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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Evaluate the Effect of Filgotinib on Semen Parameters in Adult Males with Active Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis or Non-radiographic Axial Spondyloarthritis

    Summary
    EudraCT number
    		 2018-003933-14
    Trial protocol
    		 LV   EE   BG   BE   CZ   ES  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    11 Jun 2023
    First version publication date
    11 Jun 2023
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    GLPG0634-CL-227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03926195
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Galapagos NV
    Sponsor organisation address
    Generaal De Wittelaan L11 A3, Mechelen, Belgium, 2800
    Public contact
    Galapagos Medical Information, Galapagos NV, medicalinfo@glpg.com
    Scientific contact
    Galapagos Medical Information, Galapagos NV, medicalinfo@glpg.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
    29 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of filgotinib on testicular function as defined by the proportion of participants with a ≥ 50% decrease from baseline in sperm concentration at Week 13.
    Protection of trial subjects
    This clinical study was conducted in accordance with the ethical principles that have their origin in the “Declaration of Helsinki” and its amendments in force at the time of the clinical study (2013-version). It was also carried out in conformity with the protocol, the International Council for Harmonisation for Good Clinical Practice (ICH-GCP) Guideline E6 (R2), and local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    Georgia: 4
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czechia: 23
    Country: Number of subjects enrolled
    Estonia: 6
    Country: Number of subjects enrolled
    Latvia: 1
    Worldwide total number of subjects
    109
    EEA total number of subjects
    82
    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)
    109
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Bulgaria, Czech Republic, Estonia, Georgia, Latvia, Poland, Spain, and Ukraine. The first participant was screened on 28 May 2019. A total of 308 participants were screened of which 109 participants were randomized into the study.

    Pre-assignment
    Screening details
    		 There are 3 distinct parts to the study: 1) Double-Blind Treatment Phase (DB Phase; Day 1 through Week 13 study visit); 2) Extension Phase (EXT Phase; after Week 13 study visit & up to Week 156); & 3) Monitoring Phase (up to 52 weeks). The study is ongoing. Results based on data cut-off date 30 September 2021 (up to Week 26 analysis) are reported.

    Period 1
    Period 1 title
    DB Treatment Phase (Through Week 13)
    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
    		 Filgonitib
    Arm description
    		 Participants received filgotinib 200 milligrams (mg) tablet, orally, once daily up to Week 13 in the double-blind (DB) phase. At Week 13, participants who were arthritis responders, were unblinded and received open-label (OL) treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the extension (EXT) phase and participants who were arthritis nonresponders discontinued blinded study drug and started standard of care (SOC) treatment in the EXT phase. Participants on DB treatment or OL filgotinib who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) discontinued the study drug and started SOC for up to 52 weeks.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156). Participants who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) continued on SOC treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match filgotinib tablet administered orally once daily.

    Number of subjects in period 1
    		Filgonitib Placebo
    Started
    54
    55
    Completed
    54
    53
    Not completed
    0
    2
         Withdrawal by Subject
    -
    2
    Period 2
    Period 2 title
    EXT Phase (Through Week 26)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Filgonitib
    Arm description
    		 Participants received filgotinib 200 mg tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis responders, were unblinded and received OL treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the EXT phase and participants who were arthritis nonresponders discontinued blinded study drug and started SOC treatment in the EXT phase. Participants on DB treatment or OL filgotinib who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) discontinued the study drug and started SOC for up to 52 weeks.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156). Participants who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) continued on SOC treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Standard of Care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Locally approved treatment, accepted by medical experts as a proper treatment for rheumatic conditions, prescribed according to best clinical practice, with no known testicular toxicity.

    Number of subjects in period 2 [1]
    		Filgonitib Placebo
    Started
    46
    49
    Completed
    0
    0
    Not completed
    46
    49
         Adverse Event
    5
    -
         Pre- Specified Decrease In Sperm Parameters
    12
    11
         Withdrawal by Subject
    -
    2
         Ongoing in the study
    29
    36
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 26 arthritis responder participants and 23 arthritis nonresponder participants entered the EXT phase and received SOC treatment. 39 arthritis responder participants entered the EXT phase and received OL treatment filgotinib. 7 arthritis nonresponder participants entered the EXT phase and received SOC treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Filgonitib
    Reporting group description
    		 Participants received filgotinib 200 milligrams (mg) tablet, orally, once daily up to Week 13 in the double-blind (DB) phase. At Week 13, participants who were arthritis responders, were unblinded and received open-label (OL) treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the extension (EXT) phase and participants who were arthritis nonresponders discontinued blinded study drug and started standard of care (SOC) treatment in the EXT phase. Participants on DB treatment or OL filgotinib who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) discontinued the study drug and started SOC for up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156). Participants who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) continued on SOC treatment.

