7665
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received rozanolixizumab equivalent to approximately 10 mg at pre-specified time points.

    Number of subjects in period 1
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Started
    67
    66
    67
    Completed
    42
    43
    43
    Not completed
    25
    23
    24
         Adverse event, not fatal
    2
    2
    5
         Worsening of MG Symptoms
    1
    4
    2
         Roll over to MG0004 (NCT04124965)
    7
    8
    6
         Lack of efficacy
    5
    1
    1
         Roll over to MG0007 (NCT04650854)
    10
    6
    9
         Due to COVID-19 pandemic
    -
    1
    1
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~7 mg/kg
    Reporting group description
    Participants received rozanolixizumab (RLZ) equivalent to approximately 7 milligrams/kilogram (mg/kg) subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~10 mg/kg
    Reporting group description
    Participants received rozanolixizumab equivalent to approximately 10 mg/kg subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg Total
    Number of subjects
    67 66 67 200
    Age Categorical
    Units: participants
        <=18 years
    1 0 0 1
        Between 18 and 65 years
    50 49 51 150
        >=65 years
    16 17 16 49
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.4 ± 17.7 53.2 ± 14.7 51.9 ± 16.5 -
    Sex: Female, Male
    Units: participants
        Female
    47 39 35 121
        Male
    20 27 32 79

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~7 mg/kg
    Reporting group description
    Participants received rozanolixizumab (RLZ) equivalent to approximately 7 milligrams/kilogram (mg/kg) subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~10 mg/kg
    Reporting group description
    Participants received rozanolixizumab equivalent to approximately 10 mg/kg subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Subject analysis set title
    Rozanolixizumab ~10 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received rozanolixizumab equivalent to approximately 10 mg/kg subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Primary: Change from Baseline to Day 43 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) score

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    End point title
    Change from Baseline to Day 43 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) score
    End point description
    The Myasthenia Gravis Activities of Daily Living (MG-ADL) is an 8-item patient-reported outcome (PRO) instrument developed on the basis of the Quantitative Myasthenia Gravis (QMG). The MG-ADL targeted symptoms and disability across ocular, bulbar, respiratory, and axial symptoms. The total MG-ADL score was obtained by summing the responses to each individual item (8 items; Grades: 0, 1, 2, 3), where 0 represents no symptoms or impaired performance and 3 represents the most severe symptoms or impaired performance. The total score ranges from 0 to 24, with a higher score indicating more disability. A positive change in the score indicates worsening and a negative change indicates improvement. The Randomized Set consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of the actual treatment received.
    End point type
    Primary
    End point timeframe
    Baseline and Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -0.784 ± 0.488
    -3.370 ± 0.486
    -3.403 ± 0.494
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001 [2]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -2.586
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.091
         upper limit
    -1.249
    Notes
    [1] - Mixed model repeated measure (MMRM) analysis of covariance (ANCOVA) model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [2] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001 [4]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -2.619
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.994
         upper limit
    -1.163
    Notes
    [3] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [4] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Percentage of participants achieving Myasthenia Gravis-Activities of Daily Living (MG-ADL) response at Day 43

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    End point title
    Percentage of participants achieving Myasthenia Gravis-Activities of Daily Living (MG-ADL) response at Day 43
    End point description
    The MG-ADL is an 8-item PRO instrument developed on the basis of the QMG. The MG-ADL targeted symptoms and disability across ocular, bulbar, respiratory, and axial symptoms. The total MG-ADL score was obtained by summing the responses to each individual item (8 items; Grades: 0, 1, 2, 3), where 0 represents no symptoms or impaired performance and 3 represents the most severe symptoms or impaired performance. The total score ranges from 0 to 24, with a higher score indicating more disability. A positive change in the score indicates worsening and a negative change indicates improvement. Study participants were classified as responders at Day 43 if the value was at least a 2-point improvement (decrease) from Baseline at Day 43. The Randomized Set consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: percentage of participants
        number (not applicable)
    28.4
    68.2
    61.2
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.001 [6]
    Method
    Wald test
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.273
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.653
         upper limit
    11.791
    Notes
    [5] - The OR of responder rates is estimated and tested between treatment groups using logistic regression model with treatment group, Baseline MG-ADL score and stratification factor (MuSK+ or AChR+). An OR > 1 favours rozanolixizumab.
    [6] - p-value is nominal. Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001 [8]
    Method
    Wald test
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.765
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    14.882
    Notes
    [7] - The OR of responder rates is estimated and tested between treatment groups using logistic regression model with treatment group, Baseline MG-ADL score and stratification factor (MuSK+ or AChR+). An OR > 1 favours rozanolixizumab.
    [8] - p-value is nominal. Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Change from Baseline to Day 43 in Myasthenia Gravis-Composite (MG-C) total score

