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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy and Safety Study of Two Doses of Apremilast (CC-10004) in Subjects with Active Psoriatic Arthritis.

    Summary
    EudraCT number
    2010-018386-32
    Trial protocol
    CZ   EE   GB   BE   DE   HU   ES   IT   PL   BG  
    Global end of trial date
    26 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Feb 2018
    First version publication date
    11 Feb 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-PSA-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01212757
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    ClinicalTrialDisclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Nikolay Delev, MD, Celgene Corporation, 01 908-897-5662, NDelev@celgene.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
    10 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the clinical efficacy of 2 doses of apremilast (APR) (20 mg or 30 mg orally twice daily [BID]), compared with placebo (PBO), on the signs and symptoms of Psoriatic Arthritis (PsA) after administration for16 weeks.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent. This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    Czech Republic: 88
    Country: Number of subjects enrolled
    Estonia: 66
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    South Africa: 18
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    488
    EEA total number of subjects
    314
    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)
    440
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    This study was a multicenter study with 84 sites from the United States, Canada, Europe, Russia, Australia, South Africa and Taiwan.

    Pre-assignment
    Screening details
    This study consisted of a 24-week randomized, double-blind, placebo-controlled phase, a 28-week randomized, double-blind active treatment phase and a 4-year open-label safety phase, for an overall study duration of 5 years.

    Period 1
    Period 1 title
    Placebo-controlled Phase (Week 0 - 24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Subject
    Blinding implementation details
    Blinding to treatment assignment was maintained at all sites until after the Week 52 database lock at Year 1, after all Week 52 analyses were completed and the results were released. At that time, active medication was provided. The blind was otherwise not to be broken during the study unless, in the opinion of the doctor, it was necessary to safely treat the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants initially randomized to placebo tablets twice daily (BID) in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week (Wk) 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily [(early escape (EE)].
    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 tablets (identical in appearance to apremilast) twice daily.

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Number of subjects in period 1
    Placebo Apremilast 20 mg Apremilast 30 mg
    Started
    162
    163
    163
    Received Treatment
    159
    163
    162
    Completed Week 16
    148
    151
    149
    Early Escape at Week 16
    88 [1]
    59 [2]
    64 [3]
    Completed
    143
    143
    142
    Not completed
    19
    20
    21
         Protocol deviation
    -
    1
    1
         Randomization Error
    3
    -
    1
         Miscellaneous
    1
    2
    -
         Lack of efficacy
    3
    2
    2
         Adverse event, non-fatal
    4
    5
    12
         Consent withdrawn by subject
    7
    9
    3
         Lost to follow-up
    1
    1
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 2
    Period 2 title
    Active Treatment Phase (Weeks 24 - 52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Blinding to treatment assignment was maintained at all sites until after the Week 52 database lock at Year 1, after all Week 52 analyses were completed and the results were released. At that time, active medication was provided. The blind was otherwise not to be broken during the study unless, in the opinion of the doctor, it was necessary to safely treat the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily in the active treatment/long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Arm title
    Placebo / Apremilast 20 mg EE
    Arm description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 20 mg apremilast twice daily during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice a day.

    Arm title
    Placebo / Apremilast 20 mg XO
    Arm description
    Participants initially randomized to receive placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 (XO) to receive 20 mg apremilast twice daily during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice a day.

    Arm title
    Placebo / Apremilast 30 mg EE
    Arm description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 30 mg apremilast twice daily during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice a day

    Arm title
    Placebo / Apremilast 30 mg XO
    Arm description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 to receive 30 mg apremilast twice daily during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice a day.

    Number of subjects in period 2 [4]
    Apremilast 20 mg Apremilast 30 mg Placebo / Apremilast 20 mg EE Placebo / Apremilast 20 mg XO Placebo / Apremilast 30 mg EE Placebo / Apremilast 30 mg XO
    Started
    137
    134
    43
    27
    41
    28
    Completed
    125
    114
    35
    25
    34
    28
    Not completed
    12
    20
    8
    2
    7
    0
         Non-compliance with study drug
    -
    2
    -
    -
    -
    -
         Lack of efficacy
    5
    7
    4
    -
    2
    -
         Adverse event, non-fatal
    2
    3
    1
    -
    2
    -
         Unspecified
    1
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    3
    7
    3
    1
    3
    -
         Lost to follow-up
    1
    -
    -
    1
    -
    -
    Notes
    [4] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 3
    Period 3 title
    Long-Term Safety Phase (Year 2)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily in the active treatment/long-term safety phase (LTSP).
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 20 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily in the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 continued receiving apremilast 20 mg BID in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 30 mg
    Arm description
    Participants initially randomized to placebo tablets BID in the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg BID in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Number of subjects in period 3 [5]
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg Placebo/Apremilast 30 mg
    Started
    119
    109
    58
    60
    Completed
    107
    95
    48
    51
    Not completed
    12
    14
    10
    9
         Miscellaneous
    -
    -
    -
    1
         Lack of efficacy
    4
    2
    4
    -
         Adverse event, non-fatal
    1
    1
    2
    2
         Consent withdrawn by subject
    7
    9
    4
    6
         Lost to follow-up
    -
    2
    -
    -
    Notes
    [5] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 4
    Period 4 title
    Long-Term Safety Phase (Year 3)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 20 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 30 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Number of subjects in period 4
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg Placebo/Apremilast 30 mg
    Started
    107
    95
    48
    51
    Completed
    89
    84
    42
    46
    Not completed
    18
    11
    6
    5
         Protocol deviation
    1
    -
    -
    -
         Miscellaneous
    -
    3
    -
    2
         Non-compliance with study drug
    -
    1
    -
    -
         Lack of efficacy
    8
    5
    3
    1
         Adverse event, non-fatal
    4
    1
    2
    -
         Consent withdrawn by subject
    5
    1
    1
    1
         Lost to follow-up
    -
    -
    -
    1
    Period 5
    Period 5 title
    Long-Term Safety Phase (Year 4)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment/long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 20 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily

