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    Clinical Trial Results:
    A Randomised, Phase 2, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Filgotinib, GS-9876 and GS-4059 in Adult Subjects with Active Sjogren’s Syndrome

    Summary
    EudraCT number
    2016-003558-34
    Trial protocol
    GB   ES   PL  
    Global end of trial date
    02 Oct 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Oct 2020
    First version publication date
    04 Jan 2020
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Updated the record to post final results.

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-445-4189
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03100942
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    02 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of filgotinib, lanraplenib, and tirabrutinib in adults with active Sjogren's Syndrome (SjS).
    Protection of trial subjects
    The protocol and consent forms were submitted for each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent forms (if applicable) after initial IEC/IRB approval were submitted on behalf of the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2017
    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
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    Poland: 22
    Worldwide total number of subjects
    152
    EEA total number of subjects
    46
    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)
    130
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in the United States and Europe. The first participant was screened on 01 May 2017. The last study visit occurred on 02 October 2019.

    Pre-assignment
    Screening details
    348 participants were screened.

    Period 1
    Period 1 title
    Randomized Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lanraplenib
    Arm description
    Lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for up to 49.4 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Lanraplenib
    Investigational medicinal product code
    Other name
    GS-9876
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 30 mg tablet administered orally once daily

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Arm title
    Filgotinib
    Arm description
    Filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 50.4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 200 mg tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Arm title
    Tirabrutinib
    Arm description
    Tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 50.3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tirabrutinib
    Investigational medicinal product code
    Other name
    GS-4059
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 40 mg tablet administered orally once daily

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Arm title
    Placebo
    Arm description
    Participants received filgotinib placebo + lanraplenib placebo + tirabrutinib placebo tablets orally once daily for 24 weeks. At Week 24 visit, participants were re-randomized 1:1:1, in a blinded fashion and receive either of the following study drugs through Week 48: • filgotinib + lanraplenib placebo + tirabrutinib placebo • lanraplenib + filgotinib placebo + tirabrutinib placebo • tirabrutinib + filgotinib placebo + lanraplenib placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 200 mg tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib
    Investigational medicinal product code
    Other name
    GS-9876
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 30 mg tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib
    Investigational medicinal product code
    Other name
    GS-4059
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 40 mg tablet administered orally once daily

    Number of subjects in period 1 [1]
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Started
    37
    38
    39
    36
    Completed
    26
    29
    33
    32
    Not completed
    11
    9
    6
    4
         Withdrew Consent
    4
    5
    3
    3
         Protocol Violation
    -
    1
    1
    1
         Investigator`s Discretion
    2
    1
    -
    -
         Adverse Event
    5
    2
    1
    -
         Lost to follow-up
    -
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants who were randomized but did not receive the study drug are not included in the subject disposition table.
    Period 2
    Period 2 title
    Placebo Arm Re-Randomized
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo to Lanraplenib
    Arm description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received lanraplenib (1 × 30 mg tablet) + filgotinib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 25.1 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Lanraplenib
    Investigational medicinal product code
    Other name
    GS-9876
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 30 mg tablet administered orally once daily

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Arm title
    Placebo to Filgotinib
    Arm description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 24.4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 200 mg tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Tirabrutinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Arm title
    Placebo to Tirabrutinib
    Arm description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 24.9 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tirabrutinib
    Investigational medicinal product code
    Other name
    GS-4059
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 40 mg tablet administered orally once daily

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Investigational medicinal product name
    Lanraplenib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet administered orally once daily

    Number of subjects in period 2 [2]
    Placebo to Lanraplenib Placebo to Filgotinib Placebo to Tirabrutinib
    Started
    10
    12
    10
    Completed
    10
    12
    9
    Not completed
    0
    0
    1
         Withdrew Consent
    -
    -
    1
    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: Period 2 (Placebo Arm Re-randomized) includes participants who completed 24 weeks of placebo treatment and were re-randomized to receive lanraplenib or filgotinib or tirabrutinib.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanraplenib
    Reporting group description
    Lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for up to 49.4 weeks

    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 50.4 weeks.

