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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
    v1(current)
    This version publication date
    04 Jan 2020
    First version publication date
    04 Jan 2020
    Other versions

    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
    Interim
    Date of interim/final analysis
    10 Jan 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
    United States: 106
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 9
    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 Oct 2019.

    Pre-assignment
    Screening details
    347 participants were screened. Data submitted represent interim analysis performed on data collected by the participants through Week 24. Complete data will be submitted in October 2020.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Filgotinib
    Arm description
    Filgotinib (1 x 200 mg) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 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 for 48 weeks

    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 x tablet administered orally once daily for 48 weeks

    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 x tablet administered orally once daily for 48 weeks

    Arm title
    Lanraplenib
    Arm description
    Lanraplenib (1 x 30 mg) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 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 for 48 weeks

    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 x tablet administered orally once daily for 48 weeks

    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 x tablet administered orally once daily for 48 weeks

    Arm title
    Tirabrutinib
    Arm description
    Tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) orally once daily for 48 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 for 48 weeks

    Investigational medicinal product name
    Filgotinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x tablet administered orally once daily for 48 weeks

    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 x tablet administered orally once daily for 48 weeks

    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 rerandomised 1:1:1, in a blinded fashion and received either of the three experimental study drugs orally once daily through Week 48: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)
    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 x tablet administered orally once daily for 24 weeks. At Week 24 visit, 1 x tablet administered orally once daily through Week 48 in either of the following experimental arms: • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)

    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 x tablet administered orally once daily for 24 weeks. At Week 24 visit, 1 x tablet administered orally once daily through Week 48 in either of the following experimental arms: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)

    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 x tablet administered orally once daily for 24 weeks. At Week 24 visit, 1 x tablet administered orally once daily through Week 48 in either of the following experimental arms: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet)

    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 once daily from Week 24 through Week 48

    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
    1x 30 mg tablet administered orally once daily from Week 24 through Week 48

    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 from Week 24 through Week 48

    Number of subjects in period 1 [1]
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Started
    38
    37
    39
    36
    Completed up to Week 24
    35
    30
    37
    32
    Completed
    9
    11
    13
    14
    Not completed
    29
    26
    26
    22
         Still on the Study
    22
    15
    23
    17
         Withdrew Consent
    4
    4
    2
    4
         Investigator's Discretion
    1
    1
    -
    -
         Protocol Violation
    1
    -
    -
    1
         Adverse Event
    1
    6
    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: 2 participants (Lanraplenib arm: N = 1; Placebo arm: N= 1) were randomised but did not receive a single dose of study drug and therefore are not included in the subject disposition or any further analysis. Comment regarding the number in the placebo arm for 'Completed up to week 24': 32 participants in the placebo group were rerandomized at Week 24.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 x 200 mg) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 weeks

    Reporting group title
    Lanraplenib
    Reporting group description
    Lanraplenib (1 x 30 mg) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 weeks

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) orally once daily for 48 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 rerandomised 1:1:1, in a blinded fashion and received either of the three experimental study drugs orally once daily through Week 48: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)

    Reporting group values
    Filgotinib Lanraplenib Tirabrutinib Placebo Total
    Number of subjects
    38 37 39 36 150
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.2 ± 10.54 56.2 ± 9.72 55.8 ± 10.06 53.2 ± 10.28 -
    Gender categorical
    Units: Subjects
        Female
    38 36 37 35 146
        Male
    0 1 2 1 4
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 1 1
        Asian
    1 0 1 0 2
        Black
    5 5 4 5 19
        White
    32 31 34 30 127
        Other
    0 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    4 6 1 6 17
        Not Hispanic or Latino
    34 31 38 29 132
        Not Permitted
    0 0 0 1 1
    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)
    10.2 ± 6.23 10.5 ± 4.89 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 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.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    6.3 ± 2.31 6.6 ± 1.90 5.9 ± 2.39 5.9 ± 2.24 -

    End points

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    End points reporting groups
    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 x 200 mg) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 weeks

    Reporting group title
    Lanraplenib
    Reporting group description
    Lanraplenib (1 x 30 mg) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 weeks

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) orally once daily for 48 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 rerandomised 1:1:1, in a blinded fashion and received either of the three experimental study drugs orally once daily through Week 48: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)