    Arm title
    Placebo/Apremilast 30 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily

    Number of subjects in period 5 [6]
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg Placebo/Apremilast 30 mg
    Started
    89
    84
    41
    46
    Completed
    80
    77
    37
    39
    Not completed
    9
    7
    4
    7
         Miscellaneous
    2
    -
    -
    1
         Lack of efficacy
    2
    2
    1
    1
         Adverse event, serious fatal
    -
    1
    -
    1
         Adverse event, non-fatal
    1
    2
    1
    1
         Consent withdrawn by subject
    4
    2
    1
    3
         Lost to follow-up
    -
    -
    1
    -
    Notes
    [6] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 6
    Period 6 title
    Long-Term Safety Phase (Year 5)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment/long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to 30 mg apremilast BID dose).
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 20 mg
    Arm description
    Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 20 mg tablets twice daily.

    Arm title
    Placebo/Apremilast 30 mg
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily in the active treatment / long-term safety phase.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 30 mg tablets twice daily

    Number of subjects in period 6
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg Placebo/Apremilast 30 mg
    Started
    80
    77
    37
    39
    Completed
    72
    69
    33
    37
    Not completed
    8
    8
    5
    2
         Miscellaneous
    1
    1
    -
    -
         Non-compliance with study drug
    1
    -
    -
    -
         Lack of efficacy
    1
    2
    2
    1
         Adverse event, non-fatal
    2
    2
    2
    -
         Consent withdrawn by subject
    3
    3
    1
    1
    Joined
    0
    0
    1
    0
         1 subject not counted in Year 5
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants initially randomized to placebo tablets twice daily (BID) in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week (Wk) 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily [(early escape (EE)].

    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

    Reporting group values
    Placebo Apremilast 20 mg Apremilast 30 mg Total
    Number of subjects
    162 163 163 488
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    146 149 145 440
        From 65-84 years
    16 14 18 48
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.2 ± 10.97 50.9 ± 11.82 50.5 ± 11.20 -
    Gender, Male/Female
    Units: Subjects
        Female
    87 95 95 277
        Male
    75 68 68 211
    Duration of Psoriatic Arthritis
    Units: years
        arithmetic mean (standard deviation)
    7.76 ± 8.254 7.83 ± 8.621 6.82 ± 7.592 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants initially randomized to placebo tablets twice daily (BID) in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week (Wk) 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily [(early escape (EE)].

    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily in the active treatment/long-term safety phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo / Apremilast 20 mg EE
    Reporting group description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 20 mg apremilast twice daily during the active treatment phase.

    Reporting group title
    Placebo / Apremilast 20 mg XO
    Reporting group description
    Participants initially randomized to receive placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 (XO) to receive 20 mg apremilast twice daily during the active treatment phase.

    Reporting group title
    Placebo / Apremilast 30 mg EE
    Reporting group description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 30 mg apremilast twice daily during the active treatment phase.

    Reporting group title
    Placebo / Apremilast 30 mg XO
    Reporting group description
    Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 to receive 30 mg apremilast twice daily during the active treatment phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily in the active treatment/long-term safety phase (LTSP).

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 20 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily in the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 continued receiving apremilast 20 mg BID in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 30 mg
    Reporting group description
    Participants initially randomized to placebo tablets BID in the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg BID in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment / long-term safety phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 20 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 30 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment/long-term safety phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 20 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 30 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment/long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to 30 mg apremilast BID dose).

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 20 mg
    Reporting group description
    Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose.

    Reporting group title
    Placebo/Apremilast 30 mg
    Reporting group description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily in the active treatment / long-term safety phase.

    Subject analysis set title
    Placebo /Apremilast 20 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 20 mg twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg BID in the active treatment / long-term safety phase.

    Subject analysis set title
    Placebo/Apremilast 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg BID in the active treatment / long-term safety phase.

    Subject analysis set title
    Apremilast 20 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg Apremilast twice daily in the active treatment/long-term safety phase.

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast twice daily in the active treatment/long-term safety phase.

    Subject analysis set title
    Apremilast 20 mg (Pre-switch)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received apremilast 20 mg BID, regardless of when the apremilast exposure started (at Week 0, 16, or 24). Only the TEAEs that occurred during apremilast 20 mg BID treatment (before the switch to 30 mg apremilast) were included.