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 50.3 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received filgotinib placebo + lanraplenib placebo + tirabrutinib placebo tablets orally once daily for 24 weeks. At Week 24 visit, participants were re-randomized 1:1:1, in a blinded fashion and receive either of the following study drugs through Week 48: • filgotinib + lanraplenib placebo + tirabrutinib placebo • lanraplenib + filgotinib placebo + tirabrutinib placebo • tirabrutinib + filgotinib placebo + lanraplenib placebo

    Reporting group values
    Lanraplenib Filgotinib Tirabrutinib Placebo Total
    Number of subjects
    37 38 39 36 150
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.2 ± 9.72 52.2 ± 10.54 55.8 ± 10.06 53.2 ± 10.28 -
    Gender categorical
    Units: Subjects
        Female
    36 38 37 35 146
        Male
    1 0 2 1 4
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 1 1
        Asian
    0 1 1 0 2
        Black
    5 5 4 5 19
        White
    31 32 34 30 127
        Other
    1 0 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    6 4 1 6 17
        Not Hispanic or Latino
    31 34 38 30 133
    European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI)
    Overall score (ranged from 0 (best) to 123 (worst activity)) was calculated as sum of all individual weighted domain scores . For additional details on this index, please see Endpoints section.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    10.5 ± 4.89 10.2 ± 6.23 10.4 ± 5.36 9.3 ± 3.96 -
    EULAR Sjogren's syndrome patient reported index (ESSPRI)
    The ESSPRI is a patient-reported questionnaire to assess subjective patient symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain scored on scale of 0-10 (0 =no symptoms at all and 10 = worst symptoms imaginable), and an overall score is calculated as the mean of the three individual domain scores where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    6.6 ± 1.90 6.3 ± 2.31 5.9 ± 2.39 5.9 ± 2.24 -

    End points

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    End points reporting groups
    Reporting group title
    Lanraplenib
    Reporting group description
    Lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for up to 49.4 weeks

    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 50.4 weeks.

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 50.3 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received filgotinib placebo + lanraplenib placebo + tirabrutinib placebo tablets orally once daily for 24 weeks. At Week 24 visit, participants were re-randomized 1:1:1, in a blinded fashion and receive either of the following study drugs through Week 48: • filgotinib + lanraplenib placebo + tirabrutinib placebo • lanraplenib + filgotinib placebo + tirabrutinib placebo • tirabrutinib + filgotinib placebo + lanraplenib placebo
    Reporting group title
    Placebo to Lanraplenib
    Reporting group description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received lanraplenib (1 × 30 mg tablet) + filgotinib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 25.1 weeks.

    Reporting group title
    Placebo to Filgotinib
    Reporting group description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 24.4 weeks.

    Reporting group title
    Placebo to Tirabrutinib
    Reporting group description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 24.9 weeks.

    Primary: Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline

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    End point title
    Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline
    End point description
    Response was defined as: Improvement ≥ 20% in ≥ 3 of 5 participant-reported Sjogren's syndrome (SjS) related visual analogue score (VAS) measures (participant's assessment of global disease, pain, oral dryness, ocular dryness and fatigue), with no increase defined as > 30 mm from baseline (Day 1) in any of the above 5 VAS measures, AND either ≥ 20% improvement in high sensitivity C-reactive protein (hsCRP) (if hsCRP ≥ 1.5 x upper limit of normal [ULN] on Day 1) or no increase in hsCRP to ≥ 1.5 x ULN (if hsCRP < 1.5 x ULN on Day 1). The Full Analysis Set included all randomized participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Number of subjects analysed
    35
    37
    37
    34
    Units: Percentage of participants
        number (confidence interval 95%)
    42.9 (25.0 to 60.7)
    43.2 (25.9 to 60.6)
    35.1 (18.4 to 51.9)
    26.5 (10.2 to 42.8)
    Statistical analysis title
    Lanraplenib vs Placebo
    Statistical analysis description
    For the analysis of the difference in response rates, the data with missing response values were imputed by multiple imputation method with logistic regression.
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1597 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    15.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    37.6
    Notes
    [1] - P-values were obtained from Cochran-Mantel-Haenszel (CMH) test stratified by randomization stratification factors.
    Statistical analysis title
    Filgotinib vs Placebo
    Statistical analysis description
    For the analysis of the difference in response rates, the data with missing response values were imputed by multiple imputation method with logistic regression.
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1694 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    16.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1
         upper limit
    38.3
    Notes
    [2] - P-values were obtained from CMH test stratified by randomization stratification factors.
    Statistical analysis title
    Tirabrutinib vs Placebo
    Statistical analysis description
    For the analysis of the difference in response rates, the data with missing response values were imputed by multiple imputation method with logistic regression.
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3309 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    8.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.2
         upper limit
    29.4
    Notes
    [3] - P-values were obtained from CMH test stratified by randomization stratification factors.

