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    Clinical Trial Results:
    A multi-center, randomized, double-blind, placebocontrolled, parallel group study to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of CFZ533 in patients with primary Sjögren’s syndrome

    Summary
    EudraCT number
    		 2013-004808-19
    Trial protocol
    		 GB   HU   DE  
    Global end of trial date
    29 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2019
    First version publication date
    14 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCFZ533X2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02291029
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    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
    29 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of multiple i.v. infusions of iscalimab in patients with pSS as measured by adverse events (AEs). To compare the effect of multiple i.v. infusions of iscalimab versus placebo on the clinical disease activity of pSS patients as measured by the change of the European league Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) after 12 weeks treatment.
    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
    22 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    69
    EEA total number of subjects
    50
    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)
    57
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 69 patients were enrolled in Germany (1 center), Hungary (1 center), Switzerland (1 center), United Kingdom (3 centers), United States (3 centers)

    Pre-assignment
    Screening details
    		 For each patient, there was a screening period from Day -28 to Day -2, followed by baseline evaluations at Day -1.

    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, Data analyst
    Blinding implementation details
    Cohorts 1 and 2 were double-blind. Cohort 3 was open-label. However, subjects and investigator staff remained blinded to the study treatment allocation (dosing arm) until first dosing.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 CFZ533
    Arm description
    		 CFZ533 3 mg/kg s.c.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 s.c. injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    multiple doses of CFZ533 s.c. injection

    Arm title
    		 Cohort 1 Placebo
    Arm description
    		 Placebo s.c./CFZ533 3 mg/kg s.c.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo s.c. injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    multiple doses of Placebo s.c. injection

    Arm title
    		 Cohort 2 CFZ533
    Arm description
    		 CFZ533 10 mg/kg i.v.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 intravenous infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    multiple doses of CFZ533 intravenous infusion

    Arm title
    		 Cohort 2 Placebo
    Arm description
    		 Placebo i.v./CFZ533 10 mg/kg i.v.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo intravenous infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    multiple doses of Placebo intravenous infusion

    Arm title
    		 Cohort 3 CFZ533 Arm 1
    Arm description
    		 CFZ533 600 mg s.c./CFZ533 300 mg s.c.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 s.c. injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    multiple doses of CFZ533 s.c. injection

    Arm title
    		 Cohort 3 CFZ533 Arm 2
    Arm description
    		 CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CFZ533 s.c. injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    multiple doses of CFZ533 s.c. injection

    Investigational medicinal product name
    CFZ533 intravenous infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    multiple doses of CFZ533 intravenous infusion

    Number of subjects in period 1
    		Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2
    Started
    8
    4
    21
    11
    13
    12
    Completed
    8
    3
    20
    11
    13
    12
    Not completed
    0
    1
    1
    0
    0
    0
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 CFZ533
    Reporting group description
    		 CFZ533 3 mg/kg s.c.

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Placebo s.c./CFZ533 3 mg/kg s.c.

    Reporting group title
    Cohort 2 CFZ533
    Reporting group description
    		 CFZ533 10 mg/kg i.v.

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Placebo i.v./CFZ533 10 mg/kg i.v.

    Reporting group title
    Cohort 3 CFZ533 Arm 1
    Reporting group description
    		 CFZ533 600 mg s.c./CFZ533 300 mg s.c.

    Reporting group title
    Cohort 3 CFZ533 Arm 2
    Reporting group description
    		 CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.

    Reporting group values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2 Total
    Number of subjects
    		 8 4 21 11 13 12 69
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 6 4 18 9 10 10 57
        From 65-84 years
    		 2 0 3 2 3 2 12
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 56.4 (34 to 72) 48.8 (45 to 52) 51.7 (24 to 72) 50.6 (25 to 69) 52.3 (23 to 74) 54.8 (23 to 68) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 8 4 19 11 12 10 64
        Male
    		 0 0 2 0 1 2 5
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 7 4 18 10 12 10 61
        Asian
    		 1 0 2 1 1 2 7
        Black
    		 0 0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 CFZ533
    Reporting group description
    		 CFZ533 3 mg/kg s.c.

