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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
    2010-018385-23
    Trial protocol
    DE   HU   AT   FR   GB   ES  
    Global end of trial date
    27 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Nov 2017
    First version publication date
    12 Nov 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-PSA-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01172938
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Nikolay Delev, Senior Director, Clinical Research and Development, M.D., 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
    16 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of 2 doses of apremilast (20 mg or 30 mg orally twice per day [BID]), compared with placebo, on the signs and symptoms of psoriatic arthritis (PsA) after 16 weeks’ administration.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason
    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
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Canada: 88
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Russian Federation: 44
    Country: Number of subjects enrolled
    South Africa: 74
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 135
    Worldwide total number of subjects
    504
    EEA total number of subjects
    122
    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)
    452
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    This study was a multicenter study with 83 study sites from the US, Canada, Europe, Russia, Australia, New Zealand and South Africa.

    Pre-assignment
    Screening details
    The study population was restricted to male and female subjects ≥ 18 years of age with moderate to severe Psoriatic Arthritis (PsA). Participants must have had a diagnosis of PsA by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria, including peripheral joint involvement.

    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
    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
    Placebo
    Arm description
    Subjects initially randomized to receive placebo tablets twice daily in the 24-week placebo-controlled phase. Subjects who did not have at least 20% improvement in swollen and tender joint counts at Week 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily (early escape).
    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
    Identically matched placebo tablets BID during the placebo controlled phase.

    Arm title
    Apremilast 20 mg
    Arm description
    Subjects initially randomized to receive 20 mg apremilast tablets twice daily in the 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 BID during the placebo controlled phase.

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the 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 BID during the placebo controlled phase.

    Number of subjects in period 1
    Placebo Apremilast 20 mg Apremilast 30 mg
    Started
    168
    168
    168
    Received Treatment
    168
    168
    168
    Completed Week (Wk) 16
    158
    158
    154
    Early Escape (EE) at Week 16
    107 [1]
    78 [2]
    58 [3]
    Completed
    150
    146
    148
    Not completed
    18
    22
    20
         Protocol deviation
    1
    -
    -
         Non-compliance with study drug
    -
    1
    2
         Lack of efficacy
    4
    5
    4
         Not specified
    -
    2
    1
         Adverse event, serious fatal
    -
    1
    -
         Adverse event, non-fatal
    11
    8
    10
         Consent withdrawn by subject
    2
    5
    3
    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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    Period 2
    Period 2 title
    Active Treatment Phase (Weeks 25-52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20 mg
    Arm description
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment.
    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 PO BID

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 mg apremilast tablets BIDin 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 BID

    Arm title
    Placebo / Apremilast 20 mg EE
    Arm description
    Subjects initially randomized to receive placebo twice daily who were re-randomized due to early escape (EE) at Week 16 continued to receive 20 mg apremilast 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 BID

    Arm title
    Placebo / Apremilast 20 mg XO
    Arm description
    Subjects initially randomized to receive placebo twice daily who were re-randomized at Week 24 (XO) continued to receive 20 mg apremilast tablets BID 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 BID

    Arm title
    Placebo / Apremilast 30 mg EE
    Arm description
    Subjects initially randomized to receive placebo twice daily who were re-randomized due to early escape (EE) at Week 16 continued to receive 30 mg apremilast tablets BID 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 BID

    Arm title
    Placebo / Apremilast 30 mg XO
    Arm description
    Subjects initially randomized to receive placebo twice daily who were re-randomized at Week 24 continued to receive 30 mg apremilast tablets BID 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 BID

    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
    136
    145
    51
    23
    49
    24
    Completed
    124
    130
    44
    19
    34
    22
    Not completed
    12
    15
    7
    4
    15
    2
         Non-compliance with study drug
    -
    1
    -
    -
    -
    -
         Lack of efficacy
    4
    7
    3
    1
    3
    -
         Not specified
    -
    -
    -
    -
    1
    1
         Adverse event, non-fatal
    2
    5
    1
    1
    2
    -
         Consent withdrawn by subject
    5
    1
    2
    2
    9
    1
         Lost to follow-up
    1
    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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    Period 3
    Period 3 title
    Active-Treatment Phase (Weeks 52-104)
    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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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 PO BID

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 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 30 mg tablets PO BID

    Arm title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and 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
    Initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg BID for up to 4.5 years in the active treatment / long-term safety phase.