    Secondary: Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12

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    End point title
    Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12
    End point description
    The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Number of subjects analysed
    37
    38
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -2.5 ± 0.76
    -4.7 ± 0.72
    -3.2 ± 0.73
    -3.9 ± 0.76
    Statistical analysis title
    Lanraplenib vs Placebo
    Statistical analysis description
    Least Squares (LS) Means, 95% confidence interval (CI), and P-values were obtained from Mixed Effects Model for Repeated Measures (MMRM) with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2066
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.05
    Statistical analysis title
    Filgotinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3998
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04
    Statistical analysis title
    Tirabrutinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5113
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04

    Secondary: Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12

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    End point title
    Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12
    End point description
    The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Number of subjects analysed
    37
    38
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -1.0 ± 0.34
    -1.4 ± 0.33
    -1.4 ± 0.33
    -1.0 ± 0.34
    Statistical analysis title
    Lanraplenib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9446
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    Filgotinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3977
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    Tirabrutinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4966
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Secondary: Change From Baseline in ESSDAI at Week 24

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    End point title
    Change From Baseline in ESSDAI at Week 24
    End point description
    The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Number of subjects analysed
    37
    38
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -4.3 ± 0.81
    -5.4 ± 0.75
    -4.0 ± 0.75
    -4.2 ± 0.78
    Statistical analysis title
    Lanraplenib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9564
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1
    Statistical analysis title
    Filgotinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2788
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.07
    Statistical analysis title
    Tirabrutinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8047
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06

    Secondary: Change From Baseline in ESSPRI at Week 24

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    End point title
    Change From Baseline in ESSPRI at Week 24
    End point description
    The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    Lanraplenib Filgotinib Tirabrutinib Placebo
    Number of subjects analysed
    37
    38
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -1.1 ± 0.34
    -0.8 ± 0.31
    -1.2 ± 0.31
    -0.9 ± 0.33
    Statistical analysis title
    Lanraplenib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6782
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46
    Statistical analysis title
    Filgotinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9171
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45
    Statistical analysis title
    Tirabrutinib vs Placebo
    Statistical analysis description
    LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4641
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to last dose date (Maximum: 50.4 weeks) plus 30 days
    Adverse event reporting additional description
    The Safety Analysis Set included participants who received at least one dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Lanraplenib
    Reporting group description
    Lanraplenib (1 × 30 mg tablet) + filgotinib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 49.4 weeks.

    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 50.4 weeks.

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 50.3 weeks.

    Reporting group title
    Placebo to Lanraplenib
    Reporting group description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received lanraplenib (1 × 30 mg tablet) + filgotinib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 25.1 weeks.

    Reporting group title
    Placebo to Filgotinib
    Reporting group description
    Participants who received placebo for 24 weeks were re-randomized at the Week 24 visit and received filgotinib (1 × 200 mg tablet) + lanraplenib placebo (1 × tablet) + tirabrutinib placebo (1 × tablet) orally once daily for up to 24.4 weeks.