    Subject analysis set title
    Apremilast 20 mg/30 mg (Post-switch)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who switched from apremilast 20 mg BID to apremilast 30 mg BID. Only the TEAEs that occurred during APR 30 mg BID treatment were included.

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received apremilast 30 mg BID regardless of when their apremilast-exposure started (at Weeks 0, 16, or 24).

    Primary: Percentage of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 16

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    End point title
    Percentage of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 16
    End point description
    Percentage of participants with a ACR 20 response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦Patient’s self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦C-Reactive Protein. Full analysis set (FAS) = subjects randomized as specified per protocol; subjects who were randomized in error and did not receive any dose of study drug were excluded. Subjects who withdrew early who did not have sufficient data for a determination of response status at Week 16 were counted as non-responders
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    18.9
    37.4
    32.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    In order to maintain the Type 1 error at the 0.05 significance level, the Hochberg procedure was to be used. The results of the endpoint were to be considered statistically significant if both the 30 mg apremilast dose versus placebo comparison and the 20 mg versus placebo comparison were statistically significant at the 0.05 significance level, or one of the comparisons was statistically significant at the 0.025 level.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.006 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    13.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4
         upper limit
    22.7
    Notes
    [1] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% confidence interval (CI) is based on a normal approximation to the weighted average.
    [2] - 2-sided p-value is based on the Cochran-Mantel-Haenszel (CMH) test adjusting for baseline disease modifying antirheumatic drug (DMARD) use.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    In order to maintain the Type 1 error at the 0.05 significance level, the Hochberg procedure was to be used. The results of the endpoint were to be considered statistically significant if both the 30 mg apremilast dose versus placebo comparison and the 20 mg versus placebo comparison were statistically significant at the 0.05 significance level, or one of the comparisons was statistically significant at the 0.025 level.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    = 0.0002 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    18.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.1
         upper limit
    28.2
    Notes
    [3] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [4] - 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Change from Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16

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    End point title
    Change from Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16
    End point description
    The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. FAS; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; Last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    159
    154
    Units: units on a scale
        least squares mean (standard error)
    -0.053 ± 0.0358
    -0.157 ± 0.0351
    -0.193 ± 0.0354
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Pairwise comparisons (30 mg vs placebo and 20 mg vs placebo) were conducted conditional on the primary endpoint results. If the primary endpoint was statistically significant for both apremilast dose groups, pairwise comparisons for the HAQ-DI were to be evaluated at the 0.05 level using the Hochberg procedure. If only one apremilast dose was statistically significant, then only the comparison between that apremilast dose and placebo was conducted for the HAQ-DI score, at the 0.025 level.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0042 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.236
         upper limit
    -0.045
    Notes
    [5] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Pairwise comparisons (30 mg vs placebo and 20 mg vs placebo) were conducted conditional on the primary endpoint results. If the primary endpoint was statistically significant for both apremilast dose groups, pairwise comparisons for the HAQ-DI were to be evaluated at the 0.05 level using the Hochberg procedure. If only one apremilast dose was statistically significant, then only the comparison between that apremilast dose and placebo was conducted for the HAQ-DI score, at the 0.025 level.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.032 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.104
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.199
         upper limit
    -0.009
    Notes
    [6] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Percentage of Participants with an ACR 20 Response at Week 24

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    End point title
    Percentage of Participants with an ACR 20 Response at Week 24
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦C-Reactive Protein. FAS population; subjects who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    15.7
    31.3
    24.7
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0394 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    9.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    17.8
    Notes
    [7] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [8] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0009 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    15.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.7
         upper limit
    24.7
    Notes
    [9] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [10] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

    Secondary: Change from Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 24

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    End point title
    Change from Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 24
    End point description
    The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. FAS population. subjects with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    159
    154
    Units: units on a scale
        least squares mean (standard error)
    -0.085 ± 0.0377
    -0.165 ± 0.0370
    -0.206 ± 0.0372
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.0191 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.121
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.222
         upper limit
    -0.02
    Notes
    [11] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [12] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.1179 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    0.02
    Notes
    [13] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [14] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change from Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16

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    End point title
    Change from Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    159
    153
    Units: units on a scale
        least squares mean (standard error)
    0.81 ± 0.678
    2.17 ± 0.664
    2.91 ± 0.671
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.0237 [16]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    3.92
    Notes
    [15] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [16] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.1388 [18]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    3.15
    Notes
    [17] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
    [18] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Percentage of Participants with a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16

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    End point title
    Percentage of Participants with a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16
    End point description
    Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: - 78 tender joint count, - 76 swollen joint count, - Patient global assessment of disease activity, measured on a 100 mm visual Analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest; - Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    33.3
    47.9
    48.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0065 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    14.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.3
         upper limit
    25.5
    Notes
    [19] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above. Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [20] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0071 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    14.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.1
         upper limit
    25.2
    Notes
    [21] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above. Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [22] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Change from Baseline in Patient’s Assessment of Pain at Week 16