    Arm title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and 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
    Initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg BID for up to 4.5 years in the active treatment / long-term safety phase.

    Number of subjects in period 3 [5]
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety) Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Started
    118
    121
    61
    49
    Completed
    95
    100
    46
    45
    Not completed
    23
    21
    15
    4
         Missing
    1
    -
    -
    -
         Miscellaneous
    2
    -
    -
    1
         Non-compliance with study drug
    -
    2
    -
    -
         Lack of efficacy
    7
    8
    4
    -
         Adverse event, serious fatal
    -
    1
    -
    -
         Adverse event, non-fatal
    2
    1
    3
    1
         Consent withdrawn by subject
    10
    8
    5
    2
         Lost to follow-up
    1
    1
    3
    -
    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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    Period 4
    Period 4 title
    Active-Treatment Phase Weeks (104-156)
    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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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 PO BID

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 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 30 mg tablets PO BID

    Arm title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally 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 PO BID

    Arm title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and 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 PO BID

    Number of subjects in period 4
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety) Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Started
    95
    100
    46
    45
    Completed
    84
    93
    41
    41
    Not completed
    11
    7
    5
    4
         Lack of efficacy
    4
    2
    2
    2
         Miscellaneious
    -
    2
    -
    -
         Adverse event, serious fatal
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
         Consent withdrawn by subject
    6
    3
    2
    1
         Lost to follow-up
    1
    -
    -
    -
    Period 5
    Period 5 title
    Active-Treatment Phase (Weeks 156-208)
    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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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 PO BID

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 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 30 mg tablets PO BID

    Arm title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally 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 PO BID

    Arm title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued to receive 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 PO BID

    Number of subjects in period 5
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety) Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Started
    84
    93
    41
    41
    Completed
    75
    88
    32
    34
    Not completed
    9
    5
    9
    7
         Miscellaneous
    -
    -
    1
    -
         Lack of efficacy
    1
    1
    3
    2
         Adverse event, non-fatal
    4
    1
    3
    -
         Consent withdrawn by subject
    4
    2
    2
    4
         Lost to follow-up
    -
    1
    -
    1
    Period 6
    Period 6 title
    Active-Treatment Phase (Weeks 208-260)
    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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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 subjects originally 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 PO BID

    Arm title
    Apremilast 30 mg
    Arm description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 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 30 mg tablets PO BID

    Arm title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally 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 PO BID

    Arm title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Arm description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued to receive 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 PO BID

    Number of subjects in period 6
    Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety) Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Started
    75
    88
    32
    34
    Switched from 20 mg to 30 mg BID
    62 [6]
    0 [7]
    25 [8]
    0 [9]
    Completed
    72
    80
    29
    32
    Not completed
    3
    8
    3
    2
         Protocol deviation
    -
    -
    -
    1
         Non-compliance with study drug
    1
    -
    1
    -
         Lack of efficacy
    -
    2
    -
    -
         Adverse event, serious fatal
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    1
    1
         Consent withdrawn by subject
    2
    3
    1
    -
         Lost to follow-up
    -
    1
    -
    -
    Notes
    [6] - 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    [7] - 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    [8] - 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.
    [9] - 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: The number of subjects starting the subsequent period will be less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period will enter the subsequent period.

    Baseline characteristics

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

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

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase.

    Reporting group values
    Placebo Apremilast 20 mg Apremilast 30 mg Total
    Number of subjects
    168 168 168 504
    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)
    149 157 146 452
        From 65-84 years
    19 11 22 52
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.1 ± 12.13 48.7 ± 10.99 51.4 ± 11.72 -
    Gender, Male/Female
    Units: Subjects
        Female
    80 83 92 255
        Male
    88 85 76 249
    Study Specific Characteristic | Duration of psoriatic arthritis
    Units: years
        arithmetic mean (standard deviation)
    7.31 ± 7.118 7.18 ± 6.842 8.09 ± 8.092 -

    End points

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

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

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase continued to receive 20 mg apremilast tablets BID in the active treatment.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 mg apremilast tablets BIDin the active treatment phase.

