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    Clinical Trial Results:
    A multi-center, randomized, double-blind, placebo controlled, parallel group study to preliminarily evaluate the safety, tolerability, pharmacokinetics and efficacy of CFZ533 in patients with moderate to severe myasthenia gravis

    Summary
    EudraCT number
    		 2015-000097-35
    Trial protocol
    		 DE   DK  
    Global end of trial date
    19 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2018
    First version publication date
    28 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCFZ533X2204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    19 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main opbjective for the trial were : - to evaluate the safety and tolerability of intravenous (IV) CFZ533 as an add-on therapy to standard of care in patients with moderate to severe MG throughout the study, - and to evaluate the efficacy of IV CFZ533 as an add-on therapy to standard of care in patients with moderate to severe MG
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    Taiwan: 7
    Worldwide total number of subjects
    44
    EEA total number of subjects
    9
    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)
    40
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 44 patients were randomized to receive either IV CFZ533 or IV placebo, of which 34 patients (77%) completed the study.

    Pre-assignment
    Screening details
    		 Safety analysis set, and Full analysis: 44 patients (22 treated with CFZ533 and 22 with placebo) PK analysis set : 20 patients treated with CFZ533 PD analysis set: 42 patients (20 treated with CFZ533 and 20 with placebo)

    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
    		 Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CFZ533
    Arm description
    		 CFZ533 10 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CFZ533 was provided as lyophilisate in vial (150 mg). CFZ533 was administered as a 10 mg/kg IV infusion given over 2 hours, every 28 days (q4w), for a treatment duration of 24 weeks (six doses).

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The CFZ533 matching placebo was provided as liquid in vials, and was administered as IV infusion over 2 hours, every 28 days (q4w), for a treatment duration of 24 weeks (six doses).

    Number of subjects in period 1
    		CFZ533 Placebo
    Started
    22
    22
    Completed
    17
    17
    Not completed
    5
    5
         Adverse event, serious fatal
    -
    2
         Adverse event, non-fatal
    1
    -
         subject / guardian decision
    1
    3
         Lost to follow-up
    1
    -
         abnormal lab value
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CFZ533
    Reporting group description
    		 CFZ533 10 mg/kg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 CFZ533 Placebo Total
    Number of subjects
    		 22 22 44
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 20 20 40
        From 65-84 years
    		 2 2 4
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.7 ( 13.54 ) 43.3 ( 13.92 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 12 16 28
        Male
    		 10 6 16
    Race/Ethnicity, Customized
    Units: Subjects
        caucasian|
    		 19 16 35
        Asian (Chinese)|
    		 3 5 8
        other|
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    CFZ533
    Reporting group description
    		 CFZ533 10 mg/kg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Mean change from baseline in the Quantitative Myastenia Gravis (QMG) score at week 25. Posterior Median was used as measure type.

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    End point title
    		 Mean change from baseline in the Quantitative Myastenia Gravis (QMG) score at week 25. Posterior Median was used as measure type.
    End point description
    The QMG score is an established and validated measure of disease severity used in MG trials (Jaretzki et al 2000). This scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits). Its reliability and longitudinal validity have been demonstrated in several studies (Sharshar et al 2000, Bedlack et al 2005).
    End point type
    Primary
    End point timeframe
    week 25
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    18
    18
    Units: score
        median (confidence interval 90%)
    -4.07 (-5.67 to -2.47)
    -2.93 (-4.53 to -1.33)
    Statistical analysis title
    		 Analysis primary objective
    Statistical analysis description
    The changes from baseline in QMG scores at Week 25 were analyzed using a Bayesian model that investigated effects for CFZ533 or placebo and baseline QMG score. The prior of the difference in changes from baseline between CFZ533 and placebo at week 25 was used to obtain the posterior estimates. Bayesian posterior probabilities at Week 25 were ≥ 0 or ≥ 3 points. A difference of 3 points on the mean change in QMG score was deemed clinically meaningful.
    Comparison groups
    Placebo v CFZ533
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 bayesian
    Parameter type
    		 estimate of contrast posterior median
    Point estimate
    -1.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.41
         upper limit
    		 1.14

    Secondary: Mean changes from baseline in the Myasthenia Gravis Composite (MGC) score. Posterior Median was used as measure type.