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    End point title
    Change from Baseline in Patient’s Assessment of Pain at Week 16
    End point description
    The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents “no pain,” and the right-hand boundary (score = 100 mm) represents “pain as severe as can be imagined.” The distance from the mark to the left-hand boundary was recorded in millimeters. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included; LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    151
    157
    152
    Units: mm
        least squares mean (standard error)
    -7.0 ± 1.93
    -12.5 ± 1.89
    -11.9 ± 1.90
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0648 [23]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    0.3
    Notes
    [23] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0347 [24]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    -0.4
    Notes
    [24] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change from Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16

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    End point title
    Change from Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16
    End point description
    The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) and at least 1 postbaseline value at or prior to Week 16 are included; LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    100
    105
    97
    Units: units on a scale
        least squares mean (standard error)
    -1.0 ± 0.29
    -0.9 ± 0.28
    -1.4 ± 0.29
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3496 [25]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.4
    Notes
    [25] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8874 [26]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.8
    Notes
    [26] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change from Baseline in Dactylitis Severity Score at Week 16

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    End point title
    Change from Baseline in Dactylitis Severity Score at Week 16
    End point description
    Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set. Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    63
    75
    70
    Units: units on a scale
        least squares mean (standard error)
    -1.1 ± 0.28
    -0.8 ± 0.26
    -1.3 ± 0.26
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5438 [27]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.5
    Notes
    [27] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3759 [28]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1
    Notes
    [28] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) at Week 16

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    End point title
    Change from Baseline in Clinical Disease Activity Index (CDAI) at Week 16
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: - 28 tender joint count (TJC), - 28 swollen joint count (SJC), - Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; - Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    149
    155
    146
    Units: units on a scale
        least squares mean (standard error)
    -3.30 ± 0.871
    -7.75 ± 0.851
    -6.81 ± 0.869
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0035 [29]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.86
         upper limit
    -1.16
    Notes
    [29] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [30]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -4.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.76
         upper limit
    -2.14
    Notes
    [30] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change from Baseline in the Disease Activity Score (DAS28) at Week 16

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    End point title
    Change from Baseline in the Disease Activity Score (DAS28) at Week 16
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: - 28 tender joint count - 28 swollen joint count, which do not include the distal interphalangeal (DIP) joints, the hip joint, or the joints below the knee; - C-reactive protein (CRP) - Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    150
    156
    151
    Units: units on a scale
        least squares mean (standard error)
    -0.27 ± 0.082
    -0.74 ± 0.080
    -0.67 ± 0.080
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [31]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.61
         upper limit
    -0.18
    Notes
    [31] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    -0.25
    Notes
    [32] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate

    Secondary: Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16

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    End point title
    Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means “not at all,” and 4 means “very much.” The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    157
    154
    Units: units on a scale
        least squares mean (standard error)
    0.63 ± 0.724
    0.91 ± 0.712
    2.75 ± 0.715
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7803 [33]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.65
         upper limit
    2.2
    Notes
    [33] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0318 [34]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    2.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    4.06
    Notes
    [34] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24

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    End point title
    Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    159
    154
    Units: units on a scale
        least squares mean (standard error)
    1.44 ± 0.688
    2.97 ± 0.673
    3.30 ± 0.679
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0473 [35]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    3.7
    Notes
    [35] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0997 [36]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    3.35
    Notes
    [36] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24

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    End point title
    Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24
    End point description
    Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm visual Analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    24.5
    39.9
    32.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    = 0.1195 [38]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    7.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    17.5
    Notes
    [37] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
    [38] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.0026 [40]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    15.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.6
         upper limit
    25.5
    Notes
    [39] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights
    [40] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Change From Baseline in Patient’s Assessment of Pain at Week 24

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    End point title
    Change From Baseline in Patient’s Assessment of Pain at Week 24
    End point description
    The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    152
    158
    153
    Units: mm
        least squares mean (standard error)
    -8.0 ± 1.90
    -11.5 ± 1.86
    -9.7 ± 1.88
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5067 [41]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    3.4
    Notes
    [41] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1762 [42]
    Method
    ANCOVA
    Parameter type
    LS mean Difference
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.5
         upper limit
    1.6
    Notes
    [42] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24

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    End point title
    Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24
    End point description
    The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    100
    105
    98
    Units: units on a scale
        least squares mean (standard error)
    -0.9 ± 0.29
    -0.9 ± 0.28
    -1.3 ± 0.29
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2719 [43]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.3
    Notes
    [43] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9727 [44]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.7
    Notes
    [44] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in Dactylitis Severity Score at Week 24

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    End point title
    Change From Baseline in Dactylitis Severity Score at Week 24
    End point description
    Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set. Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and at least 1 postbaseline value at or prior to Week 24 are included. LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    63
    75
    71
    Units: units on a scale
        least squares mean (standard error)
    -1.1 ± 0.27
    -0.9 ± 0.25
    -1.4 ± 0.26
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6777 [45]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.8
    Notes
    [45] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3705 [46]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.4
    Notes
    [46] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    149
    155
    148
    Units: units on a scale
        least squares mean (standard error)
    -3.21 ± 0.884
    -7.71 ± 0.864
    -6.35 ± 0.878
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097 [47]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.52
         upper limit
    -0.76
    Notes
    [47] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [48]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.85
         upper limit
    -2.16
    Notes
    [48] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 24