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

    Reporting group title
    Placebo / Apremilast 20 mg XO
    Reporting group description
    Subjects initially randomized to receive placebo twice daily who were re-randomized at Week 24 (XO) continued to receive 20 mg apremilast tablets BID during the active-treatment phase.

    Reporting group title
    Placebo / Apremilast 30 mg EE
    Reporting group description
    Subjects initially randomized to receive placebo twice daily who were re-randomized due to early escape (EE) at Week 16 continued to receive 30 mg apremilast tablets BID during the active-treatment phase

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

    Reporting group title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg BID in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and 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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 mg apremilast tablets BID in the active treatment / long-term safety phase.

    Reporting group title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose.

    Reporting group title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and 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
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 mg apremilast tablets BID in the active treatment / long-term safety phase

    Reporting group title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose.

    Reporting group title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued to receive apremilast 30 mg BID in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and 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 subjects originally receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID) in the placebo-controlled phase and continued to receive 30 mg apremilast tablets BID in the active treatment / long-term safety phase

    Reporting group title
    Placebo/Apremilast 20 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast at Week 16 or Week 24 and continued to receive apremilast 20 mg BID in the active treatment / long-term safety phase. After 30 mg apremilast BID was identified as the optimal dose, all subjects originally receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose.

    Reporting group title
    Placebo/Apremilast 30 mg (Active-Treatment/Long-Term Safety)
    Reporting group description
    Subjects initially randomized to placebo tablets BID during the placebo controlled phase and were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued to receive apremilast 30 mg BID in the active treatment / long-term safety phase.

    Subject analysis set title
    Placebo / Apremilast 20 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received placebo twice daily up to Week 16 or Week 24 and were then re-randomized to receive 20 mg apremilast twice daily.

    Subject analysis set title
    Placebo / Apremilast 30 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received placebo twice daily up to Week 16 or Week 24 and were then re-randomized to receive 30 mg apremilast twice daily.

    Subject analysis set title
    Apremilast 20 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects initially randomized to 20 mg apremilast tablets twice daily (BID).

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects initially randomized to 30 mg apremilast tablets twice daily (BID).

    Subject analysis set title
    Apremilast 20 mg (Pre-switch)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects randomized or re-randomized to apremilast 20 mg BID ; only the 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 BID (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 counted.

    Subject analysis set title
    Apremilast 30 mg BID
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who were treated with apremilast 30 mg BID throughout the study 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 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. Full analysis set (FAS) consisting of all participants randomized as specified in the protocol. Participants who withdrew 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
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    19.0
    30.4
    38.1
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.7
         upper limit
    28.3
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0166 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    11.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.2
         upper limit
    20.4
    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. Full analysis set; participants with a baseline value and at least 1 postbaseline 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
    165
    163
    159
    Units: units on a scale
        least squares mean (standard error)
    -0.086 ± 0.0360
    -0.198 ± 0.0364
    -0.244 ± 0.0364
    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
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.258
         upper limit
    -0.06
    Notes
    [5] - Based on an 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
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0252 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.211
         upper limit
    -0.014
    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 at Week 24. 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; 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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    13.1
    25.6
    35.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    22.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.4
         upper limit
    30.9
    Notes
    [7] - 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.
    [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
    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.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0038 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    12.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.2
         upper limit
    20.7
    Notes
    [9] - 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.
    [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. 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
    165
    163
    161
    Units: units on a scale
        least squares mean (standard error)
    -0.076 ± 0.0369
    -0.211 ± 0.0373
    -0.258 ± 0.0371
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005 [11]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.182
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.283
         upper limit
    -0.08
    Notes
    [11] - 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
    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.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0091 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.135
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.236
         upper limit
    -0.034
    Notes
    [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.

    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 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
    163
    163
    159
    Units: units on a scale
        least squares mean (standard error)
    1.81 ± 0.621
    3.50 ± 0.625
    4.23 ± 0.625
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0056 [13]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    2.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    4.13
    Notes
    [13] - 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
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0504 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    3.4
    Notes
    [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: 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, 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 16
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    29.8
    38.7
    46.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.0017 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    16.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    26.8
    Notes
    [15] - 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.
    [16] - 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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    8.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    18.9

    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
    165
    163
    159
    Units: mm
        least squares mean (standard error)
    -5.7 ± 1.83
    -11.5 ± 1.85
    -13.5 ± 1.85
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    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.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023 [17]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.9
         upper limit
    -2.8
    Notes
    [17] - 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
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    -0.7

    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
    95
    100
    108
    Units: units on a scale
        least squares mean (standard error)
    -0.9 ± 0.30
    -1.4 ± 0.29
    -1.3 ± 0.28
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.3

    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 severity 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
    56
    66
    Units: units on a scale
        least squares mean (standard error)
    -1.4 ± 0.28
    -1.9 ± 0.31
    -1.7 ± 0.28
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.3

    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 to 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
    158
    160
    158
    Units: units on a scale
        least squares mean (standard error)
    -3.84 ± 0.929
    -8.24 ± 0.926
    -8.72 ± 0.923
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -4.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.41
         upper limit
    -2.34
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -4.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.92
         upper limit
    -1.86

    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
    159
    161
    154
    Units: units on a scale
        least squares mean (standard error)
    -0.26 ± 0.082
    -0.73 ± 0.082
    -0.79 ± 0.083
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    -0.31
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    -0.25

    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
    162
    163
    159
    Units: units on a scale
        least squares mean (standard error)
    1.55 ± 0.693
    1.68 ± 0.696
    3.88 ± 0.695
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    2.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    4.23
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.77
         upper limit
    2.03

    Secondary: Change from Baseline in SF-36 Physical Function at Week 24

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    End point title
    Change from Baseline in SF-36 Physical Function 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 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
    163
    163
    161
    Units: units on a scale
        least squares mean (standard error)
    1.45 ± 0.671
    3.49 ± 0.675
    5.01 ± 0.671
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    3.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.72
         upper limit
    5.4
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    2.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    3.88

    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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    18.5
    31.0
    42.9
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    24.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.2
         upper limit
    34
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    12.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    21.5

    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 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
    165
    163
    162
    Units: mm
        least squares mean (standard error)
    -4.2 ± 1.78
    -11.2 ± 1.79
    -14.7 ± 1.77
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    -10.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.4
         upper limit
    -5.7
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12
         upper limit
    -2.2

    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 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
    96
    100
    110
    Units: units on a scale
        least squares mean (standard error)
    -0.8 ± 0.31
    -1.6 ± 0.30
    -1.6 ± 0.29
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    0
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean DIfference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    0.1

    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 severity 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
    64
    56
    66
    Units: units on a scale
        least squares mean (standard error)
    -1.3 ± 0.27
    -2.0 ± 0.30
    -1.8 ± 0.27
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.1

    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
    158
    161
    161
    Units: units on a scale
        least squares mean (standard error)
    -3.14 ± 0.965
    -7.55 ± 0.958
    -9.52 ± 0.949
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS mean Difference
    Point estimate
    -6.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    -3.75
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS mean Difference
    Point estimate
    -4.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.03
         upper limit
    -1.79

    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
    161
    161
    159
    Units: units on a scale
        least squares mean (standard error)
    -0.20 ± 0.087
    -0.66 ± 0.087
    -0.90 ± 0.087
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.94
         upper limit
    -0.46
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    -0.22

    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
    163
    163
    161
    Units: units on a scale
        least squares mean (standard error)
    1.12 ± 0.691
    1.52 ± 0.696
    3.33 ± 0.690
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS mean Difference
    Point estimate
    2.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    4.1
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean DIfference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    2.29

    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
    98
    103
    114
    Units: percentage of participants
        number (not applicable)
    49.0
    56.3
    52.6
    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
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.1
         upper limit
    16.7
    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
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.5
         upper limit
    21.1

