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    Clinical Trial Results:
    A single dose, double-blind, placebo-controlled, parallel study to assess the pharmacodynamics, pharmacokinetics and safety and tolerability of VAY736 in patients with primary Sjögren’s syndrome

    Summary
    EudraCT number
    		 2013-000250-22
    Trial protocol
    		 DE  
    Global end of trial date
    07 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2019
    First version publication date
    08 Feb 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CVAY736X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02149420
    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
    07 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of a single iv dose VAY736 versus placebo on the clinical disease activity of primary Sjögren’s syndrome patients as measured by the change of a modified EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) between Base line and Week 12. To assess the safety and tolerability of a single iv dose VAY736 in patients with primary Sjögren’s syndrome as measured by adverse events (AEs).
    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
    23 May 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: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    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)
    23
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 27 patients were enrolled and randomized into the study at one site in Germany.

    Pre-assignment
    Screening details
    		 The patients were enrolled in 2 sequential cohorts: Cohort 1: Six patients were randomized to receive a single dose iv of VAY736 at a dose of 3mg/kg or placebo at a 2:1 ratio. Cohort 2: Twenty one patients were randomized to receive a single iv dose of VAY736 at a dose of 10.0 mg/kg or 3.0 mg/kg or placebo at a 6:1:3 ratio.

    Period 1
    Period 1 title
    Core Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    This was a double-blind study for the duration of the treatment period (weeks 0-24), following which, treatment was unblinded on an individual patient level to determine their progress in the study (Follow-up, open-label VAY736 or EOS Visit).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single i.v. dose from infusion bag lacking active compound

    Arm title
    		 VAY736 3 mg/kg
    Arm description
    		 single dose iv of VAY736 at a dose of 3mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ianalumab
    Investigational medicinal product code
    VAY736
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single iv dose of 3 mg/kg VAY736 from infusion bag containing the active compound

    Arm title
    		 VAY736 10 mg/kg
    Arm description
    		 single dose iv of VAY736 at a dose of 10mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ianalumab
    Investigational medicinal product code
    VAY736
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single iv dose of 10 mg/kg VAY736 from infusion bag containing the active compound

    Number of subjects in period 1
    		Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Started
    9
    6
    12
    Safety analysis set
    9
    6
    12
    Completed
    9
    5
    10
    Not completed
    0
    1
    2
         Administrative problems
    -
    1
    2
    Period 2
    Period 2 title
    Open Label VAY736 10 mg/kg Extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Placebo - switched to open label VAY736
    Arm description
    		 single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ianalumab
    Investigational medicinal product code
    VAY736
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single iv dose of 10 mg/kg VAY736 from infusion bag containing the active compound

    Number of subjects in period 2 [1]
    		Placebo - switched to open label VAY736
    Started
    5
    Completed
    4
    Not completed
    1
         Administrative problems
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only patients randomized to placebo in Period 1 were eligible to enter.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)

    Reporting group title
    VAY736 3 mg/kg
    Reporting group description
    		 single dose iv of VAY736 at a dose of 3mg/kg

    Reporting group title
    VAY736 10 mg/kg
    Reporting group description
    		 single dose iv of VAY736 at a dose of 10mg/kg

    Reporting group values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg Total
    Number of subjects
    		 9 6 12 27
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 9 6 8 23
        From 65-84 years
    		 0 0 4 4
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 46.7 ( 11.29 ) 46.8 ( 8.75 ) 55.3 ( 13.35 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 7 5 11 23
        Male
    		 2 1 1 4
    Race/Ethnicity, Customized
    Units: Subjects
    Subject analysis sets

    Subject analysis set title
    VAY736 Combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combining VAY736 3mg/kg and VAY736 10mg/kg

    Subject analysis set title
    Open label VAY736
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Open label VAY736 10mg/kg

    Subject analysis sets values
    		 VAY736 Combined Open label VAY736
    Number of subjects
    18
    5
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    14
    5
        From 65-84 years
    4
    0
        85 years and over
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.3 ( 13.35 )
    55.3 ( 13.35 )
    Sex: Female, Male
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)

    Reporting group title
    VAY736 3 mg/kg
    Reporting group description
    		 single dose iv of VAY736 at a dose of 3mg/kg