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    End point title
    Change from Baseline to Day 43 in Myasthenia Gravis-Composite (MG-C) total score
    End point description
    MG-C scale is a validated assessment and scale tests 10 items with individual item being weighted differently. The items included ptosis/upward gaze (range: 0 [>45 second] - 3 [Immediate]), double vision on lateral gaze (range: 0 [>45 second] - 4 [Immediate]), eye closure (range: 0 [Normal] - 2 [severe weakness]), talking (range: 0 [Normal] - 6 [difficult to understand speech]), chewing (range: 0 [Normal] - 6 [gastric tube]), swallowing (range: 0 [Normal] - 6 [gastric tube]), breathing (range: 0 [Normal] - 9 [ventilator dependence]), neck flexion (range: 0 [Normal] - 4 [severe weakness]), shoulder abduction (range: 0 [Normal] - 5 [severe weakness]) and hip flexion (range: 0 [Normal] - 5 [severe weakness]), lower scores= lower disease activity. Total MG-C score was obtained by summing responses to each individual item and score ranges from 0 to 50, with lower scores indicating lower disease activity. A positive change indicates worsening and a negative change indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -2.029 ± 0.917
    -5.930 ± 0.916
    -7.554 ± 0.934
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.001 [10]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.525
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.303
         upper limit
    -2.968
    Notes
    [9] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [10] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.001 [12]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -3.901
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.634
         upper limit
    -1.245
    Notes
    [11] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [12] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Change from Baseline to Day 43 in Quantitative Myasthenia Gravis (QMG) total score

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    End point title
    Change from Baseline to Day 43 in Quantitative Myasthenia Gravis (QMG) total score
    End point description
    The QMG is a validated assessment and the scale tested 13 items, including ocular and facial involvement, swallowing, speech, limb strength, and forced vital capacity. The total QMG score was obtained by summing the responses to each individual item (13 items; Responses: None=0, Mild=1, Moderate=2, Severe=3) and the score ranges from 0 to 39, with lower scores indicating lower disease activity. A positive change in the score indicates worsening and a negative change indicates improvement. The Randomized Set consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -1.915 ± 0.682
    -5.398 ± 0.679
    -6.672 ± 0.692
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.001 [14]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -3.483
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.614
         upper limit
    -1.584
    Notes
    [13] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [14] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.001 [16]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -4.756
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.821
         upper limit
    -2.859
    Notes
    [15] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [16] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Muscle Weakness Fatigability' score

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    End point title
    Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Muscle Weakness Fatigability' score
    End point description
    MG symptoms PRO instrument consisted of 42 items across 5 scales: ocular muscle weakness (items 1-5); bulbar muscle weakness (items 6-15); respiratory muscle weakness (items 16-18); physical fatigue (items 19-33) and muscle weakness fatigability (items 34-42). Participants were asked to choose response option that how frequently they experienced muscle weakness fatigability (items 34-42) over past 7 days using a 5-point Likert scale (1=“none of the time” to 5=“all of the time”) for each item. Sum of each item score is linearly transformed to have all domain scores ranging from 0 to 100. Total score is calculated as: (sum of item scores within the scale)/(raw score range) x (total number of items in the scale)/(number of non-missing items in the scale) x100 and ranged from 0 to 100, where higher scores indicated severe symptoms. Randomized Set consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -10.588 ± 3.034
    -23.029 ± 3.034
    -25.751 ± 3.095
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    < 0.001 [18]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -12.441
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.804
         upper limit
    -4.089
    Notes
    [17] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [18] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.001 [20]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -15.163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.596
         upper limit
    -6.45
    Notes
    [19] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [20] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Physical Fatigue' score

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    End point title
    Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Physical Fatigue' score
    End point description
    MG symptoms PRO instrument consisted of 42 items across 5 scales: ocular muscle weakness (items 1-5); bulbar muscle weakness (items 6-15); respiratory muscle weakness (items 16-18); physical fatigue (items 19-33) and muscle weakness fatigability (items 34-42). Study participants were asked to choose the response option that how frequently they experienced physical fatigue (items 19-33) over the past 7 days using a 5-point Likert scale (1=“none of the time” to 5=“all of the time”) for each item. Sum of each item score is linearly transformed to have all domain scores ranging from 0 to 100. Total score is calculated as: (sum of item scores within the scale)/(raw score range) x (total number of items in the scale)/(number of non-missing items in the scale) x100 and ranged from 0 to 100, where higher scores indicated severe symptoms. Randomized Set consisted of all study participants who were randomized and analyzed according to treatment assigned instead of actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -10.637 ± 3.051
    -19.287 ± 3.046
    -25.459 ± 3.107
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    < 0.001 [22]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -14.822
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.759
         upper limit
    -5.936
    Notes
    [21] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [22] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.012 [24]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -8.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.058
         upper limit
    -0.134
    Notes
    [23] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [24] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Bulbar Symptoms' score