    Reporting group title
    Placebo to Tirabrutinib
    Reporting group description
    Participants who received placebo for 24 weeks were rerandomized at the Week 24 visit and received tirabrutinib (1 × 40 mg tablet) + filgotinib placebo (1 × tablet) + lanraplenib placebo (1 × tablet) orally once daily for up to 24.9 weeks.

    Reporting group title
    Placebo on Placebo Controlled Period
    Reporting group description
    Participants received filgotinib placebo + lanraplenib placebo + tirabrutinib placebo tablets orally once daily for 24 weeks in placebo controlled period. At Week 24 visit, participants were re-randomized 1:1:1, in a blinded fashion and receive either of the following study drugs through Week 48: • filgotinib + lanraplenib placebo + tirabrutinib placebo • lanraplenib + filgotinib placebo + tirabrutinib placebo • tirabrutinib + filgotinib placebo + lanraplenib placebo

    Serious adverse events
    Lanraplenib Filgotinib Tirabrutinib Placebo to Lanraplenib Placebo to Filgotinib Placebo to Tirabrutinib Placebo on Placebo Controlled Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 38 (13.16%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 36 (5.56%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lanraplenib Filgotinib Tirabrutinib Placebo to Lanraplenib Placebo to Filgotinib Placebo to Tirabrutinib Placebo on Placebo Controlled Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 37 (81.08%)
    31 / 38 (81.58%)
    32 / 39 (82.05%)
    10 / 10 (100.00%)
    10 / 12 (83.33%)
    7 / 10 (70.00%)
    23 / 36 (63.89%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    3
    0
    1
    0
    0
    Vasculitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    2
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
    2 / 10 (20.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    4
    0
    4
    2
    1
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    2
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    2
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    1
    Arthropod bite
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    1
    2
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    1
    1
    0
    0
    0
    0
    Light chain analysis increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    0
    Anaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    Lymphopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    3 / 39 (7.69%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    3
    0
    0
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Allergic sinusitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    3
    4
    1
    1
    1
    1
    Dizziness
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    3
    1
    1
    0
    0
    0
    4
    Migraine
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    0
    Corneal erosion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    3
    3
    3
    1
    2
    0
    1
    Nausea
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 38 (10.53%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    5
    2
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 38 (7.89%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    3
    2
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    Dental caries
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Lip blister
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 38 (5.26%)
    3 / 39 (7.69%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    3
    0
    0
    0
    2
    Alopecia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    2
    0
    1
    0
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 38 (10.53%)
    6 / 39 (15.38%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    4
    4
    7
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    1
    1
    0
    1
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    2
    0
    0
    0
    2
    1
    Back pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 38 (7.89%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    Exostosis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 37 (10.81%)
    6 / 38 (15.79%)
    9 / 39 (23.08%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    4
    7
    11
    0
    1
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 38 (15.79%)
    4 / 39 (10.26%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    4 / 36 (11.11%)
         occurrences all number
    3
    7
    5
    2
    2
    3
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
    4 / 39 (10.26%)
    2 / 10 (20.00%)
    2 / 12 (16.67%)
    0 / 10 (0.00%)
    6 / 36 (16.67%)
         occurrences all number
    1
    2
    4
    3
    3
    0
    6
    Sinusitis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 38 (2.63%)
    5 / 39 (12.82%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    1
    5
    1
    0
    0
    3
    Bronchitis
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 38 (7.89%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    1
    0
    1
    0
    3
    Gastroenteritis viral
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 38 (5.26%)
    3 / 39 (7.69%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    3
    2
    3
    2
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    3
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 38 (7.89%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    3
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    2
    Furuncle
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Herpes zoster
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Conjunctivitis viral
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Vaginal infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2018
    - Protocol Amendment included: 1) Addition of biomarker sample collection at Day 1 and Week 18 visits. 2) Addition of a primary and secondary analysis to be conducted after all participants either complete Week 24 visit or prematurely discontinued from the study. 3) Assembly of an internal unblinded team independent of the blinded study team to closely monitor study progress and drug safety.

    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.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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