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    End point title
    Change From Baseline in the Disease Activity Score (DAS28) at Week 24
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    150
    157
    152
    Units: units on a scale
        least squares mean (standard error)
    -0.27 ± 0.084
    -0.73 ± 0.082
    -0.65 ± 0.083
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011 [49]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.15
    Notes
    [49] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [50]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    -0.23
    Notes
    [50] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24

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    End point title
    Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    153
    157
    154
    Units: units on a scale
        least squares mean (standard error)
    0.52 ± 0.721
    0.68 ± 0.710
    2.65 ± 0.713
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0303 [51]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    2.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    4.07
    Notes
    [51] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8704 [52]
    Method
    ANCOVA
    Parameter type
    LS mean Difference
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.76
         upper limit
    2.08
    Notes
    [52] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

    Secondary: Percentage of Participants with MASES Improvement ≥ 20% at Week 16

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    End point title
    Percentage of Participants with MASES Improvement ≥ 20% at Week 16
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 16 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    104
    107
    101
    Units: percentage of participants
        number (not applicable)
    52.9
    54.2
    56.4
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.8462 [54]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.1
         upper limit
    14.7
    Notes
    [53] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
    [54] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    = 0.6022 [56]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.9
         upper limit
    17.2
    Notes
    [55] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
    [56] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

    Secondary: Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 16

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    End point title
    Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 16
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 16 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    66
    77
    73
    Units: percentage of participants
        number (not applicable)
    59.1
    62.3
    61.6
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    P-value
    = 0.7337 [58]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.3
         upper limit
    18.9
    Notes
    [57] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [58] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.6881 [60]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.7
         upper limit
    19.3
    Notes
    [59] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [60] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16

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    End point title
    Percentage of Participants with Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16
    End point description
    A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    31.4
    53.4
    48.8
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    P-value
    = 0.0014 [62]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    17.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7
         upper limit
    27.9
    Notes
    [61] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [62] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    P-value
    = 0.0001 [64]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    22.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.7
         upper limit
    32.5
    Notes
    [63] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [64] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with MASES Improvement ≥ 20% at Week 24

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    End point title
    Percentage of Participants with MASES Improvement ≥ 20% at Week 24
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 24 weeks of treatment. The MASES score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. FAS; participants with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who EE at Week 16. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    104
    107
    101
    Units: percentage of participants
        number (not applicable)
    51.0
    57.0
    57.4
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    = 0.3376 [66]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    20
    Notes
    [65] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [66] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    = 0.3756 [68]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    6.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    19.4
    Notes
    [67] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [68] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 24

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    End point title
    Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 24
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 24 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    66
    77
    73
    Units: percentage of participants
        number (not applicable)
    62.1
    68.8
    68.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    = 0.3959 [70]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    22.2
    Notes
    [69] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [70] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    P-value
    = 0.3941 [72]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    22.4
    Notes
    [71] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [72] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with Good or Moderate EULAR response at Week 24

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    End point title
    Percentage of Participants with Good or Moderate EULAR response at Week 24
    End point description
    EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    21.4
    41.7
    33.3
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    = 0.0001 [74]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    20.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.8
         upper limit
    30.3
    Notes
    [73] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [74] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    = 0.0142 [76]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.6
         upper limit
    21.7
    Notes
    [75] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [76] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with a ACR 50 Response at Week 16

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    End point title
    Percentage of Participants with a ACR 50 Response at Week 16
    End point description
    Percentage of participants with an American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o C-Reactive Protein. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    5.0
    14.7
    10.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    = 0.0589 [78]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    5.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    11.3
    Notes
    [77] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [78] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [79]
    P-value
    = 0.0034 [80]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    9.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    16.1
    Notes
    [79] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [80] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with an ACR 70 Response at Week 16

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    End point title
    Percentage of Participants with an ACR 70 Response at Week 16
    End point description
    Percentage of participants with an American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o C-Reactive Protein. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    0.6
    3.7
    1.2
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [81]
    P-value
    = 0.562 [82]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    2.7
    Notes
    [81] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [82] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [83]
    P-value
    = 0.057 [84]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    6.2
    Notes
    [83] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [84] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with an ACR 50 Response at Week 24

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    End point title
    Percentage of Participants with an ACR 50 Response at Week 24
    End point description
    Percentage of participants with an American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o C-Reactive Protein. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    8.8
    14.1
    11.7
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    = 0.3629 [86]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    9.6
    Notes
    [85] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [86] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    = 0.1323 [88]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    5.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    12.3
    Notes
    [87] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [88] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with a ACR 70 Response at Week 24

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    End point title
    Percentage of Participants with a ACR 70 Response at Week 24
    End point description
    Percentage of participants with an American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦C-Reactive Protein. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: percentage of participants
        number (not applicable)
    3.1
    5.5
    2.5
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    = 0.2929 [90]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    6.8
    Notes
    [89] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [90] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority [91]
    P-value
    = 0.7273 [92]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    3
    Notes
    [91] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [92] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 16