    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 ULN on Day 1) or no increase in hsCRP to ≥ 1.5 x ULN (if hsCRP < 1.5 x ULN on Day 1). Missing data were imputed using multiple imputations with logistic regression. The Full Analysis Set included all randomised participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Number of subjects analysed
    38
    37
    39
    36
    Units: Percentage of participants
        number (confidence interval 95%)
    43.0 (27.1 to 59.0)
    42.3 (25.9 to 58.7)
    34.7 (19.6 to 49.9)
    26.4 (11.5 to 41.3)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Filgotinib v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2082
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lanraplenib v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1373
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Tirabrutinib v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3732
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    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 patient'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 (best) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Number of subjects analysed
    38
    37
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -4.7 ± 0.73
    -2.6 ± 0.76
    -3.2 ± 0.73
    -3.8 ± 0.76
    No statistical analyses for this end point

    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 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 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. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    End point values
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Number of subjects analysed
    38
    37
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -1.4 ± 0.33
    -1.0 ± 0.34
    -1.3 ± 0.33
    -1.0 ± 0.35
    No statistical analyses for this end point

    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 patient'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. An overall score is then calculated as the sum of all individual weighted domain scores. Overall score (ranges from 0 (best) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Number of subjects analysed
    38
    37
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -5.4 ± 0.75
    -4.3 ± 0.81
    -4.0 ± 0.75
    -4.2 ± 0.79
    No statistical analyses for this end point

    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 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 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. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Number of subjects analysed
    38
    37
    39
    36
    Units: Score on a scale
        least squares mean (standard error)
    -0.8 ± 0.31
    -1.1 ± 0.35
    -1.2 ± 0.31
    -0.8 ± 0.33
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to Week 24
    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
    21.1
    Reporting groups
    Reporting group title
    Filgotinib
    Reporting group description
    Filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for 48 weeks

    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 48 weeks

    Reporting group title
    Tirabrutinib
    Reporting group description
    Tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) orally once daily for 48 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 rerandomised 1:1:1, in a blinded fashion and received either of the three experimental study drugs orally once daily through Week 48: • filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) • tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet)

    Serious adverse events
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 37 (8.11%)
    1 / 39 (2.56%)
    2 / 36 (5.56%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 39 (0.00%)
    0 / 36 (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
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (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
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 39 (0.00%)
    0 / 36 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 39 (2.56%)
    0 / 36 (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
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Filgotinib Lanraplenib Tirabrutinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 38 (60.53%)
    16 / 37 (43.24%)
    22 / 39 (56.41%)
    21 / 36 (58.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 39 (2.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    2 / 39 (5.13%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 37 (10.81%)
    1 / 39 (2.56%)
    0 / 36 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 37 (10.81%)
    1 / 39 (2.56%)
    0 / 36 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 39 (5.13%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 37 (5.41%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    1 / 39 (2.56%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    1
    4
    Headache
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    2 / 39 (5.13%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    3
    1
    Sciatica
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    2 / 39 (5.13%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    3
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    2 / 39 (5.13%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 37 (8.11%)
    0 / 39 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    3
    0
    1
    Nausea
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    1 / 39 (2.56%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 37 (5.41%)
    3 / 39 (7.69%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    3
    2
    Alopecia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    2 / 39 (5.13%)
    2 / 36 (5.56%)
         occurrences all number
    2
    0
    2
    2
    Pruritus generalised
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 37 (5.41%)
    4 / 39 (10.26%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Muscle spasms
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 39 (2.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 37 (5.41%)
    4 / 39 (10.26%)
    4 / 36 (11.11%)
         occurrences all number
    7
    2
    4
    5
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 37 (5.41%)
    4 / 39 (10.26%)
    4 / 36 (11.11%)
         occurrences all number
    4
    2
    5
    5
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 39 (2.56%)
    6 / 36 (16.67%)
         occurrences all number
    0
    0
    1
    6
    Bronchitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    1 / 39 (2.56%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    1
    3
    Gastroenteritis viral
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    3 / 39 (7.69%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Sinusitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    1 / 39 (2.56%)
    3 / 36 (8.33%)
         occurrences all number
    0
    2
    1
    3
    Pharyngitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    2
    0
    0
    2
    Oral herpes
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 39 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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 subjects either complete Week 24 visit or prematurely discontinue from the study. 3) Assembly of an internal unblinded team independent of the blinded study team to closely monitor study progress and drug safety. - “Pharmacogenomic” was changed to “Genomic” for consistency with the Patient Information Sheet/Informed Consent Form.

    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.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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