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    End point title
    		 Mean changes from baseline in the Myasthenia Gravis Composite (MGC) score. Posterior Median was used as measure type.
    End point description
    The MGC score is another key efficacy outcome measure. It is reliable and demonstrates concurrent and longitudinal construct validity in the MG practice care setting (Burns et al 2010). The MGC scale covers 10 important functional domains most frequently involved in patients with MG. The proportion of bulbar and respiratory items reflect the clinical importance of these domains in the disease, and are appropriately weighted. The assessment of each of the 10 test items provides immediate insight into the status of that particular functional domain.
    End point type
    Secondary
    End point timeframe
    From baseline to week 49
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    18
    18
    Units: score
        median (confidence interval 90%)
    -8.00 (-9.83 to -6.16)
    -5.62 (-7.45 to -3.78)
    No statistical analyses for this end point

    Secondary: Proportion of patients with improvement or worsening by ≥ 3 points in the QMG score

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    End point title
    		 Proportion of patients with improvement or worsening by ≥ 3 points in the QMG score
    End point description
    End point type
    Secondary
    End point timeframe
    at week 49
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    18
    19
    Units: participants
        improvement by ≥ 3 points in the QMG score|
    10
    9
        worsening by ≥ 3 points in the QMG score|
    2
    2
    No statistical analyses for this end point

    Secondary: Proportion of patients intolerant to steroid taper

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    End point title
    		 Proportion of patients intolerant to steroid taper
    End point description
    End point type
    Secondary
    End point timeframe
    week 49
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    22 [1]
    22 [2]
    Units: participants
    0
    0
    Notes
    [1] - this data was not collected
    [2] - this data was not collected
    No statistical analyses for this end point

    Secondary: Proportion of patients who discontinued due to inefficacy or worsening

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    End point title
    		 Proportion of patients who discontinued due to inefficacy or worsening
    End point description
    End point type
    Secondary
    End point timeframe
    week 49
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    22
    22
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Mean change from baseline in the Myasthenia Gravis-specific Activities of Daily Living scale (MG-ADL)

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    End point title
    		 Mean change from baseline in the Myasthenia Gravis-specific Activities of Daily Living scale (MG-ADL)
    End point description
    The MG-ADL is an 8-item survey to assess functional performance of daily activities that are sometimes impaired by MG e.g. talking, breathing, swallowing etc. (Muppidi et al 2011). The higher score on MG-ADL scale (0-24 points) indicates worse functional performance of daily activities.
    End point type
    Secondary
    End point timeframe
    week 25
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    19
    18
    Units: score
        arithmetic mean (standard deviation)
    -2.6 ( 2.97 )
    -1.1 ( 3.23 )
    No statistical analyses for this end point

    Secondary: Mean changes from baseline in the QMG score at week 49

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    End point title
    		 Mean changes from baseline in the QMG score at week 49
    End point description
    End point type
    Secondary
    End point timeframe
    week 49
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    18
    19
    Units: change from baseline
        arithmetic mean (standard deviation)
    -2.9 ( 5.16 )
    -2.6 ( 4.30 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline in the Myasthenia Gravis Quality of Life (MG QOL-15)

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    End point title
    		 Mean change from baseline in the Myasthenia Gravis Quality of Life (MG QOL-15)
    End point description
    The MG-QOL15 is a 15-item survey, completed by MG patients and it is designed to assess some aspects of quality of life (QoL) related to MG (Burns et al 2011) e.g. assesment of mood, eating, speaking, driving a car etc.. The higher score on MG-QOL15 scale (0-60 points) indicates worse QoL.
    End point type
    Secondary
    End point timeframe
    week 25
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    19
    19
    Units: score
        arithmetic mean (standard deviation)
    -9.7 ( 11.0 )
    -6.7 ( 10.86 )
    No statistical analyses for this end point

    Secondary: Free CD40 on B cells

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    End point title
    		 Free CD40 on B cells
    End point description
    CD40 receptor occupancy by CFZ533 in peripheral blood was assessed by flow cytometry analysis, measuring free or total CD40 receptors on whole blood B cells. Free CD40 on CD19-positive B cells, using PE-conjugated CFZ533 whose binding was prevented by bound, unconjugated CFZ533 (drug bound to CD40 on peripheral blood B cells). The more CD40 was occupied by unlabeled CFZ533, the less binding of labeled CFZ533, manifest as a lower mean fluorescence intensity (MFI) of CD40 on B cells. MFI from free CD40 on B cells was converted into Molecules of Equivalent Soluble Fluorochrome (MESF) using PE-MESF beads.
    End point type
    Secondary
    End point timeframe
    week 1, week 25
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    22 [3]
    22 [4]
    Units: MESF
    arithmetic mean (standard deviation)
        week 1
    34242.9 ( 18455.80 )
    31025.9 ( 16138.97 )
        week 25
    5259.1 ( 11341.57 )
    24908.3 ( 5022.03 )
    Notes
    [3] - 14 participants at week 1, 8 participants at week 25
    [4] - 17 participants at week 1, 12 participants at week 25
    No statistical analyses for this end point