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    End point title
    Percentage of Participants Achieving a MASES Score of Zero at Week 16
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 16 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    104
    107
    101
    Units: percentage of participants
        number (not applicable)
    23.1
    29.0
    20.8
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    = 0.7023 [94]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.5
         upper limit
    9.1
    Notes
    [93] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [94] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    = 0.3305 [96]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.9
         upper limit
    17.7
    Notes
    [95] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [96] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16

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    End point title
    Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 16 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    66
    77
    73
    Units: percentage of participants
        number (not applicable)
    40.9
    42.9
    41.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    = 0.9698 [98]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16
         upper limit
    16.6
    Notes
    [97] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [98] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    superiority [99]
    P-value
    = 0.8205 [100]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.3
         upper limit
    18.1
    Notes
    [99] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [100] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 24

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    End point title
    Percentage of Participants Achieving a MASES Score of Zero at Week 24
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 24 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    104
    107
    101
    Units: percentage of participants
        number (not applicable)
    24.0
    29.9
    22.8
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority [101]
    P-value
    = 0.8424 [102]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.7
         upper limit
    10.3
    Notes
    [101] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [102] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [103]
    P-value
    = 0.3395 [104]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    17.8
    Notes
    [103] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [104] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

    Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 24

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    End point title
    Percentage of Participants Achieving a Dactylitis Score of Zero at Week 24
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 24 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    68
    59
    68
    Units: percentage of participants
        number (not applicable)
    40.9
    44.2
    46.6
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority [105]
    P-value
    = 0.4811 [106]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.3
         upper limit
    22.1
    Notes
    [105] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [106] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority [107]
    P-value
    = 0.6965 [108]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.3
         upper limit
    19.5
    Notes
    [107] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
    [108] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

    Secondary: Percentage of Participants with a ACR 20 Response at Week 52

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    End point title
    Percentage of Participants with a ACR 20 Response at Week 52
    End point description
    A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦Patient's assessment of pain (measured on a 100 mm VAS); ◦Patient's global assessment of disease activity (measured on a 100 mm VAS; ◦Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦Patient's self-assessment of physical function; ◦C-Reactive Protein. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population consists of all participants who were randomized or re-randomized to apremilast at any time during the study; only those who had sufficient data for a definitive determination of response at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    61
    121
    116
    Units: percentage of participants
        number (confidence interval 95%)
    53.3 (40.0 to 63.3)
    47.5 (34.6 to 60.7)
    52.9 (43.6 to 62.0)
    52.6 (43.1 to 61.9)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52

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    End point title
    Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52
    End point description
    The HAQ-DI is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. Apremilast Subjects as Randomized/Re-randomized (AAR) Population consisted of subjetcs who were randomized or re-randomized to apremilast at any time during the study. Only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    63
    125
    117
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.208 ± 0.4831
    -0.310 ± 0.5990
    -0.192 ± 0.5729
    -0.330 ± 0.5089
    No statistical analyses for this end point

    Secondary: Change from Baseline in the SF-36 Physical Functioning Scale Score at Week 52

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    End point title
    Change from Baseline in the SF-36 Physical Functioning Scale Score at Week 52
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    63
    124
    115
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.13 ± 9.106
    5.97 ± 9.612
    4.05 ± 8.752
    4.97 ± 9.656
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Modified PsARC Response at Week 52

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    End point title
    Percentage of Participants with a Modified PsARC Response at Week 52
    End point description
    Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts = a decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments = a decrease or increase, from baseline by ≥ 20 mm VAS. 2 sided 95% confidence interval is based on the Clopper-Pearson method. Apremilast Subjects as Randomized/Re-randomized (AAR) population; only subjects who had sufficient data for a definitive response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    60
    123
    114
    Units: percentage of participants
        number (confidence interval 95%)
    78.3 (65.8 to 87.9)
    73.3 (60.3 to 83.9)
    72.4 (63.6 to 80.0)
    74.6 (65.6 to 82.3)
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Patient Assessment of Pain at Week 52

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    End point title
    Change from Baseline in the Patient Assessment of Pain at Week 52
    End point description
    The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    62
    125
    117
    Units: mm
        arithmetic mean (standard deviation)
    -15.6 ± 23.77
    -16.0 ± 24.48
    -13.5 ± 27.78
    -12.9 ± 26.54
    No statistical analyses for this end point

    Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 52

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    End point title
    Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 52
    End point description
    The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing enthesopathy) and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    40
    39
    80
    78
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.5 ± 4.41
    -2.5 ± 2.73
    -1.7 ± 3.12
    -2.1 ± 2.82
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Dactylitis Severity Score at Week 52

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    End point title
    Change from Baseline in the Dactylitis Severity Score at Week 52
    End point description
    Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing dactylitis) and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    23
    27
    57
    60
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.9 ± 1.14
    -2.1 ± 2.32
    -1.8 ± 1.98
    -1.8 ± 2.06
    No statistical analyses for this end point

    Secondary: Change from Baseline in the CDAI Score at Week 52

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    End point title
    Change from Baseline in the CDAI Score at Week 52
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    60
    123
    114
    Units: units on a scale
        arithmetic mean (standard deviation)
    -13.66 ± 9.811
    -13.13 ± 13.148
    -12.03 ± 10.492
    -14.38 ± 11.531
    No statistical analyses for this end point