    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 severity 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
    68
    59
    68
    Units: percentage of participants
        number (not applicable)
    57.4
    66.1
    60.3
    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
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.4
         upper limit
    19.3
    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
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.1
         upper limit
    24.6

    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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    29.8
    46.4
    48.8
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    19.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9
         upper limit
    29.3
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    16.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.4
         upper limit
    26.8

    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 subjects with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline 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. FAS; subjects with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for those who escaped early at subjects 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
    98
    103
    114
    Units: percentage of participants
        number (not applicable)
    46.9
    58.3
    60.5
    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
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    13.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    26.5
    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
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    11.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    25

    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 severity 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
    68
    59
    68
    Units: percentage of participants
        number (not applicable)
    60.3
    69.5
    69.1
    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
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    8.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    24.6
    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
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    24.2

    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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    16.1
    30.4
    42.3
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    26.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.1
         upper limit
    35.5
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    14.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.4
         upper limit
    23.1

    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: ◦ 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, 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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    6.0
    15.5
    16.1
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    10.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.7
         upper limit
    16.8
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3
         upper limit
    16

    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: ◦ 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, 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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    1.2
    6.0
    4.2
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    6.5
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    8.7

    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: ◦ 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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    4.2
    14.3
    19.0
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    14.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.3
         upper limit
    21.5
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    10.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4
         upper limit
    16.1

    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
    168
    168
    168
    Units: percentage of participants
        number (not applicable)
    0.6
    5.4
    10.1
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.8
         upper limit
    14.2
    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
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    8.3

    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
    98
    103
    114
    Units: percentage of participants
        number (not applicable)
    15.3
    27.2
    22.8
    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
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    7.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    17.9
    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
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    11.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    23

    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 severity 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
    68
    59
    68
    Units: percentage of participants
        number (not applicable)
    39.7
    42.4
    38.2
    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
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.7
         upper limit
    14.8
    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
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.8
         upper limit
    19.6

    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. FAS; subjects with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for subjects who escaped early at Week 16. Subjects 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
    Week 24
    End point values
    Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    98
    103
    114
    Units: percentage of participants
        number (not applicable)
    14.3
    31.1
    31.6
    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
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    17.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    28.2
    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
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    16.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.6
         upper limit
    27.9

    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 severity 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
    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)
    39.7
    49.2
    45.6
    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
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    5.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.7
         upper limit
    22.4
    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
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Adjusted Difference
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.5
         upper limit
    26.2

    Secondary: Number of Participants with Adverse Events During the Placebo-Controlled Period

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    End point title
    Number of Participants with Adverse Events During the Placebo-Controlled 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). An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16 for placebo participants who entered early escape 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
    168
    168
    168
    Units: participants
        Treatment Emergent Adverse Events
    81
    101
    103
        Drug-related TEAE
    32
    54
    70
        Severe TEAE
    6
    8
    11
        Serious TEAE (SAE)
    7
    8
    9
        Drug-related Serious AE
    2
    0
    3
        TEAE Leading to Drug Interruption
    9
    10
    17
        TEAE Leading to Drug Withdrawal
    8
    10
    12
        TEAE Leading to Death
    0
    1
    0
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Adverse Events During the Apremilast-Exposure Period
    End point description
    A TEAE is an AE with a start date on or after the date of the first dose of Investigational Product (IP) and no later than 28 days after the last dose of IP. An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 260; median total exposure to Apremilast was 170 weeks
    End point values
    Apremilast 20 mg (Pre-switch) Apremilast 20 mg/30 mg BID (post-switch) Apremilast 30 mg BID
    Number of subjects analysed
    245
    87
    245
    Units: participants
        Treatment Emergent Adverse Events (TEAEs)
    203
    39
    213
        Drug-related TEAE
    96
    5
    131
        Severe TEAE
    35
    1
    30
        Serious TEAE (SAE)
    41
    6
    49
        Drug-related SAE
    4
    1
    9
        TEAE leading to drug interruption
    47
    3
    49
        TEAE leading to drug withdrawal
    27
    0
    30
        TEAE leading to death
    1
    0
    2
    No statistical analyses for this end point