    Reporting group title
    VAY736 10 mg/kg
    Reporting group description
    		 single dose iv of VAY736 at a dose of 10mg/kg
    Reporting group title
    Placebo - switched to open label VAY736
    Reporting group description
    		 single dose iv of Placebo (+ Option to receive Open label VAY736 10 mg/kg at Week 24)

    Subject analysis set title
    VAY736 Combined
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combining VAY736 3mg/kg and VAY736 10mg/kg

    Subject analysis set title
    Open label VAY736
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Open label VAY736 10mg/kg

    Primary: Change in EULAR Sjögren's syndrome disease activity index (ESSDAI)

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    End point title
    		 Change in EULAR Sjögren's syndrome disease activity index (ESSDAI)
    End point description
    The effect of VAY736 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
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg VAY736 Combined
    Number of subjects analysed
    9
    6
    12
    18
    Units: Points
    arithmetic mean (standard deviation)
        Baseline|
    11.1 ( 4.08 )
    14.5 ( 9.44 )
    11.5 ( 4.38 )
    12.5 ( 6.38 )
        Week 12|
    10.2 ( 5.29 )
    10.7 ( 7.69 )
    10.0 ( 5.36 )
    10.2 ( 6.01 )
        Change from Baseline to Week 12|
    -0.9 ( 2.98 )
    -3.8 ( 8.66 )
    -1.5 ( 3.00 )
    -2.3 ( 5.40 )
    Statistical analysis title
    		 Change in ESSDAI
    Statistical analysis description
    Per protocol the primary analysis was between placebo and the combined VAY736 groups at Week 12.
    Comparison groups
    Placebo v VAY736 Combined
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.678
    Method
    		 repeated measures Bayesian analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.007
         upper limit
    		 3.18
    Variability estimate
    Standard deviation
    Dispersion value
    2.058

    Primary: Overall incidence of Adverse Events

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    End point title
    		 Overall incidence of Adverse Events [1]
    End point description
    Number of subjects with Adverse Events during the double blind treatment period.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were calculated.
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg VAY736 Combined
    Number of subjects analysed
    9
    6
    12
    18
    Units: Participants
        Subjects with AEs|
    8
    6
    11
    17
        Subjects with AEs within 24hr|
    2
    6
    11
    17
        Subjects with AEs post 24hr|
    8
    6
    8
    14
        Subjects with Study drug-related AEs|
    5
    6
    11
    17
        Subjects with Infusion related AEs|
    1
    6
    9
    15
    No statistical analyses for this end point

    Secondary: Change in EULAR Sjögren's Syndrome Patient Response Index (ESSPRI)

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    End point title
    		 Change in EULAR Sjögren's Syndrome Patient Response Index (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. During the study all individual scores were reported as 1 to 10 instead. A linear transformation was reported to map the scores to the range of 0-10.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Number of subjects analysed
    9
    6
    12
    Units: Points
    arithmetic mean (standard deviation)
        Baseline|
    5.967 ( 2.2179 )
    6.049 ( 1.2759 )
    6.235 ( 1.5379 )
        Week 12|
    5.926 ( 1.5822 )
    6.173 ( 1.4753 )
    4.568 ( 2.5966 )
        Change from Baseline to Week 12|
    -0.041 ( 1.7805 )
    0.123 ( 1.0120 )
    -1.667 ( 1.8918 )
    No statistical analyses for this end point

    Secondary: Change in Short Form (36) Health Survey (SF-36)

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    End point title
    		 Change in Short Form (36) Health Survey (SF-36)
    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
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Number of subjects analysed
    9
    6
    12
    Units: Points
    arithmetic mean (standard deviation)
        Physical component score: Baseline|
    46.886 ( 6.3905 )
    39.445 ( 4.2857 )
    46.015 ( 9.3533 )
        Physical component score: Week 12|
    44.788 ( 8.3513 )
    45.493 ( 7.3060 )
    47.671 ( 9.2804 )
        Physical component score: Change from Baseline|
    -2.098 ( 7.9084 )
    6.048 ( 4.7189 )
    1.656 ( 5.4113 )
        Mental component score: Baseline|
    36.913 ( 15.2776 )
    37.517 ( 6.8994 )
    43.628 ( 11.3667 )
        Mental component score: Week 12|
    41.012 ( 13.2991 )
    40.170 ( 11.9815 )
    46.700 ( 11.3182 )
        Mental component score: Change from Baseline|
    4.099 ( 5.3361 )
    2.653 ( 17.1261 )
    3.073 ( 11.5823 )
    No statistical analyses for this end point