    Secondary: Total soluble CD40 (sCD40) in plasma

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    End point title
    		 Total soluble CD40 (sCD40) in plasma
    End point description
    End point type
    Secondary
    End point timeframe
    week 1, week 25
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    22 [5]
    22 [6]
    Units: ng/mL
    arithmetic mean (standard deviation)
        week 1
    0.1778 ( 0.13077 )
    0.1577 ( 0.17243 )
        week 25
    191.1278 ( 69.67597 )
    0.1163 ( 0.18298 )
    Notes
    [5] - 21 participants at week 1, 18 participants at week 25
    [6] - 20 participants at week 1, 19 participants at week 25
    No statistical analyses for this end point

    Secondary: plasma CFZ533 concentration at steady state conditions

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    End point title
    		 plasma CFZ533 concentration at steady state conditions
    End point description
    End point type
    Secondary
    End point timeframe
    week 17
    End point values
    		 CFZ533 Placebo
    Number of subjects analysed
    18
    22 [7]
    Units: microg/mL
    arithmetic mean (standard deviation)
        week 17 (steady state)
    120 ( 4.05 )
    0 ( 0 )
    Notes
    [7] - only patients treated with CFZ533, therefore patients treated with placebo were not analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo IV infusion
    Reporting group description
    		 Placebo IV infusion

    Reporting group title
    CFZ533 10 mg/kg IV infusion
    Reporting group description
    		 CFZ533 10 mg/kg IV infusion

    Serious adverse events
    		 Placebo IV infusion CFZ533 10 mg/kg IV infusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
    7 / 22 (31.82%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Brachial plexopathy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radial nerve palsy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo IV infusion CFZ533 10 mg/kg IV infusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 22 (95.45%)
    20 / 22 (90.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    4
    Feeling cold
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Hyperthermia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Infusion site bruising
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Breast pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Laryngeal inflammation
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Sinus disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Nervousness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Panic attack
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Activated partial thromboplastin time shortened
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Free haemoglobin present
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    3
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Procedural headache
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Von Willebrand's disease
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    3
    3
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 22 (18.18%)
         occurrences all number
    5
    7
    Migraine
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Myasthenia gravis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Nerve compression
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Lymphocytosis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Neutropenia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Neutrophilia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dental caries
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Food poisoning
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Gastroduodenitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 22 (13.64%)
         occurrences all number
    3
    6
    Pancreatitis chronic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Arthritis reactive
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    5
    0
    Muscular weakness
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Osteochondrosis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Ear infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Herpes virus infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Laryngitis viral
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 22 (9.09%)
         occurrences all number
    4
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    4
    Respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
         occurrences all number
    4
    5
    Rhinitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Skin candida
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Systemic infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Tooth infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Tracheobronchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 22 (4.55%)
         occurrences all number
    7
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Dyslipidaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2015
    The purpose of this amendment was to incorporate a second screening visit (Visit 2) to allow safety laboratory results to be available prior to randomization at Day 1. Moreover, some inclusion/exclusion criteria were modified, in consultation with the investigators, to simplify recruitment.
    29 Jul 2015
    The purpose of this amendment was to incorporate requests following Health Authority and Ethic Committee review. Suggestions following investigators feedback were also implemented. Given the limited clinical safety data available to date, an independent DMC was instituted to routinely monitor the safety data as requested after Health Authority Review. The manual randomization process was replaced by using a validated Interactive response technology system for patient randomization.
    19 May 2016
    The purpose of this amendment was to make the optional autoantibodies (anti-AChR and anti-MuSK) diagnostic test at screening visit mandatory for all patients as an inclusion criterion to confirm eligibility. This assessment was already foreseen at screening, only in case of absence of AChR or MuSK autoantibodies with a positive medical history of MG. To allow consistency in all patients for AChR or MuSK autoantibodies assessment and a positive diagnosis of MG, the assessment was made mandatory at visit 1.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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