    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
    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. 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
    64
    60
    119
    130
    Units: Participants
        number (confidence interval 95%)
    53.1 (40.2 to 65.7)
    50.0 (36.8 to 63.2)
    63.0 (53.7 to 71.7)
    54.6 (45.7 to 63.4)
    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 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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population.
    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
    64
    61
    120
    132
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.27 ± 0.562
    -0.29 ± 0.590
    -0.37 ± 0.479
    -0.32 ± 0.547
    No statistical analyses for this end point

    Secondary: Change From Baseline in the SF-36 Physical Functioning Domain at Week 52

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    End point title
    Change From Baseline in the SF-36 Physical Functioning Domain 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. 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
    64
    61
    120
    130
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.46 ± 8.8877
    4.62 ± 9.979
    6.98 ± 9.425
    5.69 ± 8.995
    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 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,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; includes those who had sufficient data of response status 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
    61
    59
    120
    129
    Units: subjects
        number (confidence interval 95%)
    73.8 (60.9 to 84.2)
    71.2 (57.9 to 82.2)
    77.5 (69.0 to 84.6)
    73.6 (65.2 to 81.0)
    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
    64
    60
    120
    131
    Units: mm
        arithmetic mean (standard deviation)
    -20.2 ± 26.76
    -21.0 ± 25.83
    -17.8 ± 24.50
    -20.3 ± 23.37
    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.
    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
    36
    36
    69
    89
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.2 ± 4.03
    -1.9 ± 3.89
    -2.7 ± 2.41
    -1.9 ± 2.93
    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 severity 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. 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
    26
    48
    49
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.8 ± 2.10
    -2.4 ± 3.58
    -2.7 ± 3.79
    -1.8 ± 3.23
    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. 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
    61
    59
    120
    129
    Units: units on a scale
        arithmetic mean (standard deviation)
    -15.00 ± 11.137
    -14.03 ± 14.900
    -15.41 ± 13.039
    -14.54 ± 12.009
    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. 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
    64
    60
    120
    129
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.47 ± 1.103
    -1.15 ± 1.272
    -1.40 ± 1.125
    -1.31 ± 1.114
    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
    63
    61
    120
    128
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.33 ± 8.183
    4.15 ± 11.712
    4.27 ± 8.488
    3.67 ± 9.078
    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.
    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
    36
    36
    69
    89
    Units: percentage of subjects
        number (confidence interval 95%)
    69.4 (51.9 to 83.7)
    55.6 (38.1 to 72.1)
    84.1 (73.3 to 91.8)
    75.3 (65.0 to 83.8)
    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 severity 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. 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
    26
    48
    49
    Units: percentage of subjects
        number (confidence interval 95%)
    65.2 (42.7 to 83.6)
    73.1 (52.2 to 88.4)
    85.4 (72.2 to 93.9)
    77.6 (63.4 to 88.2)
    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. 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
    64
    60
    120
    129
    Units: percentage of subjects
        number (not applicable)
    82.8
    70.0
    75.0
    74.4
    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. 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
    63
    61
    117
    130
    Units: percentage of subjects
        number (confidence interval 95%)
    25.4 (15.3 to 37.9)
    27.9 (17.1 to 40.8)
    24.8 (17.3 to 33.6)
    24.6 (17.5 to 32.9)
    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. 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
    62
    61
    117
    130
    Units: percentage of subjects
        number (confidence interval 95%)
    4.8 (1.0 to 13.5)
    14.8 (7.0 to 26.2)
    15.4 (9.4 to 23.2)
    13.8 (8.4 to 21.0)
    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 (AAR) Population; only those participants with a baseline value > 0 (i.e., pre-existing enthesopathy) 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
    36
    36
    69
    89
    Units: percentage of subjects
        number (confidence interval 95%)
    33.3 (18.6 to 51.0)
    27.8 (14.2 to 45.2)
    50.7 (38.4 to 63.0)
    38.2 (28.1 to 49.1)
    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 severity 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. 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
    26
    48
    49
    Units: percentage of subjects
        number (confidence interval 95%)
    52.2 (30.6 to 73.2)
    53.8 (33.4 to 73.4)
    68.8 (53.7 to 81.3)
    68.3 (48.3 to 76.6)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events During the Apremilast-Exposure Period