    Secondary: Change in Multidimensional Fatigue Inventory (MFI)

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    End point title
    		 Change in Multidimensional Fatigue Inventory (MFI)
    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. A reduction from baseline in MFI indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Number of subjects analysed
    9
    6
    12
    Units: Points
    arithmetic mean (standard deviation)
        General Fatigue: Baseline|
    14.0 ( 4.72 )
    17.0 ( 2.37 )
    15.9 ( 3.34 )
        General Fatigue: Week 12|
    12.8 ( 4.84 )
    14.2 ( 6.40 )
    12.4 ( 3.99 )
        General Fatigue: Change from Baseline|
    -1.2 ( 1.64 )
    -2.8 ( 5.04 )
    -3.5 ( 4.12 )
        Physical Fatigue: Baseline|
    12.9 ( 4.14 )
    15.7 ( 2.34 )
    14.2 ( 3.41 )
        Physical Fatigue: Week 12|
    12.2 ( 3.99 )
    11.2 ( 5.15 )
    10.4 ( 4.66 )
        Physical Fatigue: Change from Baseline|
    -0.7 ( 1.32 )
    -4.5 ( 6.57 )
    -3.8 ( 4.77 )
        Mental Fatigue: Baseline|
    11.9 ( 4.78 )
    14.3 ( 3.78 )
    13.0 ( 3.28 )
        Mental Fatigue: Week 12|
    11.7 ( 4.12 )
    11.3 ( 4.18 )
    9.8 ( 5.17 )
        Mental Fatigue: Change from Baseline|
    -0.2 ( 2.95 )
    -3.0 ( 6.07 )
    -3.2 ( 5.84 )
        Reduced motivation: Baseline|
    12.4 ( 4.93 )
    12.3 ( 3.93 )
    10.9 ( 2.68 )
        Reduced motivation: Week 12|
    12.0 ( 5.32 )
    10.0 ( 4.52 )
    9.8 ( 4.97 )
        Reduced motivation: Change from Baseline|
    -0.4 ( 2.40 )
    -2.3 ( 4.50 )
    -1.1 ( 4.56 )
        Reduced activity: Baseline|
    11.8 ( 2.86 )
    10.8 ( 1.72 )
    12.2 ( 2.69 )
        Reduced activity: Week 12|
    10.4 ( 3.81 )
    8.7 ( 3.61 )
    9.3 ( 5.08 )
        Reduced activity: Change from Baseline|
    -1.3 ( 1.80 )
    -2.2 ( 4.83 )
    -2.9 ( 4.25 )
    No statistical analyses for this end point

    Secondary: Change in the physician's global assessment by means of Visual Analog Scale (VAS)

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    End point title
    		 Change in the physician's global assessment by means of Visual Analog Scale (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
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Number of subjects analysed
    9
    6
    12
    Units: Points
    arithmetic mean (standard deviation)
        Baseline|
    57.3 ( 17.73 )
    66.2 ( 17.53 )
    65.0 ( 11.74 )
        Week 12|
    59.8 ( 23.35 )
    43.0 ( 23.82 )
    48.5 ( 17.33 )
        Change from Baseline to Week 12|
    2.4 ( 12.21 )
    -23.2 ( 31.10 )
    -16.5 ( 18.96 )
    No statistical analyses for this end point

    Secondary: Change in the patient's global assessment by means of Visual Analog Scale (VAS)

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    End point title
    		 Change in the patient's global assessment by means of Visual Analog Scale (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
    Baseline, week 12
    End point values
    		 Placebo VAY736 3 mg/kg VAY736 10 mg/kg
    Number of subjects analysed
    9
    6
    12
    Units: Points
    arithmetic mean (standard deviation)
        Baseline|
    56.2 ( 24.86 )
    67.2 ( 13.69 )
    59.8 ( 24.30 )
        Week 12|
    55.2 ( 21.57 )
    44.2 ( 22.75 )
    40.8 ( 20.49 )
        Change from Baseline to Week 12|
    -1.0 ( 17.71 )
    -23.0 ( 25.73 )
    -19.0 ( 21.08 )
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - AUCinf