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    End point title
    Change from Baseline to Day 43 in the Myasthenia Gravis (MG) Symptoms Patient Reported Outcome (PRO) 'Bulbar Symptoms' score
    End point description
    The MG symptoms PRO instrument consisted of 42 items across 5 scales: ocular muscle weakness (items 1-5); bulbar muscle weakness (items 6-15); respiratory muscle weakness (items 16-18); physical fatigue (items 19-33) and muscle weakness fatigability (items 34-42). Study participants were asked to choose response option that best described severity of bulbar muscle weakness (items 6-15) symptoms over past 7 days using a 4-point Likert scale (1=“none” to 4=“severe”) for each item. Sum of each item score is linearly transformed to have all domain scores ranging from 0 to 100. Total score is calculated as: (sum of item scores within the scale)/(raw score range) x (total number of items in the scale)/(number of non-missing items in the scale) x100 and ranged from 0 to 100, where higher scores indicated severe symptoms. The Randomized Set consisted of all study participants who were randomized and analyzed according to the treatment assigned instead of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 43
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    66
    67
    Units: units on a scale
        least squares mean (standard error)
    -3.519 ± 2.397
    -14.839 ± 2.406
    -14.224 ± 2.464
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~7 mg/kg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    < 0.001 [26]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -11.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.958
         upper limit
    -4.998
    Notes
    [25] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [26] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    A sequential testing procedure was used. The parallel gatekeeping testing procedure with a truncated Hochberg test was used to control the familywise type I error rate at a 2-sided alpha level of 0.05.
    Comparison groups
    Placebo v Rozanolixizumab ~10 mg/kg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.001 [28]
    Method
    Lehmacher and Wassmer method
    Parameter type
    LS Mean Difference
    Point estimate
    -10.705
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.787
         upper limit
    -3.998
    Notes
    [27] - MMRM ANCOVA model included treatment group, Baseline score, region, stratification factor (MuSK+ or AChR+) and treatment group by day (interaction term) as fixed factors and participant as a random effect.
    [28] - Confidence intervals and p-values are based on stage-wise inverse normal combination using the Lehmacher and Wassmer method.

    Secondary: Number of Participants With treatment-emergent adverse events (TEAEs)

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    End point title
    Number of Participants With treatment-emergent adverse events (TEAEs) [29]
    End point description
    A TEAE is defined as an AE starting on or after the time of first administration of investigational medicinal product (IMP) up to and including 8 weeks after the last dose. The Safety Set consisted of all randomized study participants who received at least one dose of IMP and analyzed according to the actual treatment the participants received. Two participants randomized to RLZ ~7mg/kg, were administered RLZ ~10mg/kg at baseline visit. So, these two participants were included in RLZ ~7 mg/kg group in randomized set, but in RLZ ~10 mg/kg group in safety set.
    End point type
    Secondary
    End point timeframe
    From Baseline until End of Study Visit (up to Week 14)
    Notes
    [29] - 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 formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    64
    69
    Units: participants
    45
    52
    57
    No statistical analyses for this end point

    Secondary: Number of Participants With treatment-emergent adverse events (TEAEs) leading to withdrawal of investigational medicinal product (IMP)

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    End point title
    Number of Participants With treatment-emergent adverse events (TEAEs) leading to withdrawal of investigational medicinal product (IMP) [30]
    End point description
    A TEAE is defined as an AE starting on or after the time of first administration of IMP up to and including 8 weeks after the last dose. The Safety Set consisted of all randomized study participants who received at least one dose of IMP and analyzed according to the actual treatment the participants received. Two participants randomized to RLZ ~7mg/kg, were administered RLZ ~10mg/kg at baseline visit. So, these two participants were included in RLZ ~7 mg/kg group in randomized set, but in RLZ ~10 mg/kg group in safety set.
    End point type
    Secondary
    End point timeframe
    From Baseline until End of Study Visit (up to Week 14)
    Notes
    [30] - 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 formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    Placebo Rozanolixizumab ~7 mg/kg Rozanolixizumab ~10 mg/kg
    Number of subjects analysed
    67
    64
    69
    Units: participants
    2
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until End of Study Visit (up to Week 14)
    Adverse event reporting additional description
    Safety Set was analyzed for TEAEs. Two participants randomized to RLZ ~7mg/kg, were administered RLZ ~10mg/kg at baseline visit. So, these two participants were included in RLZ ~7 mg/kg group in randomized set, but in RLZ ~10 mg/kg group in safety set.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~10 mg/kg
    Reporting group description
    Participants received rozanolixizumab equivalent to approximately 10 mg/kg subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Reporting group title
    Rozanolixizumab ~7 mg/kg
    Reporting group description
    Participants received rozanolixizumab equivalent to approximately 7 mg/kg, subcutaneously on a weekly basis over a 6-week Treatment Period. After 6-week Treatment Period, participants were followed for up to 8 weeks (up to Week 14).

    Serious adverse events
    Placebo Rozanolixizumab ~10 mg/kg Rozanolixizumab ~7 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 67 (8.96%)
    7 / 69 (10.14%)
    5 / 64 (7.81%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 69 (2.90%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Rozanolixizumab ~10 mg/kg Rozanolixizumab ~7 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 67 (38.81%)
    42 / 69 (60.87%)
    40 / 64 (62.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 69 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    0
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 67 (19.40%)
    26 / 69 (37.68%)
    29 / 64 (45.31%)
         occurrences all number
    31
    51
    54
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 67 (1.49%)
    14 / 69 (20.29%)
    8 / 64 (12.50%)
         occurrences all number
    1
    25
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 67 (13.43%)
    11 / 69 (15.94%)
    16 / 64 (25.00%)
         occurrences all number
    14
    18
    18
    Nausea
         subjects affected / exposed
    5 / 67 (7.46%)
    8 / 69 (11.59%)
    5 / 64 (7.81%)
         occurrences all number
    12
    8
    7
    Vomiting
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 69 (5.80%)
    1 / 64 (1.56%)
         occurrences all number
    4
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 67 (2.99%)
    5 / 69 (7.25%)
    3 / 64 (4.69%)
         occurrences all number
    2
    5
    4
    Myalgia
         subjects affected / exposed
    1 / 67 (1.49%)
    4 / 69 (5.80%)
    2 / 64 (3.13%)
         occurrences all number
    1
    4
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 67 (4.48%)
    5 / 69 (7.25%)
    1 / 64 (1.56%)
         occurrences all number
    4
    5
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 67 (5.97%)
    2 / 69 (2.90%)
    2 / 64 (3.13%)
         occurrences all number
    4
    2
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2019
    Protocol Amendment 1 (dated 30 Oct 2019) was implemented to add an additional “other” efficacy endpoint (time to first rescue therapy), an additional exploratory objective and endpoint (tetanus IgG antibodies), amend 2 secondary endpoints (both patient-reported outcomes [PROs] with text added to include muscle/limb weakness in the score), and remove 2 “other” efficacy endpoints at each scheduled assessment during the Treatment and Observation Periods as follows: 1) value and change from Baseline in the MG Symptoms PRO multi-component total score and 2) value and change from Baseline in the enhanced MG Symptoms PRO total score.
    04 Mar 2020
    Protocol Amendment 2 (dated 04 Mar 2020) was implemented to incorporate the harmonization of inclusion criteria with studies performed across the rozanolixizumab development program, and include a new section to include temporary discontinuation of IMP in case of low IgG levels observed in study participants. Furthermore, additional blood and PK samples, as well details pertaining to a substudy were incorporated to provide the opportunity to increase confidence in the PK exposure from the selected doses and help clinically validate the ADA assay’s drug tolerance through analysis of a drug onboard postdose sample as opposed to the predose samples that were likely to be below the limit of quantification (BLQ). Protocol Amendment 2 was an internally approved document, which was not implemented at the study sites or submitted to the regulatory authorities. Protocol Amendment 3 included changes related to the coronavirus disease 2019 (COVID-19) pandemic and incorporated the changes made in Protocol Amendment 2.
    29 Jul 2020
    Protocol Amendment 3 (dated 29 Jul 2020) was implemented to introduce the MG0007 study as the OLE study to MG0003 and closure of the MG0004 study once the MG0007 study was available, decrease the complexity of assessments to be performed (including revising the MG Impairment Index [MGII] from mandatory to optional), to clarify some operational aspects of the study, and to include the management of study participant treatment during the COVID-19 pandemic, including contingency measures.
    23 Feb 2021
    Protocol Amendment 4 (dated 23 Feb 2021) included the following changes: • Updated the requirement for study participants who received rescue therapy to be followed up through to the end of the Observation Period • Updated the criteria for discontinuation due to other adverse events (AEs) or medical conditions • Remove the participant exit interview. • Additional updates have been incorporated to provide further clarity on the protocol and/or to correct errors.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Due to Covid pandemic
    29 May 2020

    Limitations and caveats

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