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    End point title
    Number of Subjects with Adverse Events During the Apremilast-Exposure Period
    End point description
    A TEAE is an AE with a start date on or after the date of the first dose of Investigational Product (IP) and no later than 28 days after the last dose of IP. An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 260; median total exposure to Apremilast was 170 weeks
    End point values
    Apremilast 20 mg (Pre-switch) Apremilast 20 mg/30 mg BID (post-switch) Apremilast 30 mg BID
    Number of subjects analysed
    245
    87
    245
    Units: subjects
        Treatment Emergent Adverse Events (TEAEs)
    203
    39
    213
        Drug-related TEAE
    96
    5
    131
        Severe TEAE
    35
    1
    30
        Serious TEAE (SAE)
    41
    6
    49
        Drug-related SAE
    4
    1
    9
        TEAE Leading to Drug Interruption
    47
    3
    49
        TEAE Leading to Drug Withdrawal
    27
    0
    30
        TEAE Leading to Death
    1
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo-controlled Phase: Week 0 to Week 16 for placebo subjects who entered early escape at Week 16 and up to Week 24 for all other subjects. Apremilast-exposure Phase: Baseline to Week 260; median total exposure to Apremilast was 170 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    V14.0
    Reporting groups
    Reporting group title
    Week 0-24: Placebo (Placebo-Controlled Phase)
    Reporting group description
    Subjects received placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for subjects who escaped early, and through Week 24 for all other subjects.

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

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

    Reporting group title
    Apremilast Exposure up to 5 Years: Apremilast 20 mg
    Reporting group description
    Subjects randomized or re-randomized to apremilast 20 mg BID. Only the 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 BID
    Reporting group description
    Subjects who switched from apremilast 20 mg BID to apremilast 30 mg BID. Only the TEAEs that occurred during APR 30 mg BID treatment were counted.

    Reporting group title
    Apremilst Exposure up to 5 Years: Apremilast 30 mg BID
    Reporting group description
    Subjects who were treated with apremilast 30 mg BID throughout the study regardless of when their apremilast-exposure started (at Weeks 0, 16, or 24).

    Serious adverse events
    Week 0-24: Placebo (Placebo-Controlled Phase) Week 0-24: Apremilast 20 mg (Placebo- Controlled Phase) Week 0-24: Apremilast 30 mg (Placebo- Controlled Phase) Apremilast Exposure up to 5 Years: Apremilast 20 mg Apremilast Exposure Up to 5 Years: Apremilast 20/30 mg BID Apremilst Exposure up to 5 Years: Apremilast 30 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 168 (4.17%)
    8 / 168 (4.76%)
    9 / 168 (5.36%)
    41 / 245 (16.73%)
    6 / 87 (6.90%)
    49 / 245 (20.00%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Hypotension
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Shock
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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 / 1
    Varicose vein
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         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)
    Breast cancer
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Morton's neuroma
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    0 / 245 (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
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Borderline personality disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Depression
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    3 / 245 (1.22%)
    0 / 87 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thinking abnormal
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexa uteri cyst
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Endometriosis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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 haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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 / 1
    Joint dislocation
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Meniscus lesion
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Road traffic accident
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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 / 1
    Traumatic fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Investigations
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    2 / 245 (0.82%)
    0 / 87 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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 pectoris
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    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 fibrillation
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Cardiac failure congestive
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Coronary artery disease
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    0 / 245 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Tachycardia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Asthma
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Bronchiectasis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Haemoptysis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Pleural effusion
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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 failure
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Convulsion
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Hemiparesis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Sciatica
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 245 (0.00%)
    0 / 87 (0.00%)
    1 / 245 (0.41%)
         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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (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
    Retinal detachment
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 245 (0.41%)
    0 / 87 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0</