    Secondary: Change from baseline in the DAS28 at Week 52

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    End point title
    Change from baseline in the DAS28 at Week 52
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    62
    125
    117
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.18 ± 1.015
    -1.18 ± 1.366
    -1.11 ± 1.059
    -1.30 ± 1.033
    No statistical analyses for this end point

    Secondary: Change from Baseline in the FACIT-Fatigue Scale Score at Week 52

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    End point title
    Change from Baseline in the FACIT-Fatigue Scale Score at Week 52
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    59
    63
    123
    115
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.97 ± 8.544
    4.95 ± 9.414
    2.45 ± 9.481
    4.38 ± 9.847
    No statistical analyses for this end point

    Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 52

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    End point title
    Percentage of Participants With MASES Improvement ≥ 20% at Week 52
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 52 weeks. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants with a baseline MASES > 0 and who had sufficient data for a definitive response at Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    40
    39
    80
    78
    Units: percentage of participants
        number (confidence interval 95%)
    72.5 (56.1 to 85.4)
    79.5 (63.5 to 90.7)
    70.0 (58.7 to 79.7)
    69.2 (57.8 to 79.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 52

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    End point title
    Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 52
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    23
    27
    57
    60
    Units: percentage of participants
        number (confidence interval 95%)
    95.7 (78.1 to 99.9)
    88.9 (70.8 to 97.6)
    80.7 (68.1 to 90.0)
    85.0 (73.4 to 92.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Good or Moderate EULAR Response at Week 52

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    End point title
    Percentage of Participants Achieving Good or Moderate EULAR Response at Week 52
    End point description
    A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    60
    62
    125
    117
    Units: percentage of participants
        number (not applicable)
    70.0
    64.5
    68.0
    67.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an ACR 50 Response at Week 52

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    End point title
    Percentage of Participants with an ACR 50 Response at Week 52
    End point description
    Percentage of participants with an American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦C-Reactive Protein. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    59
    62
    120
    118
    Units: percentage of participants
        number (confidence interval 95%)
    30.5 (19.2 to 43.9)
    27.4 (16.9 to 40.2)
    26.7 (19.0 to 35.5)
    18.6 (12.1 to 26.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an ACR 70 Response at Week 52

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    End point title
    Percentage of Participants with an ACR 70 Response at Week 52
    End point description
    Percentage of participants with an American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    59
    63
    123
    118
    Units: percentage of participants
        number (confidence interval 95%)
    16.9 (8.4 to 29.0)
    14.3 (6.7 to 25.4)
    9.8 (5.1 to 16.4)
    6.8 (3.0 to 12.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 52

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    End point title
    Percentage of Participants Achieving a MASES Score of Zero at Week 52
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 24 weeks. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Two-sided 95% confidence interval is based on the Clopper-Pearson method. Apremilast Subjects as Randomized/Re-randomized Population; subjects with a baseline value > 0 and who had sufficient data for a definitive response at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    40
    39
    80
    78
    Units: percentage of participants
        number (confidence interval 95%)
    42.5 (27.0 to 59.1)
    41.0 (25.6 to 57.9)
    40.0 (29.2 to 51.6)
    37.2 (26.5 to 48.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 52

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    End point title
    Percentage of Participants Achieving a Dactylitis Score of Zero at Week 52
    End point description
    Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo /Apremilast 20 mg Placebo/Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    23
    27
    57
    60
    Units: percentage of participants
        number (confidence interval 95%)
    78.3 (56.3 to 92.5)
    77.8 (57.7 to 91.4)
    57.9 (44.1 to 70.9)
    65.0 (51.6 to 76.9)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events During the Placebo-Controlled Phase

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    End point title
    Number of Participants with Treatment Emergent Adverse Events During the Placebo-Controlled Phase
    End point description
    A Treatment Emergent Adverse Event (TEAE) is an AE with a start date on or after the date of the first dose of Investigational Product (IP). The severity of each adverse event (AE) and serious AE (SAE) was assessed by the investigator and graded based on a scale from Mild to Severe AEs. A serious adverse event (SAE) is any AE which: • Resulted in death • Was life-threatening • Required inpatient hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability/incapacity • Was a congenital anomaly/birth defect • Constituted an important medical event; Safety population included all participants who were randomized and received at least one dose of IP.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16 for placebo participants who entered EE at Week 16 and up to Week 24 for all other participants (placebo participants who remained on placebo through week 24 and participants randomized to the APR 20 mg BID or APR 30 mg BID)
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    159
    163
    162
    Units: Participants
        Any TEAE|
    72
    106
    96
        Any Drug-Related TEAE|
    28
    53
    57
        Any Severe TEAE|
    5
    3
    11
        Any Serious TEAE (SAE)|
    3
    6
    4
        Any Drug-Related SAE|
    0
    3
    1
        Any TEAE Leading to Drug Interruption|
    11
    16
    31
        Any TEAE Leading to Drug Withdrawal|
    3
    5
    12
        Any TEAE Leading to Death|
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with TEAEs During the Apremilast-Exposure Period