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Placebo s.c./CFZ533 3 mg/kg s.c.

    Reporting group title
    Cohort 2 CFZ533
    Reporting group description
    		 CFZ533 10 mg/kg i.v.

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Placebo i.v./CFZ533 10 mg/kg i.v.

    Reporting group title
    Cohort 3 CFZ533 Arm 1
    Reporting group description
    		 CFZ533 600 mg s.c./CFZ533 300 mg s.c.

    Reporting group title
    Cohort 3 CFZ533 Arm 2
    Reporting group description
    		 CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.

    Primary: Change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)

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    End point title
    		 Change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)
    End point description
    The effect of CFZ533 on clinical disease activity was measured by the change in ESSDAI (EULAR Sjögren's syndrome disease activity index) between baseline and week 12. The instrument contains 12 organ-specific domains contributing to disease activity. For each domain, features of disease activity are scored in 3 or 4 levels according to their severity. These scores are then summed across the 12 domains in a weighted manner to provide the total score (range 0-123). A reduction from baseline indicates improvement in patients.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2
    Number of subjects analysed
    8
    4
    21
    11
    13
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    12.0 ( 3.78 )
    11.8 ( 3.86 )
    10.6 ( 4.44 )
    11.0 ( 5.16 )
    12.7 ( 6.06 )
    10.4 ( 5.87 )
        Week 12
    9.6 ( 5.45 )
    9.8 ( 3.30 )
    4.2 ( 4.25 )
    9.7 ( 9.05 )
    7.2 ( 6.69 )
    2.8 ( 2.48 )
        Chage from Baseline to Week 12
    -2.4 ( 2.77 )
    -2.0 ( 2.45 )
    -6.4 ( 4.00 )
    -1.3 ( 8.06 )
    -5.5 ( 5.49 )
    -7.6 ( 7.14 )
    Statistical analysis title
    		 Change from baseline in ESSDAI
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.397 [1]
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 2.89
    Notes
    [1] - One-sided p-value
    Statistical analysis title
    		 Change from baseline in ESSDAI
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.009 [2]
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.46
         upper limit
    		 -0.96
    Notes
    [2] - One-sided p-value
    Statistical analysis title
    		 Change from baseline in ESSDAI
    Comparison groups
    Cohort 3 CFZ533 Arm 1 v Cohort 3 CFZ533 Arm 2
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.344 [3]
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 7.45
    Notes
    [3] - two-sided p-value

    Secondary: Change from baseline in EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI)

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    End point title
    		 Change from baseline in EULAR Sjögren’s Syndrome Patient Reported Intensity (ESSPRI)
    End point description
    The ESSPRI is a patient self-reported outcome measure to assess dryness, limb pain, fatigue and mental fatigue, where each of the domains normally reported as 0 (not at all) to 10 (extremely severe). The final ESSPRI score is the average of three: dryness, pain and fatigue. A reduction from baseline indicates the improvement of symptoms.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2
    Number of subjects analysed
    8
    4
    21
    11
    13
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    6.75 ( 1.909 )
    7.00 ( 1.826 )
    6.71 ( 1.678 )
    7.18 ( 1.486 )
    7.00 ( 1.604 )
    6.00 ( 2.344 )
        Week 12
    5.71 ( 1.240 )
    7.08 ( 2.251 )
    5.03 ( 2.413 )
    6.24 ( 2.039 )
    5.33 ( 2.269 )
    4.83 ( 2.552 )
        Change from Baseline to Week 12
    -1.04 ( 1.201 )
    0.08 ( 0.631 )
    -1.68 ( 1.954 )
    -0.94 ( 1.246 )
    -1.67 ( 1.841 )
    -1.17 ( 2.333 )
    Statistical analysis title
    		 Change from baseline in ESSPRI
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.205
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 0.8
    Statistical analysis title
    		 Change from baseline in ESSPRI
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.188
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.41
         upper limit
    		 0.5
    Statistical analysis title
    		 Change from baseline in ESSPRI
    Comparison groups
    Cohort 3 CFZ533 Arm 1 v Cohort 3 CFZ533 Arm 2
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.663
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 1.35

    Secondary: Change from baseline in Physician global assessment of the patient’s overall disease activity (VAS)

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    End point title
    		 Change from baseline in Physician global assessment of the patient’s overall disease activity (VAS)
    End point description
    The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2
    Number of subjects analysed
    8
    4
    21
    11
    13
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    57.9 ( 15.72 )
    57.8 ( 17.19 )
    51.9 ( 12.62 )
    47.9 ( 19.18 )
    50.4 ( 12.39 )
    47.1 ( 18.34 )
        Week 12
    40.5 ( 16.42 )
    55.5 ( 12.01 )
    22.8 ( 11.78 )
    34.2 ( 13.90 )
    25.4 ( 16.65 )
    27.3 ( 16.74 )
        Change from Baseline to Week 12
    -17.6 ( 24.60 )
    -2.3 ( 10.90 )
    -28.7 ( 16.02 )
    -13.7 ( 22.97 )
    -25.0 ( 15.30 )
    -19.8 ( 21.96 )
    Statistical analysis title
    		 Change from baseline in VAS
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.161
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.9
         upper limit
    		 7.38
    Statistical analysis title
    		 Change from baseline in VAS
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.017
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.94
         upper limit
    		 -2.38

    Secondary: Change from baseline in Patient’s global assessment of their disease activity (VAS)

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    End point title
    		 Change from baseline in Patient’s global assessment of their disease activity (VAS)
    End point description
    The visual analogue scale used is a 100 mm VAS ranging from "no disease" (0 mm) to "maximal disease activity" (100 mm).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo Cohort 3 CFZ533 Arm 1 Cohort 3 CFZ533 Arm 2
    Number of subjects analysed
    8
    4
    21
    11
    13
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    47.13 ( 32.406 )
    73.00 ( 12.623 )
    58.43 ( 19.881 )
    54.91 ( 21.002 )
    63.69 ( 25.799 )
    52.08 ( 22.138 )
        Week 12
    49.06 ( 24.519 )
    75.50 ( 24.393 )
    34.85 ( 24.564 )
    42.27 ( 24.483 )
    38.46 ( 26.965 )
    53.17 ( 25.305 )
        Change from Baseline to Week 12
    1.94 ( 26.023 )
    2.50 ( 17.861 )
    -23.05 ( 26.920 )
    -12.64 ( 26.871 )
    -25.23 ( 29.833 )
    1.08 ( 23.283 )
    Statistical analysis title
    		 Change from baseline in VAS
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.456
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.2
         upper limit
    		 17.3
    Statistical analysis title
    		 Change from baseline in VAS
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.376
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.67
         upper limit
    		 10.39

    Secondary: Change from baseline in Short Form (36) Health Survey (SF-36) Physical component score

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    End point title
    		 Change from baseline in Short Form (36) Health Survey (SF-36) Physical component score [4]
    End point description
    The SF-36 is a 36-item, patient self-reported outcome measure (questionnaires) of patient health. The outcome of the questionnaires in eight scales results in two summary scores, physical component and mental component, both ranging from 0 - 100. An increase from baseline in either component summary score indicates reduced disease burden.
    End point type
    Secondary
    End point timeframe
    12 weeks
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Anylysis not conducted for all arms.
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo
    Number of subjects analysed
    8
    4
    21
    11
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    42.218 ( 6.9437 )
    31.215 ( 12.5562 )
    38.163 ( 8.5905 )
    38.819 ( 5.9689 )
        Week 12
    40.374 ( 9.2230 )
    36.123 ( 13.0002 )
    44.001 ( 9.3943 )
    40.298 ( 8.9392 )
        Change from Baseline to Week 12
    -1.005 ( 4.5380 )
    4.908 ( 4.2349 )
    5.546 ( 7.1760 )
    1.479 ( 8.2497 )
    Statistical analysis title
    		 Change from baseline in SF-36
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.172
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.91
         upper limit
    		 2.91
    Statistical analysis title
    		 Change from baseline in SF-36
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.175
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 9.48

    Secondary: Change from baseline in Short Form (36) Health Survey (SF-36) Mental component score

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    End point title
    		 Change from baseline in Short Form (36) Health Survey (SF-36) Mental component score [5]
    End point description
    The SF-36 is a 36-item, patient self-reported outcome measure (questionnaires) of patient health. The outcome of the questionnaires in eight scales results in two summary scores, physical component and mental component, both ranging from 0 - 100. An increase from baseline in either component summary score indicates reduced disease burden.
    End point type
    Secondary
    End point timeframe
    12 weeks
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Anylysis not conducted for all arms.
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo
    Number of subjects analysed
    8
    4
    21
    11
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    46.838 ( 7.8986 )
    43.118 ( 16.3701 )
    37.071 ( 12.2914 )
    39.512 ( 15.4212 )
        Week 12
    48.076 ( 12.5197 )
    43.660 ( 13.9997 )
    44.688 ( 10.2469 )
    43.785 ( 13.2982 )
        Change from Baseline to Week 12
    0.373 ( 6.3174 )
    0.543 ( 4.0309 )
    8.212 ( 11.1378 )
    4.273 ( 10.7671 )
    Statistical analysis title
    		 Change from baseline in SF-36
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.986
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.49
         upper limit
    		 8.35
    Statistical analysis title
    		 Change from baseline in SF-36
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.175
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 9.48

    Secondary: Change from baseline in Multidimensional Fatigue Inventory (MFI)

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    End point title
    		 Change from baseline in Multidimensional Fatigue Inventory (MFI) [6]
    End point description
    The MFI is a patient self-reported outcome measure (questionnaires) to assess fatigue covering the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Each dimension has a posible range from 4-20. The reported total score has a range from 20-100. A reduction from baseline in MFI indicates improvement.
    End point type
    Secondary
    End point timeframe
    12 weeks
    Notes
    [6] - 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: Anylysis not conducted for all arms.
    End point values
    		 Cohort 1 CFZ533 Cohort 1 Placebo Cohort 2 CFZ533 Cohort 2 Placebo
    Number of subjects analysed
    8
    4
    21
    11
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    54.1 ( 16.23 )
    78.0 ( 17.80 )
    70.0 ( 17.51 )
    66.2 ( 17.59 )
        Week 12
    53.5 ( 13.96 )
    69.8 ( 17.75 )
    55.2 ( 16.65 )
    63.3 ( 16.99 )
        Change from Baseline to Week 12
    -0.6 ( 8.12 )
    -8.3 ( 8.18 )
    -14.5 ( 18.09 )
    -2.9 ( 12.37 )
    Statistical analysis title
    		 Change from baseline in MFI
    Comparison groups
    Cohort 1 CFZ533 v Cohort 1 Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.807
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.48
         upper limit
    		 13.15
    Statistical analysis title
    		 Change from baseline in MFI
    Comparison groups
    Cohort 2 CFZ533 v Cohort 2 Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.074
    Method
    		 Repeated measures model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.66
         upper limit
    		 1.01

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Cohort 1 and 2: 255 days (30 days post study completion) Cohort 3: 171 days (30 days post study completion)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    CFZ533 3 mg/kg s.c.
    Reporting group description
    		 CFZ533 3 mg/kg s.c.

    Reporting group title
    Placebo s.c./CFZ533 3 mg/kg s.c.
    Reporting group description
    		 Placebo s.c./CFZ533 3 mg/kg s.c.

    Reporting group title
    CFZ533 10 mg/kg i.v.
    Reporting group description
    		 CFZ533 10 mg/kg i.v.

    Reporting group title
    Placebo i.v./CFZ533 10 mg/kg i.v.
    Reporting group description
    		 Placebo i.v./CFZ533 10 mg/kg i.v.