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    End point title
    		 VAY736 serum concentration - AUCinf [2]
    End point description
    The area under the serum concentration-time curve from time zero to infinity [mass × time / volume]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.
    Notes
    [2] - 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: day*ug/mL
        median (full range (min-max))
    389 (186 to 457)
    1140 (515 to 1610)
    971 (849 to 1340)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - AUClast

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    End point title
    		 VAY736 serum concentration - AUClast [3]
    End point description
    The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass × time / volume]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.
    Notes
    [3] - 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: day*ug/mL
        median (full range (min-max))
    385 (184 to 457)
    1140 (514 to 1610)
    971 (848 to 1340)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - CL

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    End point title
    		 VAY736 serum concentration - CL [4]
    End point description
    The systemic (or total body) clearance from serum following intravenous administration [volume / time]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: L/day
        median (full range (min-max))
    0.594 (0.427 to 0.844)
    0.584 (0.550 to 1.30)
    0.686 (0.427 to 0.750)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - Cmax

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    End point title
    		 VAY736 serum concentration - Cmax [5]
    End point description
    The observed maximum serum concentration following drug administration [mass / volume]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: ug/mL
        median (full range (min-max))
    65.0 (45.4 to 76.5)
    213 (150 to 283)
    205 (174 to 217)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - T1/2

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    End point title
    		 VAY736 serum concentration - T1/2 [6]
    End point description
    Apparent terminal half-life, determined as the ln2/lambda_z or 0.693/lambda_z. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: days
        median (full range (min-max))
    8.43 (6.99 to 13.8)
    9.51 (5.38 to 15.2)
    11.0 (4.94 to 17.4)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - Tmax

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    End point title
    		 VAY736 serum concentration - Tmax [7]
    End point description
    The time to reach the maximum concentration after drug administration [time]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.
    Notes
    [7] - 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: hours
        median (full range (min-max))
    2.03 (2.00 to 2.20)
    2.03 (2.00 to 2.30)
    2.10 (2.02 to 2.17)
    No statistical analyses for this end point

    Secondary: VAY736 serum concentration - Vz

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    End point title
    		 VAY736 serum concentration - Vz [8]
    End point description
    The volume of distribution during the terminal elimination phase following intravenous administration [volume]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks.
    Notes
    [8] - 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: PK was not assessed for Placebo
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Open label VAY736
    Number of subjects analysed
    6
    12
    5
    Units: Liter
        median (full range (min-max))
    7.83 (6.55 to 10.7)
    8.68 (7.15 to 12.4)
    10.3 (4.93 to 18.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    VAY736 3mg/kg
    Reporting group description
    		 VAY736 3mg/kg

    Reporting group title
    VAY736 10mg/kg
    Reporting group description
    		 VAY736 10mg/kg

    Reporting group title
    Open label VAY736 10mg/kg
    Reporting group description
    		 Open label VAY736 10mg/kg

    Serious adverse events
    		 Placebo VAY736 3mg/kg VAY736 10mg/kg Open label VAY736 10mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst torsion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo VAY736 3mg/kg VAY736 10mg/kg Open label VAY736 10mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    6 / 6 (100.00%)
    11 / 12 (91.67%)
    5 / 5 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 6 (100.00%)
    9 / 12 (75.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    6
    18
    6
    Ligament rupture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
    1 / 5 (20.00%)
         occurrences all number
    4
    3
    4
    2
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Keratitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitreous detachment
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Auriculotemporal syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Noninfective sialoadenitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sjogren's syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    2
    Synovitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    2
    Cystitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 6 (83.33%)
    4 / 12 (33.33%)
    5 / 5 (100.00%)
         occurrences all number
    2
    6
    12
    10
    Oral herpes
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Tooth infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urogenital infection bacterial
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2015
    The purpose of this amendment was to introduce the option of open-label VAY736 single dose treatment to patients that previously received placebo during the study. This change offered each patient the opportunity to receive active VAY736 treatment which has the potential to provide clinical benefits for their condition.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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