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    Clinical Trial Results:
    A randomized, partial-blind, placebo-controlled trial evaluating the efficacy, safety, pharmacokinetics and pharmacodynamics of VAY736 in the treatment of patients with pemphigus vulgaris

    Summary
    EudraCT number
    		 2013-001217-33
    Trial protocol
    		 AT  
    Global end of trial date
    25 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Oct 2020
    First version publication date
    10 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CVAY736X2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01930175
    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
    25 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to compare the efficacy of single i.v. doses of VAY736 relative to placebo in reducing clinical disease activity of pemphigus vulgaris (PV) patients, as determined by the change in Pemphigus Disease Area Index (PDAI) between baseline and 12 weeks
    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
    18 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    13
    EEA total number of subjects
    7
    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)
    11
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 13 participants were enrolled and randomized into the study from Austria (1 center); Bulgaria (1 center); Taiwan (1 center); USA (2 centers).

    Pre-assignment
    Screening details
    		 The study was planned to be conducted in approximately 32 patients. However, after enrolling 13 patients, the recruitment was terminated due to strategic reasons related to the development of the compound.

    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

    Arms
    Are arms mutually exclusive
    Yes

    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
    VAY736
    Investigational medicinal product code
    Other name
    Ianalumab
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose iv of VAY736 at a dose of 3mg/kg

    Arm title
    		 VAY736 10 mg/kg
    Arm description
    		 single dose iv of VAY736 at a dose of 10mg/kg initiated following a safety review of patients receiving VAY736 3 mg/kg or placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    VAY736
    Investigational medicinal product code
    Other name
    Ianalumab
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose iv of VAY736 at a dose of 10mg/kg initiated following a safety review of patients receiving VAY736 3 mg/kg or placebo.

    Arm title
    		 Placebo
    Arm description
    		 single dose iv of Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose iv of Placebo

    Number of subjects in period 1
    		VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Started
    7
    2
    4
    Safety analysis set
    7
    2
    4
    Pharmacokinetics (PK) analysis set
    7
    2
    0 [1]
    Completed
    7
    1
    3
    Not completed
    0
    1
    1
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: patients not analysed for PK
    Period 2
    Period 2 title
    Open Label VAY736 10 mg/kg at Week 24
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Patients randomized to placebo in period 1 received open label VAY736 10mg/kg at week 24.

    Arms
    Arm title
    		 Placebo
    Arm description
    		 single dose iv of Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    VAY736 10 mg/kg
    Investigational medicinal product code
    Other name
    Ianalumab
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose iv of VAY736 at a dose of 10mg/kg at week 24

    Number of subjects in period 2 [2]
    		Placebo
    Started
    3
    Completed
    3
    Notes
    [2] - 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

    Baseline characteristics

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    Baseline characteristics reporting groups
    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 initiated following a safety review of patients receiving VAY736 3 mg/kg or placebo

    Reporting group title
    Placebo
    Reporting group description
    		 single dose iv of Placebo

    Reporting group values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo Total
    Number of subjects
    		 7 2 4 13
    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)
    		 6 2 3 11
        From 65-84 years
    		 1 0 1 2
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.6 ( 10.45 ) 35.0 ( 8.49 ) 56.0 ( 8.83 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 0 2 5
        Male
    		 4 2 2 8
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 2 1 1 4
        Caucasian
    		 4 1 3 8
        Other
    		 1 0 0 1

    End points

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    End points reporting groups
    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 initiated following a safety review of patients receiving VAY736 3 mg/kg or placebo

    Reporting group title
    Placebo
    Reporting group description
    		 single dose iv of Placebo
    Reporting group title
    Placebo
    Reporting group description
    		 single dose iv of Placebo

    Primary: Pemphigus Disease Area Index (PDAI) at week 12

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    End point title
    		 Pemphigus Disease Area Index (PDAI) at week 12 [1]
    End point description
    PDAI is specific cutaneous and mucosal disease activity assessment performed by investigator based on evaluation of lesions in well-defined anatomical locations. The score weighted for the number and size of lesions with score of 0 (absent) to 10 given for skin (12 body locations), scalp and mucous membrane showing disease activity (erosions/blisters or new erythema). Damage, such as post inflammatory hyperpigmentation or erythema from resolving lesion, scored separately from the main score as absent (0) or present (1) for each body area or scalp resulting in a score of 0 to 12 or 0 to 1, respectively. Thus, PDAI ranged from 0 to 263, with 250 points representing disease activity (120 points for skin activity; 10 points for scalp activity; 120 points for mucosal activity) and 13 points representing disease damage. No statistical analysis was performed as the study was terminated.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed as the study was terminated.
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    3
    Units: Score on the scale
        arithmetic mean (standard deviation)
    5.90 ( 1.836 )
    10.15 ( 8.273 )
    22.07 ( 25.628 )
    No statistical analyses for this end point

    Secondary: Autoimmune Skin disease Intensity Score (ABSIS) at baseline and week 12.

