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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study To Evaluate The Efficacy And Safety Of Apremilast (Cc-10004) In The Treatment Of Active Ankylosing Spondylitis

    Summary
    EudraCT number
    		 2011-001555-37
    Trial protocol
    		 GB   HU   DE   SK   NL   ES   PL   SE   CZ   AT   BG   FR   EE  
    Global end of trial date
    25 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2019
    First version publication date
    11 Nov 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-AS-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01583374
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Sue Cheng, MD, Celgene Corporation, 01 908 887-3916, SuCheng@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
    25 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of APR 30 BID, compared with placebo, in the reduction of signs and symptoms in subjects with active AS at 16 weeks of treatment.
    Protection of trial subjects
    Patient Confidentiality, Informed Consent, Archiving of Essential Documents
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 30
    Country: Number of subjects enrolled
    Czech Republic: 75
    Country: Number of subjects enrolled
    Estonia: 25
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    490
    EEA total number of subjects
    354
    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)
    458
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study enrolled participants at 88 study sites and in 18 countries (Australia, Austria, Bulgaria, Czech Republic, Estonia, France, Germany, Hungary, the Netherlands, Poland, Romania, Russia, Slovakia, Spain, the United Kingdom, Canada, Sweden, and the United States [US]).

    Pre-assignment
    Screening details
    		 Randomized participants were stratified by the following 2 parameters: 1. C-Reactive Protein (CRP) concentration (normal: ≤ 1.5 mg/dL or elevated: > 1.5 mg/dL) from screening; 2. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score < 6.0 or BASDAI score ≥ 6.0 from baseline.

    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, Carer, Assessor
    Blinding implementation details
    The blind was not to be broken during the course of the study unless, in the opinion of the Investigator, it was absolutely necessary to safely treat the subject. If it was medically imperative to know what IP the subject was receiving, the Investigator or authorized person could call the IVRS for unblinded dose information according to the procedure supplied by the IVRS vendor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants initially randomized to receive placebo tablets BID in the 24-week placebo-controlled phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets (identical in appearance to apremilast) twice daily

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

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

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

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

    Number of subjects in period 1
    		Placebo Apremilast 20 mg Apremilast 30 mg
    Started
    164
    163
    163
    Received Treatment
    164
    163
    163
    Completed Week 16
    150
    151
    144
    Early Escape at Week 16
    51 [1]
    49 [2]
    49 [3]
    Completed
    145
    147
    138
    Not completed
    19
    16
    25
         Consent withdrawn by subject
    8
    3
    5
         Adverse event, non-fatal
    6
    7
    12
         Non-compliance with study drug
    1
    1
    -
         Unspecified
    -
    1
    -
         Lost to follow-up
    1
    2
    -
         Lack of efficacy
    3
    2
    5
         Protocol deviation
    -
    -
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 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
    Extension Phase (Weeks 24 to 52)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The blind was not to be broken during the course of the study unless, in the opinion of the Investigator, it was absolutely necessary to safely treat the subject. If it was medically imperative to know what IP the subject was receiving, the Investigator or authorized person could call the IVRS for unblinded dose information according to the procedure supplied by the IVRS vendor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apremilast 20 mg
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase, continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo / Apremilast 30 mg Early Escape (EE)
    Arm description
    		 Participants initially randomized to receive placebo tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the Assessment of SpondyloArthritis International Society (ASAS) domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo/Apremilast 30 mg Crossover (XO)
    Arm description
    		 Participants initially randomized to placebo tablets BID in the 24-week placebo controlled phase were transitioned to 30 mg apremilast tablets BID at Week 24 and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg /Apremilast 30 mg EE
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase who did not have at least 20% improvement or a ≥ 1-unit improvement from baseline in 2 of the 4 ASAS domains at Week 16 continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 20 mg /Apremilast 30 mg EE
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg /Apremilast 30 mg Second Escape (SE)
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains from baseline at Week 24 continued to receive 30 mg apremilast tablets BID (second escape) for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 20 mg/Apremilast 30 mg SE
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 24 were transitioned to 30 mg apremilast tablets BID (second escape) and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Number of subjects in period 2 [4]
    		Apremilast 20 mg Apremilast 30 mg Placebo / Apremilast 30 mg Early Escape (EE) Placebo/Apremilast 30 mg Crossover (XO) Apremilast 30 mg /Apremilast 30 mg EE Apremilast 20 mg /Apremilast 30 mg EE Apremilast 30 mg /Apremilast 30 mg Second Escape (SE) Apremilast 20 mg/Apremilast 30 mg SE
    Started
    74
    65
    47
    91
    48
    48
    25
    23
    Completed
    69
    61
    41
    85
    43
    43
    22
    21
    Not completed
    5
    4
    6
    6
    5
    5
    3
    2
         Non-compliance study drug
    2
    1
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    1
    -
    1
    2
    -
    -
    -
         Adverse event, non-fatal
    1
    2
    -
    1
    1
    -
    1
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
    -
         Lack of efficacy
    2
    -
    6
    3
    2
    5
    1
    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 Extension Phase (Weeks 52-260)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apremilast 20 mg
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase, continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo / Apremilast 30 mg Early Escape (EE)
    Arm description
    		 Participants initially randomized to receive placebo tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the Assessment of SpondyloArthritis International Society (ASAS) domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo/Apremilast 30 mg Crossover (XO)
    Arm description
    		 Participants initially randomized to placebo tablets BID in the 24-week placebo controlled phase were transitioned to 30 mg apremilast tablets BID at Week 24 and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg /Apremilast 30 mg EE
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase who did not have at least 20% improvement or a ≥ 1-unit improvement from baseline in 2 of the 4 ASAS domains at Week 16 continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 20 mg /Apremilast 30 mg EE
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 30 mg /Apremilast 30 mg Second Escape (SE)
    Arm description
    		 Participants initially randomized to 30 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains from baseline at Week 24 continued to receive 30 mg apremilast tablets BID (second escape) for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast 20 mg/Apremilast 30 mg SE
    Arm description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 24 were transitioned to 30 mg apremilast tablets BID (second escape) and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Arm type
    		 Experimental