    Reporting group title
    CFZ533 600 mg s.c./CFZ533 300 mg s.c.
    Reporting group description
    		 CFZ533 600 mg s.c./CFZ533 300 mg s.c.

    Reporting group title
    CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.
    Reporting group description
    		 CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.

    Serious adverse events
    		 CFZ533 3 mg/kg s.c. Placebo s.c./CFZ533 3 mg/kg s.c. CFZ533 10 mg/kg i.v. Placebo i.v./CFZ533 10 mg/kg i.v. CFZ533 600 mg s.c./CFZ533 300 mg s.c. CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 CFZ533 3 mg/kg s.c. Placebo s.c./CFZ533 3 mg/kg s.c. CFZ533 10 mg/kg i.v. Placebo i.v./CFZ533 10 mg/kg i.v. CFZ533 600 mg s.c./CFZ533 300 mg s.c. CFZ533 10 mg/kg i.v./CFZ533 300 mg s.c.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    4 / 4 (100.00%)
    11 / 21 (52.38%)
    7 / 11 (63.64%)
    12 / 13 (92.31%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal wall neoplasm
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Injection site bruising
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Injection site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Injection site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nodule
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Breast cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Endometrial disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Polymenorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Uterine pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Uterine prolapse
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Allergic sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Dry throat
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Hyperventilation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Rhinalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Body temperature increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Red blood cells urine positive
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    Corneal abrasion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Epicondylitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    Incision site hypoaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Post procedural swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Procedural dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Procedural nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tendon injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    2 / 13 (15.38%)
    4 / 12 (33.33%)
         occurrences all number
    0
    1
    3
    2
    3
    5
    Hemianopia homonymous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Increased tendency to bruise
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Deafness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cataract
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    2
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tongue ulceration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Onychoclasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    1
    2
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rosacea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Swelling face
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    1
    0
    1
    0
    2
    Arthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sjogren's syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Infections and infestations
    Angular cheilitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bacterial infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Body tinea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Candida infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    3
    0
    Conjunctivitis viral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    Lymph gland infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nail bed infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    2 / 11 (18.18%)
    1 / 13 (7.69%)
    4 / 12 (33.33%)
         occurrences all number
    0
    0
    0
    2
    1
    4
    Oral herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Otitis media
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 4 (50.00%)
    2 / 21 (9.52%)
    2 / 11 (18.18%)
    4 / 13 (30.77%)
    2 / 12 (16.67%)
         occurrences all number
    3
    2
    2
    4
    5
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    Urogenital infection bacterial
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 4 (25.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 4 (0.00%)
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2014
    This amended protocol was developed to incorporate the changes requested by UK Health Authority Medicines and Healthcare Products Regulatory Agency (MHRA).
    09 Feb 2015
    This protocol amendment was primarily written to update the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) table based on a published correction where the neurological domain scoring was updated.
    05 Mar 2015
    This protocol amendment was developed to provide clarification of the inclusion criterion of stimulated salivary flow to include only patients who have detectable saliva upon stimulation and assessment schedule aligned with complement ESSDAI assessments requirements.
    06 Aug 2015
    This protocol amendment was developed to change the dosing regimen of iscalimab. Furthermore, changes in the permitted concomitant medications were made 1) to clarify the use of medications that may potentially cause sicca symptoms and 2) to allow azathioprine in a stable dose.
    24 Feb 2016
    The protocol was amended to reflect the use of the new 6 mL ACD-B tubes. This change lead to an increase of the total blood taken from approximately 606 mL to 669 mL for the entire study over 36 weeks.
    31 Jan 2017
    This amendment was developed to include an additional cohort of pSS patients (Cohort 3) to explore whether either an i.v. loading dose or an s.c. loading dose, both followed by a s.c. maintenance dose, would be adequate to overcome target mediated disposition and to deliver steady state plasma concentrations similar to the i.v. Cohort 2.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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