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    End point title
    		 Autoimmune Skin disease Intensity Score (ABSIS) at baseline and week 12.
    End point description
    The ABSIS Score is a quality- and quantity-based score for cutaneous and oral mucosal lesions combining the extent of the affected body surface area (BSA), the quality of the skin lesions and oral involvement. The ABSIS score ranged from 0 to 206 with 150 points for skin involvement, 11 points for oral involvement and 45 points for subjective discomfort during eating and drinking. A reduction from baseline (or, a negative change from baseline) in ABSIS indicates improvement in patients.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    4
    Units: Score on the scale
    arithmetic mean (standard deviation)
        Baseline
    13.26 ( 7.621 )
    16.38 ( 12.905 )
    33.75 ( 21.620 )
        Week 12
    2.19 ( 3.465 )
    5.55 ( 7.707 )
    16.17 ( 25.838 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Investigator Global Assessment (IGA) at week 12

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    End point title
    		 Change from baseline in Investigator Global Assessment (IGA) at week 12
    End point description
    The IGA score ranges from 0 to 4 and the decrease or reduction from baseline in IGA score indicates improvement in patients. IGA score scale: 0=Clear, 1=Near Clear, 2=Mild, 3=Moderate, 4=Severe active disease
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    3
    Units: Score on the scale
        arithmetic mean (standard deviation)
    -1.4 ( 0.79 )
    -1.0 ( 0.00 )
    -0.7 ( 0.58 )
    No statistical analyses for this end point

    Secondary: VAY736 Serum Concentration - AUCinf

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    End point title
    		 VAY736 Serum Concentration - AUCinf
    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
    predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    0 [2]
    Units: day*ug/mL
        arithmetic mean (standard deviation)
    440 ( 114 )
    1480 ( 231 )
    ( )
    Notes
    [2] - PK not analyzed for placebo arm
    No statistical analyses for this end point

    Secondary: VAY736 Serum Concentration - AUClast

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    End point title
    		 VAY736 Serum Concentration - AUClast
    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
    predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    0 [3]
    Units: day*ug/mL
        arithmetic mean (standard deviation)
    440 ( 114 )
    1480 ( 231 )
    ( )
    Notes
    [3] - PK not analyzed for placebo arm
    No statistical analyses for this end point

    Secondary: VAY736 Serum Concentration - Cmax

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    End point title
    		 VAY736 Serum Concentration - Cmax
    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
    predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    0 [4]
    Units: ug/mL
        arithmetic mean (standard deviation)
    77.1 ( 13.0 )
    230 ( 2.83 )
    ( )
    Notes
    [4] - PK not analyzed for placebo arm
    No statistical analyses for this end point

    Secondary: VAY736 Serum Concentration - Tmax

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    End point title
    		 VAY736 Serum Concentration - Tmax
    End point description
    Tmax is 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
    predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    0 [5]
    Units: Hours
        median (full range (min-max))
    2.05 (2.00 to 2.22)
    2.11 (2.00 to 2.22)
    ( to )
    Notes
    [5] - PK not analyzed for placebo arm
    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
    End point description
    T1/2 is the terminal elimination half-life [time]. The concentration of VAY736 was measured in the serum.
    End point type
    Secondary
    End point timeframe
    predose, 2, 24 hours and weeks 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks
    End point values
    		 VAY736 3 mg/kg VAY736 10 mg/kg Placebo
    Number of subjects analysed
    7
    2
    0 [6]
    Units: Days
        arithmetic mean (standard deviation)
    11.2 ( 2.01 )
    15.4 ( 1.93 )
    ( )
    Notes
    [6] - PK not analyzed for placebo arm
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study for up to 5 years.
    Adverse event reporting additional description
    Any sign or symptom until end of study for up to 5 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    VAY736 3 mg/kg
    Reporting group description
    		 VAY736 3 mg/kg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Open label VAY736 10 mg/kg
    Reporting group description
    		 Patients randomized to placebo in period 1 received open label VAY736 10mg/kg at week 24

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

    Serious adverse events
    		 VAY736 3 mg/kg Placebo Open label VAY736 10 mg/kg VAY736 10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (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
    Skin and subcutaneous tissue disorders
    Pemphigus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 VAY736 3 mg/kg Placebo Open label VAY736 10 mg/kg VAY736 10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    3 / 4 (75.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
         occurrences all number
    3
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    1
    2
    Sciatica
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    2
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingival recession
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mechanical urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatophytosis of nail
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Herpes simplex
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2014
    This protocol was amended to address comments received from review by country Health Authorities and Ethics Committees. The amendment clarified the randomization range and the use of standard of care (SoC) medication. Wording was added to clarify the purpose of the Safety Data Review Committee. Minor protocol text inconsistencies were corrected.
    13 Sep 2016
    The protocol was amended to implement a change in the safety follow up strategy in order to lower patient burden by reducing the frequency of safety follow-up visits and the assessments during these visits whilst still ensuring appropriate safety-follow-up of the patients. The follow-up visit frequency was reduced from once every 12 weeks to once every 24 weeks after one year (week 52) of follow-up and after 2 years (week 100) reduced from once every 12 weeks to once every 48 weeks.
    04 Nov 2016
    The purpose of this amendment was to include measurement of immunoglobulin (Ig) and immunoglobulin subsets in the safety follow-up. It was reported that in a few patients who experienced a severe infection after chronic rituximab treatment (a drug that has similar mode of action than VAY736), early reductions in IgG levels in association with concomitant treatment with high dose glucocorticoids were factors associated with late onset severe infections. Although the patients in this study have received only a single dose of VAY736, monitoring of total immunoglobulin and immunoglobulin subsets levels may provide additional information on safety of patients following VAY736 treatment. At this stage, all patients, the Investigator and Novartis have been open label, as all have completed the double blind Week 24 treatment period.
    09 Apr 2019
    The protocol was amended to allow for study termination 2 years after last VAY736 dose. Based on the review of the most recent data from the current study as well as from other VAY736 treated patients enrolled in other clinical studies (261 treated with VAY736), it was not considered necessary to continue for the present study a follow-up of the patients beyond 2 years.

    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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