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    End point title
    Number of Participants with TEAEs During the Apremilast-Exposure Period
    End point description
    A Treatment Emergent Adverse Event (TEAE) is an AE with a start date on or after the date of the first dose of Investigational Product (IP). The severity of each adverse event (AE) and serious AE (SAE) was assessed by the investigator and graded based on a scale from Mild to Severe AEs. A serious adverse event (SAE) is any AE which: • Resulted in death • Was life-threatening • Required inpatient hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability/incapacity • Was a congenital anomaly/birth defect • Constituted an important medical event; apremilast subjects as treated who received at least 1 dose of apremilast at any time during the study.
    End point type
    Secondary
    End point timeframe
    Week 0-260; overall median duration of exposure for APR 20 mg and 30 mg was 198 weeks
    End point values
    Apremilast 20 mg (Pre-switch) Apremilast 20 mg/30 mg (Post-switch) Apremilast 30 mg
    Number of subjects analysed
    234
    113
    234
    Units: participants
        Any TEAE|
    202
    53
    207
        Any Drug-related TEAE|
    102
    5
    100
        Any Severe TEAE|
    35
    2
    37
        Any Serious TEAE|
    41
    5
    41
        Any Serious Drug-related TEAE|
    6
    1
    6
        Any TEAE Leading to Drug Interruption|
    47
    4
    65
        Any TEAE Leading to Drug Withdrawal|
    24
    3
    30
        Any TEAE Leading to Death|
    0
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are reported for the placebo-controlled phase from Week 0 - Week 16 for subjects who entered EE at Week 16 and up to Week 24 for all other subjects. AEs are reported for the apremilast exposure period from Week 0 to Week 260.
    Adverse event reporting additional description
    Overall median exposure to apremilast was 198 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    V14.0
    Reporting groups
    Reporting group title
    Weeks 0-24: Placebo (Placebo-Controlled Phase)
    Reporting group description
    Participants received placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for participants who escaped early, and through Week 24 for all other participants.

    Reporting group title
    Weeks 0-24: Apremilast 20 mg (Placebo-Controlled Phase)
    Reporting group description
    Participants received 20 mg apremilast tablets PO BID during the 24-week placebo-controlled phase.

    Reporting group title
    Weeks 0-24: Apremilast 30 mg (Placebo-Controlled Phase)
    Reporting group description
    Participants received 30 mg apremilast tablets PO BID during the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast Exposure Period Up to 5 Years: Apremilast 20 mg
    Reporting group description
    Participants who received apremilast 20 mg twice daily regardless of when the apremilast exposure started (at Week 0, 16 or 24). Only TEAEs that occurred during apremilast 20 mg BID treatment (before the switch to 30 mg apremilast) were included.

    Reporting group title
    Apremilast Exposure Up to 5 Years: Apremilast 20/30 mg
    Reporting group description
    Subjects who switched from apremilast 20 mg twice daily to apremilast 30 mg twice daily. Only the TEAEs that occurred during apremilast 30 mg twice daily were included.

    Reporting group title
    Apremilst Exposure up to 5 Years: Apremilast 30 mg
    Reporting group description
    Participants who received apremilast 30 mg twice daily throughout the study regardless of when the apremilast-exposure started (at Weeks 0, 16, or 24).

    Serious adverse events
    Weeks 0-24: Placebo (Placebo-Controlled Phase) Weeks 0-24: Apremilast 20 mg (Placebo-Controlled Phase) Weeks 0-24: Apremilast 30 mg (Placebo-Controlled Phase) Apremilast Exposure Period Up to 5 Years: Apremilast 20 mg Apremilast Exposure Up to 5 Years: Apremilast 20/30 mg Apremilst Exposure up to 5 Years: Apremilast 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 159 (1.89%)
    6 / 163 (3.68%)
    4 / 162 (2.47%)
    41 / 234 (17.52%)
    5 / 113 (4.42%)
    41 / 234 (17.52%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial thrombosis limb
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    2 / 234 (0.85%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Hypertension
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    1 / 162 (0.62%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Benign renal neoplasm
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Colon adenoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage 0
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    1 / 113 (0.88%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Renal cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    1 / 113 (0.88%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    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
    Tonsil cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    2 / 234 (0.85%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 163 (0.61%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Depression
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 163 (0.61%)
    0 / 162 (0.00%)
    3 / 234 (1.28%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menometrorrhagia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    1 / 162 (0.62%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 163 (0.61%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic floor muscle weakness
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    1 / 113 (0.88%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Uterine polyp
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Contusion
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    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
    Tendon injury
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    1 / 162 (0.62%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    2 / 234 (0.85%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Atrial tachycardia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Cardiac arrest
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Hypertensive heart disease
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    1 / 162 (0.62%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 163 (0.61%)
    0 / 162 (0.00%)
    2 / 234 (0.85%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 163 (0.61%)
    0 / 162 (0.00%)
    2 / 234 (0.85%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    0 / 234 (0.00%)
    0 / 113 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    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
    Nasal septum deviation
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 163 (0.00%)
    0 / 162 (0.00%)
    1 / 234 (0.43%)
    0 / 113 (0.00%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis