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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 Who Have Not Been Previously Treated with Disease-modifying Antirheumatic Drugs

    Summary
    EudraCT number
    2010-020324-22
    Trial protocol
    GB   HU   BE   CZ   LT   IT   PL   BG   EE  
    Global end of trial date
    26 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Oct 2018
    First version publication date
    12 Oct 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-PSA-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01307423
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, NJ, United States, 07901
    Public contact
    ClinicalTrialDisclosure, Celgene Corporation, +1 8882601599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Nikolay Delev, MD, Celgene Corporation, +1 908-897-5662, 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
    17 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2017
    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
    This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Estonia: 25
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Lithuania: 17
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Poland: 74
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 108
    Worldwide total number of subjects
    527
    EEA total number of subjects
    238
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    109
    From 65 to 84 years
    418
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted in 16 countries including the United States, Canada, Europe, New Zealand, Australia and Russia.

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

    Period 1
    Period 1 title
    Placebo-controlled Phase (Week 0 - 24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    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
    Participants initially randomized to receive placebo tablets twice daily (BID) in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week (Wk) 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily (early escape).
    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
    Participants initially randomized to receive placebo tablets twice daily (BID) in the 24-week placebo- controlled phase.

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo- controlled phase.

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo- controlled phase.

    Number of subjects in period 1
    Placebo Apremilast 20mg Apremilast 30mg
    Started
    176
    175
    176
    Received Treatment
    176
    175
    175
    Completed Week 16
    166
    168
    166
    Early Escape at Week 16
    103 [1]
    73 [2]
    79 [3]
    Completed
    156
    160
    155
    Not completed
    20
    15
    21
         Protocol deviation
    1
    -
    -
         Non-compliance with Study Drug
    -
    1
    1
         Lack of efficacy
    1
    3
    2
         Adverse event, non-fatal
    4
    4
    6
         Unspecified
    1
    2
    -
         Consent withdrawn by subject
    8
    4
    10
         Lost to follow-up
    5
    1
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 2
    Period 2 title
    Active Treatment Phase (Week 25-52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Blinding to treatment assignment was maintained at all sites until after the Week 52 database lock at Year 1, after all Week 52 analyses were completed and the results were released. At that time, active medication was provided. The blind was otherwise not to be broken during the study unless, in the opinion of the doctor, it was necessary to safely treat the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20mg
    Arm description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Apremilast 30mg
    Arm description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

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

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

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

    Arm title
    Placebo / Apremilast 30 mg XO
    Arm description
    Participants initially randomized to placebo twice daily were re-randomized at Week 24 to 30 mg apremilast twice daily in 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
    Participants initially randomized to receive placebo twice daily were re-randomized at Week 24 (XO) to 30 mg apremilast tablets twice daily in the active treatment phase.

    Number of subjects in period 2 [4]
    Apremilast 20mg Apremilast 30mg Placebo/ 20mg Apremilast EE Placebo / Apremilast 20 mg XO Placebo / Apremilast 30 mg EE Placebo / Apremilast 30 mg XO
    Started
    151
    150
    46
    26
    46
    26
    Completed
    132
    141
    38
    23
    43
    25
    Not completed
    19
    9
    8
    3
    3
    1
         Protocol deviation
    -
    -
    -
    -
    1
    -
         Non-compliance with Study Drug
    -
    -
    -
    -
    1
    -
         Lack of efficacy
    5
    5
    3
    1
    -
    -
         Adverse event, non-fatal
    3
    2
    2
    2
    -
    -
         Unspecified
    -
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    11
    2
    -
    -
    1
    1
         Lost to follow-up
    -
    -
    2
    -
    -
    -
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 3
    Period 3 title
    Long-term Safety Phase (Year 2)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20mg
    Arm description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Apremilast 30mg
    Arm description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in 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
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in active treatment / long-term safety phase.

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 30 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in active treatment / long-term safety phase.

    Number of subjects in period 3 [5]
    Apremilast 20mg Apremilast 30mg Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)] Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Started
    122
    134
    57
    67
    Completed
    99
    109
    48
    60
    Not completed
    23
    25
    9
    7
         Noncompliance with Study Drug
    -
    1
    -
    -
         Miscellaneous
    1
    -
    1
    1
         Lack of efficacy
    7
    5
    4
    3
         Adverse event, non-fatal
    2
    7
    1
    1
         Consent withdrawn by subject
    13
    12
    3
    2
    Notes
    [5] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 4
    Period 4 title
    Long-term Safety Phase (Year 3)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20mg
    Arm description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Apremilast 30mg
    Arm description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]
    Arm description
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in 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
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in active treatment / long-term safety phase.

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 30 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in active treatment / long-term safety phase.

    Number of subjects in period 4
    Apremilast 20mg Apremilast 30mg Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)] Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Started
    99
    109
    48
    60
    Completed
    90
    91
    40
    49
    Not completed
    9
    18
    8
    11
         Miscellaneous
    1
    -
    1
    -
         Noncompliance with Study Drug
    1
    1
    -
    -
         Lack of efficacy
    2
    4
    1
    2
         Adverse event, non-fatal
    1
    2
    3
    4
         Consent withdrawn by subject
    2
    8
    2
    4
         Lost to follow-up
    2
    3
    1
    1
    Period 5
    Period 5 title
    Long-term Safety Phase (Year 4)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20mg
    Arm description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

    Arm title
    Apremilast 30mg
    Arm description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

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

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 30 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in active treatment / long-term safety phase.

    Number of subjects in period 5 [6]
    Apremilast 20mg Apremilast 30mg Placebo/Apremilast 20 mg (LTSP) Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Started
    89
    91
    40
    49
    Completed
    81
    86
    38
    44
    Not completed
    8
    5
    2
    5
         Miscellaneous
    -
    -
    1
    -
         Lack of efficacy
    1
    -
    -
    1
         Adverse event, non-fatal
    2
    -
    -
    -
         Consent withdrawn by subject
    5
    4
    1
    4
         Lost to follow-up
    -
    1
    -
    -
    Notes
    [6] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
    Period 6
    Period 6 title
    Long-term Safety Phase (Year 5)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast 20mg
    Arm description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).
    Arm type
    Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long- term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).

    Arm title
    Apremilast 30mg
    Arm description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long- term safety phase.

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in active treatment / long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).

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

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 30 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in active treatment / long-term safety phase.

    Number of subjects in period 6
    Apremilast 20mg Apremilast 30mg Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)] Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Started
    81
    86
    38
    44
    Completed
    71
    80
    37
    41
    Not completed
    10
    6
    1
    3
         Miscellaneous
    -
    2
    1
    1
         Lack of efficacy
    2
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    1
         Consent withdrawn by subject
    6
    2
    -
    1
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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

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

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

    Reporting group values
    Placebo Apremilast 20mg Apremilast 30mg Total
    Number of subjects
    176 175 176 527
    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)
    160 159 161 480
        From 65-84 years
    16 16 15 47
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.5 ± 11.58 49.2 ± 12.00 48.4 ± 12.52 -
    Gender, Male/Female
    Units: Subjects
        Female
    86 95 96 277
        Male
    90 80 80 250
    Duration of Psoriatic Arthritis
    Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis that, depending on the method of ascertainment, occurs in 6% to 39% of patients with psoriasis. Disease onset typically occurs between the ages of 30 and 55 years and affects both sexes equally. In the majority of patients, psoriasis precedes PsA by several years. The diagnosis of PsA is made on clinical grounds in patients with psoriasis having skin, scalp or nail changes.
    Units: years
        arithmetic mean (standard deviation)
    3.42 ± 5.103 3.19 ± 4.706 3.62 ± 5.041 -

    End points

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

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

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.
    Reporting group title
    Apremilast 20mg
    Reporting group description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

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

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

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

    Reporting group title
    Placebo / Apremilast 30 mg XO
    Reporting group description
    Participants initially randomized to placebo twice daily were re-randomized at Week 24 to 30 mg apremilast twice daily in the active treatment phase.
    Reporting group title
    Apremilast 20mg
    Reporting group description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

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

    Reporting group title
    Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Reporting group description
    Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20mg
    Reporting group description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

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

    Reporting group title
    Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Reporting group description
    Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20mg
    Reporting group description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

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

    Reporting group title
    Placebo/Apremilast 30 mg (Long-Term Safety Phase)
    Reporting group description
    Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in the active treatment / long-term safety phase.
    Reporting group title
    Apremilast 20mg
    Reporting group description
    Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).

    Reporting group title
    Apremilast 30mg
    Reporting group description
    Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years in the active treatment / long-term safety phase.

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

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

    Subject analysis set title
    Placebo / Apremilast 20 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants 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
    Full analysis
    Subject analysis set description
    Participants 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
    Full analysis
    Subject analysis set description
    Participants initially randomized to receive apremilast 20 mg tablets twice daily.

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants initially randomized to receive apremilast 30 mg tablets twice daily.

    Subject analysis set title
    Apremilast 20 mg (Pre-Switch)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received 20 mg apremilast tablets twice daily, regardless of when the apremilast exposure started (at Week 0, 16 or 24). Only the TEAEs that occurred during apremilast 20 mg BID were counted.

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

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who received apremilast 30 mg twice daily regardless of when the apremilast-exposure started (at Week 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
    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 consisting of all subjects randomized as specified in the protocol; one participant randomized in error and did not receive any dose of investigational product (IP) was excluded. Participants who withdrew early or 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    15.9
    28.0
    30.7
    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 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0062
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.5
         upper limit
    20.7
    Notes
    [1] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution
    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 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.001
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.1
         upper limit
    23.5
    Notes
    [2] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    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 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 20mg Apremilast 30mg
    Number of subjects analysed
    167
    168
    167
    Units: units on a scale
        least squares mean (standard error)
    0.012 ± 0.0350
    -0.156 ± 0.0349
    -0.205 ± 0.0350
    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 20mg
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008 [3]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.168
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.265
         upper limit
    -0.071
    Notes
    [3] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, 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 30mg
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.217
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.314
         upper limit
    -0.12
    Notes
    [4] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, and the baseline value as a covariate

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

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    End point title
    Percentage of Participants with an ACR 20 Response at Week 24
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Full analysis set; Participants who discontinued early, escaped 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    13.1
    29.1
    24.4
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.0002 [6]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    16.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.7
         upper limit
    24.4
    Notes
    [5] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    [6] - 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
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0063 [8]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.3
         upper limit
    19.4
    Notes
    [7] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    [8] - 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

    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 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 20mg Apremilast 30mg
    Number of subjects analysed
    167
    169
    167
    Units: units on a scale
        least squares mean (standard error)
    0.012 ± 0.0370
    -0.156 ± 0.0368
    -0.207 ± 0.0369
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0014 [10]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.168
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.271
         upper limit
    -0.065
    Notes
    [9] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and baseline value as a covariate.
    [10] - 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
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.219
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.322
         upper limit
    -0.117
    Notes
    [11] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and baseline value as a covariate.
    [12] - 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

    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). SF-36 domain scores were first calculated to range from 0 to100 and then transformed to norm-based scores (the norm-based scores in the US general population have an average of 50 and a standard deviation of 10). Norm-based scores were used in analyses, with higher scores indicating 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: units on a scale
        least squares mean (standard error)
    0.01 ± 0.588
    2.39 ± 0.586
    3.19 ± 0.590
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.0043 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    2.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    4.01
    Notes
    [13] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and baseline value as a covariate
    [14] - 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.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.0002 [16]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.55
         upper limit
    4.82
    Notes
    [15] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and baseline value as a covariate
    [16] - 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

    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=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    24.4
    38.9
    45.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.0037 [18]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    14.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.8
         upper limit
    24
    Notes
    [17] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    [18] - 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.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.0001 [20]
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.3
         upper limit
    30.7
    Notes
    [19] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    [20] - 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.

    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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: mm
        least squares mean (standard error)
    -2.6 ± 1.81
    -7.7 ± 1.79
    -10.5 ± 1.80
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0485 [22]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    0
    Notes
    [21] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, and the baseline value as a covariate
    [22] - 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
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.0022 [24]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.8
         upper limit
    -2.8
    Notes
    [23] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, and the baseline value as a covariate
    [24] - 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

    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 Achilles 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 20mg Apremilast 30mg
    Number of subjects analysed
    115
    117
    111
    Units: units on a scale
        least squares mean (standard error)
    -0.5 ± 0.24
    -0.5 ± 0.24
    -1.5 ± 0.25
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.7696
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.6
    Notes
    [25] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.0038 [27]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.3
    Notes
    [26] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
    [27] - 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

    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 to Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    90
    89
    84
    Units: units on a scale
        least squares mean (standard error)
    -1.0 ± 0.25
    -1.9 ± 0.25
    -1.7 ± 0.26
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.2
    Notes
    [28] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    0
    Notes
    [29] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

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

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    End point title
    Change from Baseline in Clinical Disease Activity Index (CDAI) at Week 16
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    163
    166
    164
    Units: units on a scale
        least squares mean (standard error)
    -1.98 ± 0.770
    -6.89 ± 0.763
    -7.63 ± 0.768
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -4.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.04
         upper limit
    -2.78
    Notes
    [30] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.78
         upper limit
    -3.51
    Notes
    [31] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

    Secondary: Change in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment

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    End point title
    Change in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment
    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 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    164
    164
    167
    Units: units on a scale
        least squares mean (standard error)
    -0.15 ± 0.076
    -0.61 ± 0.076
    -0.68 ± 0.075
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.67
         upper limit
    -0.25
    Notes
    [32] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    [33]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    -0.32
    Notes
    [33] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate.

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

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    End point title
    Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    167
    168
    166
    Units: units on a scale
        least squares mean (standard error)
    0.07 ± 0.631
    1.19 ± 0.629
    2.62 ± .0633
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    Method
    Parameter type
    Difference in LS Means
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    2.87
    Notes
    [34] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    Method
    Parameter type
    Difference in LS Means
    Point estimate
    2.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    4.31
    Notes
    [35] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate.

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

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    End point title
    Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall QOL and consists of 36 questions in 8 domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). SF-36 domain scores were first calculated to range from 0 to100 and then transformed to norm-based scores (the norm-based scores in the US population have an average of 50 and a standard deviation of 10). Norm-based scores were used in analyses, with higher scores indicating 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. FAS; subjects 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 those who EE at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: units on a scale
        least squares mean (standard error)
    0.16 ± 0.609
    2.13 ± 0.605
    3.88 ± 0.611
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    Method
    Parameter type
    LS Means Difference
    Point estimate
    1.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    3.65
    Notes
    [36] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    3.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.02
         upper limit
    5.41
    Notes
    [37] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate

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

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    End point title
    Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24
    End point description
    Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm visual Analog scale (VAS), where 0=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=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 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    17.0
    36.6
    35.2
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    19.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.5
         upper limit
    28.6
    Notes
    [38] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    18.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.2
         upper limit
    27.2
    Notes
    [39] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    Secondary: Change from Baseline in Participants Assessment of Pain at Week 24

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    End point title
    Change from Baseline in Participants 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 20mg Apremilast 30mg
    Number of subjects analysed
    167
    169
    167
    Units: mm
        least squares mean (standard error)
    -3.8 ± 1.83
    -9.4 ± 1.82
    -9.6 ± 1.83
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    -0.5
    Notes
    [40] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    -0.7
    Notes
    [41] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate

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

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    End point title
    Change from Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24
    End point description
    The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Achilles 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 20mg Apremilast 30mg
    Number of subjects analysed
    111
    113
    106
    Units: units on a scale
        least squares mean (standard error)
    -0.6 ± 0.25
    -0.9 ± 0.25
    -1.5 ± 0.26
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.4
    Notes
    [42] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.2

    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 20mg Apremilast 30mg
    Number of subjects analysed
    87
    85
    79
    Units: units on a scale
        least squares mean (standard error)
    -1.0 ± 0.26
    -2.0 ± 0.26
    -1.7 ± 0.27
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.3
    Notes
    [43] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    superiority [44]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    0.1
    Notes
    [44] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

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

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    End point title
    Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: units on a scale
        least squares mean (standard error)
    -2.23 ± 0.807
    -7.30 ± 0.803
    -7.36 ± 0.810
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.31
         upper limit
    -2.84
    Notes
    [45] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -5.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.38
         upper limit
    -2.89
    Notes
    [46] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

    Secondary: Change in Disease Activity Score (DAS 28) at Week 24

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    End point title
    Change in Disease Activity Score (DAS 28) 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 20mg Apremilast 30mg
    Number of subjects analysed
    167
    167
    167
    Units: units on a scale
        least squares mean (standard error)
    -0.22 ± 0.084
    -0.69 ± 0.084
    0.68 ± 0.084
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    334
    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
    -0.23
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [47]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    -0.22
    Notes
    [47] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

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

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    End point title
    Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24
    End point description
    The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    167
    169
    166
    Units: units on a scale
        least squares mean (standard error)
    0.25 ± 0.652
    1.37 ± 0.648
    2.58 ± 0.655
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    2.93
    Notes
    [48] - Based on an analysis of covariance model (Ancova) for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    2.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    4.15
    Notes
    [49] - Based on an analysis of covariance model (Ancova) for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

    Secondary: Percentage of Participants with ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score at Week 16

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    End point title
    Percentage of Participants with ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score 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 Achilles 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 20mg Apremilast 30mg
    Number of subjects analysed
    115
    117
    111
    Units: percentage of participants
        number (not applicable)
    46.1
    48.7
    63.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.2
         upper limit
    15.5
    Notes
    [50] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.2
         upper limit
    29.8
    Notes
    [51] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    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 20mg Apremilast 30mg
    Number of subjects analysed
    90
    89
    84
    Units: percentage of participants
        number (not applicable)
    60.0
    66.3
    61.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority [52]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.8
         upper limit
    20.4
    Notes
    [52] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.6
         upper limit
    16.4
    Notes
    [53] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    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
    The EULAR response criteria classify each subject as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject’s DAS28 as the measure of severity of disease. Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2. 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    25.0
    41.1
    44.3
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [54]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    16.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.4
         upper limit
    25.8
    Notes
    [54] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    19.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.6
         upper limit
    29.1
    Notes
    [55] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

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    End point title
    Percentage of Participants with MASES Improvement ≥ 20% at Week 24
    End point description
    Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 24 weeks of treatment. The 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 Achilles 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 24
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    115
    117
    111
    Units: percentage of participants
        number (not applicable)
    48.7
    54.7
    66.7
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    18.8
    Notes
    [56] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.3
         upper limit
    30.6
    Notes
    [57] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    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 20mg Apremilast 30mg
    Number of subjects analysed
    90
    89
    84
    Units: percentage of participants
        number (not applicable)
    57.8
    69.7
    63.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority [58]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    11.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    25.9
    Notes
    [58] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    5.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    19.8
    Notes
    [59] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    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
    The EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on th DAS-28. Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    17.0
    34.9
    28.4
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [60]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    17.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.8
         upper limit
    26.8
    Notes
    [60] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.7
         upper limit
    20
    Notes
    [61] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: Percentage of participants
        number (not applicable)
    4.5
    11.4
    11.4
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [62]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    12.5
    Notes
    [62] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    12.4
    Notes
    [63] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    Secondary: Percentage of Participants with a ACR 70 response at Week 16

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    End point title
    Percentage of Participants with a 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    1.1
    4.0
    4.0
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [64]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    6.2
    Notes
    [64] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    6.1
    Notes
    [65] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    Secondary: Percentage of Participants with a ACR 50 response at Week 24

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    End point title
    Percentage of Participants with a 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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    6.3
    16.0
    12.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [66]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    9.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.2
         upper limit
    16.3
    Notes
    [66] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    12.3
    Notes
    [67] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    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 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    176
    Units: percentage of participants
        number (not applicable)
    4.0
    4.0
    4.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    351
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    4.1
    Notes
    [68] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    4.8
    Notes
    [69] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    Secondary: Percentage of Participants with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 at Week 16

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    End point title
    Percentage of Participants with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 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 Achilles 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 20mg Apremilast 30mg
    Number of subjects analysed
    115
    117
    111
    Units: percentage of participants
        number (not applicable)
    19.1
    21.4
    36.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority [70]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.1
         upper limit
    12.6
    Notes
    [70] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    17.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.3
         upper limit
    29.3
    Notes
    [71] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 at Week 16

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    End point title
    Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 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
    Baseline and Week 16
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    90
    89
    84
    Units: percentage of participants
        number (not applicable)
    33.3
    42.7
    40.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority [72]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    9.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.8
         upper limit
    23.5
    Notes
    [72] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    21.5
    Notes
    [73] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

    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
    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 Achilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data (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 20mg Apremilast 30mg
    Number of subjects analysed
    115
    117
    111
    Units: percentage of participants
        number (not applicable)
    22.6
    29.1
    37.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.8
         upper limit
    17.7
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    superiority [74]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    15.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    27.1
    Notes
    [74] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    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
    Baseline and Week 24
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    90
    89
    84
    Units: percentage of participants
        number (not applicable)
    35.6
    46.1
    40.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 20mg
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    10.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    24.8
    Notes
    [75] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 30mg
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [76]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    19.3
    Notes
    [76] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

    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 consists of all participants who were randomized or re-randomized to apremilast at any time during the study. 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
    67
    131
    138
    Units: Percentage of Participants
        number (confidence interval 95%)
    59.7 (46.4 to 71.9)
    56.7 (44.0 to 68.8)
    53.4 (44.5 to 62.2)
    58.7 (50.0 to 67.0)
    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 changes from Baseline in the overall score indicate improvement in functional ability. 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
    62
    68
    132
    139
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.21 ± 0.450
    -0.25 ± 0.533
    -0.32 ± 0.559
    -0.39 ± 0.567
    No statistical analyses for this end point

    Secondary: Change From Baseline in the SF-36v2 Physical Functioning Scale Score at Week 52

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    End point title
    Change From Baseline in the SF-36v2 Physical Functioning Scale Score at Week 52
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    62
    68
    132
    139
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.76 ± 8.236
    6.87 ± 7.241
    5.68 ± 8.467
    5.87 ± 8.008
    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
    Measure 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=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    61
    67
    131
    137
    Units: Percentage of Participants
        number (confidence interval 95%)
    73.8 (60.9 to 84.2)
    79.1 (67.4 to 88.1)
    75.6 (67.3 to 82.7)
    75.9 (67.9 to 82.8)
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Participants Assessment of Pain using the Visual Analog Scale at Week 52

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    End point title
    Change from Baseline in the Participants Assessment of Pain using the Visual Analog Scale 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
    62
    68
    132
    139
    Units: mm
        arithmetic mean (standard deviation)
    -13.1 ± 25.57
    -18.9 ± 24.28
    -15.6 ± 27.29
    -14.2 ± 28.14
    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 Achilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing enthesopathy) and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    41
    42
    91
    85
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.7 ± 2.38
    -1.8 ± 2.34
    -1.5 ± 2.62
    -1.8 ± 3.03
    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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing dactylitis) and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    32
    38
    70
    64
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.2 ± 1.89
    2.9 ± 2.47
    -2.2 ± 4.09
    -2.9 ± 3.55
    No statistical analyses for this end point

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

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    End point title
    Change From Baseline in the CDAI Score at Week 52
    End point description
    The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: 28 tender joint count (TJC), 28 swollen joint count (SJC), Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    61
    67
    131
    137
    Units: units on a scale
        arithmetic mean (standard deviation)
    -11.0 ± 10.288
    -14.67 ± 11.943
    -14.32 ± 11.128
    -13.98 ± 10.541
    No statistical analyses for this end point

    Secondary: Change From Baseline in the DAS28 at Week 52

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    End point title
    Change From Baseline in the DAS28 at Week 52
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    62
    68
    130
    138
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.08 ± 1.113
    -1.28 ± 1.044
    -1.37 ± 1.128
    -1.39 ± 0.970
    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
    62
    67
    131
    139
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.03 ± 8.787
    4.27 ± 9.461
    2.39 ± 10.197
    5.89 ± 10.471
    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 Achilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline MASES > 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
    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
    41
    42
    91
    85
    Units: Percentage of Participants
        number (confidence interval 95%)
    70.0 (54.5 to 83.9)
    81.0 (65.9 to 91.4)
    65.9 (55.3 to 75.5)
    69.4 (58.5 to 79.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline by ≥ 1 at Week 52

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    End point title
    Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline by ≥ 1 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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    32
    38
    70
    64
    Units: Percentage of Participants
        number (confidence interval 95%)
    93.8 (79.2 to 99.2)
    94.7 (82.3 to 99.4)
    87.1 (77.0 to 93.9)
    85.9 (75.0 to 93.4)
    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
    The EULAR response criteria classify each subject as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject’s DAS28 as the measure of severity of disease. A Good response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 A Moderate Response is defined as either: an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    62
    68
    130
    138
    Units: Percentage of Participants
        number (not applicable)
    64.5
    73.5
    75.4
    79.0
    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
    A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in 78 tender joint count; ≥ 50% improvement in 76 swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); 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 consists of all participants who were randomized or re-randomized to apremilast at any time during the study. Only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    62
    67
    129
    138
    Units: Percentage of Participants
        number (confidence interval 95%)
    30.6 (19.6 to 43.7)
    25.4 (15.5 to 37.5)
    27.1 (19.7 to 35.7)
    31.9 (24.2 to 40.4)
    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
    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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    61
    68
    131
    138
    Units: Percentage of Participants
        number (confidence interval 95%)
    8.2 (2.7 to 18.1)
    10.3 (4.2 to 20.1)
    13.7 (8.4 to 20.8)
    18.1 (12.1 to 25.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Pre-existing Enthesopathy whose MASES Improves from Baseline to 0 at Week 52

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    End point title
    Percentage of Participants with Pre-existing Enthesopathy whose MASES Improves from Baseline to 0 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 Achilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; 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
    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
    41
    42
    91
    85
    Units: percentage of participants
        number (confidence interval 95%)
    39.0 (24.2 to 55.5)
    61.9 (45.6 to 76.4)
    39.6 (29.5 to 50.4)
    45.9 (35.0 to 57.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline to 0 at Week 52

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    End point title
    Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline to 0 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. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo / Apremilast 20 mg Placebo / Apremilast 30 mg Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    32
    38
    70
    64
    Units: Percentage of Participants
        number (confidence interval 95%)
    75.0 (56.6 to 88.5)
    78.9 (62.7 to 90.4)
    68.6 (56.4 to 79.1)
    68.8 (55.9 to 79.8)
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Treatment Emergent Adverse Events During the Placebo Controlled Phase
    End point description
    A TEAE is an adverse event (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 subject during the course of a study. A serious AE is any AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. For both AEs and SAEs the investigator assessed the severity of the event according to the grading scale: Mild: asymptomatic or with mild symptoms, Moderate: symptoms causing moderate discomfort or Severe: symptoms causing severe discomfort or pain. Safety population included participants who were randomized and received at least one dose of IP.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16 for placebo participants who entered EE at Week 16 and up to Week 24 for all other participants (placebo participants who remained on placebo through week 24 and participants randomized to the APR 20 mg BID or APR 30 mg BID)
    End point values
    Placebo Apremilast 20mg Apremilast 30mg
    Number of subjects analysed
    176
    175
    175
    Units: Participants
        Any TEAE
    73
    87
    99
        Any Drug-Related TEAE
    25
    40
    58
        Any Severe TEAE
    6
    4
    2
        Any Serious TEAE (SAE)
    5
    3
    1
        Drug-Related (SAE)
    0
    0
    1
        Any TEAE Leading to Drug Interruption
    8
    11
    0
        Any TEAE Leading to Drug Wirhdrawal
    4
    4
    6
        Any TEAE Leading to Death
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Treatment Emergent 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 IP and no later than 28 days after the last dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. A SAE = AE that results in death; is life-threatening; requires inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. For both AEs and SAEs the severity of the event was applied to the grading scale: Mild: asymptomatic or with mild symptoms, Moderate: symptoms causing moderate discomfort or Severe: symptoms causing severe discomfort. Apremilast Subjects as Treated (AAT) received at least 1 dose of APR at any time during the study. Subjects were included in the treatment group corresponding to the APR dosing regimen they received, irrespective of the treatment group to which they were randomized or re-randomized.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 260; median duration of exposure to apremilast 20 mg BID was 168.93 weeks and 229.36 weeks for apremilast 30 mg BID
    End point values
    Apremilast 20 mg (Pre-Switch) Apremilast 20/30 mg (Post-Switch) Apremilast 30 mg
    Number of subjects analysed
    252
    122
    252
    Units: Participants
        Any TEAE
    188
    60
    204
        Any Drug-Related TEAE
    89
    16
    113
        Any Severe TEAE
    24
    3
    23
        Any Serious TEAE (SAE)
    35
    5
    36
        Drug-Related (SAE)
    6
    1
    6
        Any TEAE Leading to Drug Interruption
    41
    5
    36
        Any TEAE Leading to Drug Wirhdrawal
    22
    2
    26
        Any TEAE Leading to Death
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are reported for the placebo-controlled phase from Week 0 to Week 16 for placebo subjects who entered EE at Week 16 and up to Week 24 for all others and reported for the Apremilast Exposure Period from Week 0 to Week 260
    Adverse event reporting additional description
    Median duration of APR 20 mg BID was 168.93 weeks and 229.36 weeks for apremilast 30 mg twice daily
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    V14.0
    Reporting groups
    Reporting group title
    Weeks 0-24: Placebo (Placebo-Controlled Phase)
    Reporting group description
    Participants received placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for participants who escaped early, and through Week 24 for all other participants.

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

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

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

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

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

    Serious adverse events
    Weeks 0-24: Placebo (Placebo-Controlled Phase) Weeks 0-24: Apremilast 20 mg (Placebo-Controlled Phase) Weeks 0-24: Apremilast 30 mg (Placebo-Controlled Phase) APR Exposure Period Up to 5 Years: Apremilast 20 mg APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg APR Exposure Period Up to 5 Years: Apremilast 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 176 (2.84%)
    3 / 175 (1.71%)
    1 / 175 (0.57%)
    35 / 252 (13.89%)
    5 / 122 (4.10%)
    36 / 252 (14.29%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Femoral artery occlusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Varicose vein
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Lung squamous cell carcinoma stage unspecified
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Papilloma
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Prostate cancer
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Endometrial atrophy
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    0 / 252 (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
    Metrorrhagia
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Rectocele
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Contusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Incisional hernia
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    1 / 122 (0.82%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Multiple injuries
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Post procedural fistula
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Radius fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Tibia fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Angina pectoris
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    2 / 252 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    2 / 252 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Coronary artery disease
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    2 / 252 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Palpitations
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Pericarditis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Haemoptysis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    0 / 252 (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
    Nasal polyps
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Blood and lymphatic system disorders
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         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 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Epilepsy
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Sciatica
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Spinal cord compression
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    2 / 252 (0.79%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo CNS origin
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Eye disorders
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Anal fissure
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Colitis
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Diarrhoea
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    0 / 122 (0.00%)
    0 / 252 (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
    Enterocele
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Inguinal hernia
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 252 (0.40%)
    1 / 122 (0.82%)
    3 / 252 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Pancreatitis acute
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 176 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 252 (0.00%)
    0 / 122 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0