    Reporting group values
    		 Filgonitib Placebo Total
    Number of subjects
    		 54 55 109
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40 ( 8.5 ) 39 ( 7.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 54 55 109
    Ethnicity (NIH/ OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 53 55 108
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 54 55 109
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Sperm Concentration
    Units: millions (M)/ milliliter (mL)
        arithmetic mean (standard deviation)
    		 71.2 ( 41.00 ) 66.9 ( 38.72 ) -
    Total Sperm Count
    Units: M/ejaculate
        arithmetic mean (standard deviation)
    		 208.4 ( 136.94 ) 225.2 ( 137.39 ) -
    Sperm Total Motility
    Units: percentage of motile sperm
        arithmetic mean (standard deviation)
    		 55.9 ( 8.99 ) 58.2 ( 8.48 ) -
    Ejaculate Volume
    Units: mL
        arithmetic mean (standard deviation)
    		 3.1 ( 1.26 ) 3.5 ( 1.29 ) -
    Percent Normal Sperm Morphology
    Units: percentage of normal sperm
        arithmetic mean (standard deviation)
    		 43 ( 6.2 ) 43 ( 6.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Filgonitib
    Reporting group description
    		 Participants received filgotinib 200 milligrams (mg) tablet, orally, once daily up to Week 13 in the double-blind (DB) phase. At Week 13, participants who were arthritis responders, were unblinded and received open-label (OL) treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the extension (EXT) phase and participants who were arthritis nonresponders discontinued blinded study drug and started standard of care (SOC) treatment in the EXT phase. Participants on DB treatment or OL filgotinib who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) discontinued the study drug and started SOC for up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156). Participants who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) continued on SOC treatment.
    Reporting group title
    Filgonitib
    Reporting group description
    		 Participants received filgotinib 200 mg tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis responders, were unblinded and received OL treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the EXT phase and participants who were arthritis nonresponders discontinued blinded study drug and started SOC treatment in the EXT phase. Participants on DB treatment or OL filgotinib who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) discontinued the study drug and started SOC for up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156). Participants who entered the monitoring phase (if their sperm parameters met ≥50% decrease threshold in pre-specified semen parameters) continued on SOC treatment.

    Subject analysis set title
    Filgotinib/OL Filgotinib (Responder)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received filgotinib 200 mg tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis responders, were unblinded and received OL treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the EXT phase.

    Subject analysis set title
    Placebo/SOC (Responder)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis responders, were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156).

    Subject analysis set title
    Filgotinib/SOC (Nonresponder)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received filgotinib 200 mg tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis nonresponders discontinued blinded study drug and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156).

    Subject analysis set title
    Placebo/SOC (Nonresponder)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase. At Week 13, participants who were arthritis nonresponders, were unblinded and started SOC treatment in the EXT phase for up to approximately 143 weeks (until Week 156).

    Primary: Percentage of Participants With a ≥ 50% Decrease From Baseline in Sperm Concentration at Week 13

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    End point title
    		 Percentage of Participants With a ≥ 50% Decrease From Baseline in Sperm Concentration at Week 13
    End point description
    Baseline for sperm/semen parameters was the mean of 2 evaluable semen samples at screening. The normal range for sperm concentration is ≥15 M/mL. Percentage change = ([mean at Week 13 − baseline] / baseline) × 100; value at Week 13 was the mean of 2 evaluable samples collected at Week 13. The Semen Analysis Set included all randomized and treated (≥ 1 dose of double-blind study drug) participants who had 2 semen samples that were eligible for mean calculation at baseline and at the Week 13 analysis visit with the date of the first chronologic semen sample used for purposes of assigning analysis visit windows.
    End point type
    Primary
    End point timeframe
    Baseline to Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    53
    Units: percentage of participants
        number (not applicable)
    13.0
    7.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Filgonitib v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 19.2
    Notes
    [1] - Difference in percentage and 95% confidence interval (CI) was based on a stratified Mantel-Haenszel test.

    Secondary: Percentage of Participants With a ≥ 50% Decrease From Baseline in Sperm Concentration at Week 26

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    End point title
    		 Percentage of Participants With a ≥ 50% Decrease From Baseline in Sperm Concentration at Week 26
    End point description
    Arthritis responder: For rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and nonradiographic axial spondyloarthritis (nrAxSpA), a participant with an improvement in the Physician’s Global Assessment of Disease Activity (PhGADA) of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant’s disease severity on a visual analogue scale (VAS) ranged from 0 (no disease)-100 (worst disease) millimeters (mm). The normal range for sperm concentration is ≥15 M/mL. The Week 26 Semen Analysis Set included all participants treated (≥ 1 dose of open-label filgotinib or SOC in the extension phase) who had 2 evaluable samples at baseline and at Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    39
    25
    7
    23
    Units: percentage of participants
        number (not applicable)
    10.3
    8.0
    14.3
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sperm Total Motility at Week 13

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    End point title
    		 Change From Baseline in Sperm Total Motility at Week 13
    End point description
    The normal range for sperm total motility is ≥40%. Participants in the Semen Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    52
    Units: percentage of motile sperms
        median (confidence interval 95%)
    -2.3 (-8.1 to 1.4)
    -1.7 (-5.8 to 0.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Filgonitib v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 3.5
    Notes
    [2] - Difference in Medians and 95% CI for change from baseline at Week 13 was based on quantile regression.

    Secondary: Change From Baseline in Sperm Total Motility at Week 26

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    End point title
    		 Change From Baseline in Sperm Total Motility at Week 26
    End point description
    Arthritis responder: For RA, PsA, AS, and nrAxSpA, a participant with an improvement in the PhGADA of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant's disease severity on a VAS ranged from 0 (no disease)-100 (worst disease) mm. The normal range for sperm total motility is ≥40%. Participants in the Week 26 Semen Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    38
    25
    7
    23
    Units: percentage of motile sperms
        median (confidence interval 95%)
    -2.4 (-9.3 to 1.0)
    0.9 (-5.2 to 6.3)
    -1.4 (-13.3 to 13.0)
    -2.8 (-8.5 to 2.9)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Sperm Count at Week 13

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    End point title
    		 Change From Baseline in Total Sperm Count at Week 13
    End point description
    The normal range for total sperm count is ≥ 39 M/ejaculate. Participants in the Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    53
    Units: M/ejaculate
        median (confidence interval 95%)
    -2.1 (-41.7 to 31.0)
    -9.6 (-36.2 to 18.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Filgonitib v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.1
         upper limit
    		 36.8
    Notes
    [3] - Difference in medians and 95% CI for change from baseline at Week 13 was based on quantile regression.

    Secondary: Change From Baseline in Total Sperm Count at Week 26

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    End point title
    		 Change From Baseline in Total Sperm Count at Week 26
    End point description
    Arthritis responder: For RA, PsA, AS, and nrAxSpA, a participant with an improvement in the PhGADA of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant's disease severity on a VAS ranged from 0 (no disease)-100 (worst disease) mm. The normal range for total sperm count is ≥ 39 M/ejaculate. Participants in the Week 26 Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    39
    25
    7
    23
    Units: M/ejaculate
        median (confidence interval 95%)
    -0.2 (-39.5 to 44.5)
    16.8 (-49.3 to 60.6)
    32.2 (-60.8 to 121.3)
    -29.9 (-79.8 to 36.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sperm Concentration at Week 13

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    End point title
    		 Change From Baseline in Sperm Concentration at Week 13
    End point description
    The normal range for sperm concentration is ≥15 M/mL. Participants in the Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    53
    Units: M/mL
        median (confidence interval 95%)
    3.7 (-7.2 to 13.1)
    -0.4 (-6.1 to 7.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Filgonitib
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 19.9
    Notes
    [4] - Difference in Medians and 95% CI for change from baseline at Week 13 was based on quantile regression.

    Secondary: Change From Baseline in Sperm Concentration at Week 26

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    End point title
    		 Change From Baseline in Sperm Concentration at Week 26
    End point description
    Arthritis responder: For RA, PsA, AS, and nrAxSpA, a participant with an improvement in the PhGADA of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant's disease severity on a VAS ranged from 0 (no disease)-100 (worst disease) mm. The normal range for sperm concentration is ≥15 M/mL. Participants in the Week 26 Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    39
    25
    7
    23
    Units: M/mL
        median (confidence interval 95%)
    1.7 (-8.9 to 21.2)
    9.6 (-3.7 to 29.0)
    10.3 (-43.5 to 36.3)
    -5.8 (-12.9 to 4.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Ejaculate Volume at Week 13

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    End point title
    		 Change From Baseline in Ejaculate Volume at Week 13
    End point description
    The normal range for ejaculate volume is ≥1.5 mL. Participants in the Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    53
    Units: mL
        median (confidence interval 95%)
    -0.3 (-0.6 to 0.1)
    -0.2 (-0.4 to 0.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Filgonitib v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.1
    Notes
    [5] - Difference in Medians and 95% CI for change from baseline at Week 13 was based on quantile regression.

    Secondary: Change From Baseline in Ejaculate Volume at Week 26

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    End point title
    		 Change From Baseline in Ejaculate Volume at Week 26
    End point description
    Arthritis responder: For RA, PsA, AS, and nrAxSpA, a participant with an improvement in the PhGADA of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant's disease severity on a VAS ranged from 0 (no disease)-100 (worst disease) mm. The normal range for ejaculate volume is ≥1.5 mL. Participants in the Week 26 Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    39
    25
    7
    23
    Units: mL
        median (confidence interval 95%)
    -0.2 (-0.7 to 0.4)
    -0.6 (-0.7 to -0.2)
    0.2 (-1.0 to 1.1)
    -0.3 (-0.6 to 0.2)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Normal Sperm Morphology at Week 13

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    End point title
    		 Change From Baseline in Percent Normal Sperm Morphology at Week 13
    End point description
    The normal range for percent normal sperm morphology is ≥30% normal sperms. Participants in the Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 Filgonitib Placebo
    Number of subjects analysed
    54
    53
    Units: percentage of normal sperms
        median (confidence interval 95%)
    1 (-1 to 2)
    1 (-1 to 3)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Filgonitib v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1
    Notes
    [6] - Difference in Medians and 95% CI for change from baseline at Week 13 was based on quantile regression.

    Secondary: Change From Baseline in Percent Normal Sperm Morphology at Week 26

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    End point title
    		 Change From Baseline in Percent Normal Sperm Morphology at Week 26
    End point description
    Arthritis responder: For RA, PsA, AS, and nrAxSpA, a participant with an improvement in the PhGADA of at least 20% compared with baseline (Day 1) at the specified assessment time. Arthritis nonresponder: For RA, PsA, AS, or nrAxSpA, a participant who did not fulfill the definition of arthritis responder at the specified assessment timepoint. PhGADA: Physician measured the participant's disease severity on a VAS ranged from 0 (no disease)-100 (worst disease) mm. The normal range for percent normal sperm morphology is ≥30% normal sperms. Participants in the Week 26 Semen Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Filgotinib/OL Filgotinib (Responder) Placebo/SOC (Responder) Filgotinib/SOC (Nonresponder) Placebo/SOC (Nonresponder)
    Number of subjects analysed
    39
    25
    7
    23
    Units: percentage of normal sperms
        median (confidence interval 95%)
    1 (-2 to 5)
    3 (-2 to 8)
    3 (-15 to 6)
    4 (1 to 8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to Week 26
    Adverse event reporting additional description
    The Safety Analysis Set included all randomized participants who took ≥ 1 dose of double-blind study drug. Serious adverse events and non-serious adverse events are presented combined for Filgotinib + Placebo per DB phase and EXT phase as the study is still ongoing and blinded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    EXT Phase: Filgotinib + Placebo
    Reporting group description
    		 Participants who received filgotinib in DB phase and were arthritis responders at Week 13, were unblinded and received OL treatment filgotinib 200 mg, tablet, orally, once daily up to approximately 143 weeks (until Week 156) in the EXT phase and participants who were arthritis nonresponders discontinued blinded study drug and started SOC treatment in the EXT phase. Participants who received placebo (matched to filgotinib) in DB phase, were unblinded at Week 13 and started SOC treatment in the EXT phase for up toapproximately 143 weeks (until Week 156).

    Reporting group title
    DB Phase: Filgotinib + Placebo
    Reporting group description
    		 Participants received filgotinib 200 mg placebo (matched to filgotinib) tablet, orally, once daily up to Week 13 in the DB phase.

    Serious adverse events
    		 EXT Phase: Filgotinib + Placebo DB Phase: Filgotinib + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 95 (5.26%)
    3 / 109 (2.75%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Radiculopathy
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EXT Phase: Filgotinib + Placebo DB Phase: Filgotinib + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 95 (15.79%)
    8 / 109 (7.34%)
    Infections and infestations
    COVID-19
         subjects affected / exposed
    10 / 95 (10.53%)
    0 / 109 (0.00%)
         occurrences all number
    10
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 95 (5.26%)
    8 / 109 (7.34%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2020
    This amendment was initiated to address comments related to new safety information suggesting an increased risk of thromboembolic events in participants treated with JAK inhibitors. In addition, several sections were revised in line with the template update. General minor administrative updates were made throughout the protocol, including terminology, punctuation, abbreviations, dates, numbers, and format for clarity and consistency.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35614292
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