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

    Number of subjects in period 3 [5]
    		Apremilast 20 mg Apremilast 30 mg Placebo / Apremilast 30 mg Early Escape (EE) Placebo/Apremilast 30 mg Crossover (XO) Apremilast 30 mg /Apremilast 30 mg EE Apremilast 20 mg /Apremilast 30 mg EE Apremilast 30 mg /Apremilast 30 mg Second Escape (SE) Apremilast 20 mg/Apremilast 30 mg SE
    Started
    66
    61
    35
    81
    39
    38
    21
    20
    Completed
    40
    41
    22
    50
    22
    20
    12
    10
    Not completed
    26
    20
    13
    31
    17
    18
    9
    10
         Adverse event, serious fatal
    -
    -
    -
    1
    -
    1
    -
    -
         Noncomplinace with IP
    -
    -
    -
    1
    -
    -
    1
    1
         Consent withdrawn by subject
    11
    11
    1
    12
    7
    5
    3
    3
         Adverse event, non-fatal
    5
    2
    2
    6
    2
    2
    3
    1
         Miscellaneous
    5
    1
    2
    -
    1
    5
    -
    1
         Lost to follow-up
    1
    -
    1
    1
    -
    1
    -
    -
         Lack of efficacy
    4
    6
    7
    10
    7
    4
    2
    4
    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.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants initially randomized to receive placebo tablets BID in the 24-week placebo-controlled phase.

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

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

    Reporting group values
    		 Placebo Apremilast 20 mg Apremilast 30 mg Total
    Number of subjects
    		 164 163 163 490
    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)
    		 147 156 155 458
        From 65-84 years
    		 17 7 8 32
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ( 12.89 ) 45.2 ( 11.90 ) 44.8 ( 11.75 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 40 42 56 138
        Male
    		 124 121 107 352
    Duration of Ankylosing Spondylitis
    Units: Subjects
        ≤ 2 years
    		 41 48 40 129
        > 2 to ≤ 5 years
    		 29 23 26 78
        > 5 to ≤ 10 years
    		 33 29 33 95
        > 10 years
    		 61 63 64 188
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 2 2 0 4
        Black or African American
    		 1 2 2 5
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        White
    		 158 154 158 470
        Other
    		 1 2 3 6
        Missing
    		 1 3 0 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 1 1 7
        Not Hispanic or Latino
    		 158 159 162 479
        Unknown or Not Reported
    		 1 3 0 4
    Duration of Ankylosing Spondylitis (Lower Back Pain and Stiffness)
    Units: years
        arithmetic mean (standard deviation)
    		 10.40 ( 10.375 ) 11.06 ( 11.302 ) 10.32 ( 9.887 ) -
    Baseline Bath Ankylosing Spondylitis Functional Index (BASFI) Score (0 - 10 NRS)
    The BASFI was a composite score based on a participant self-administered survey of ten questions using a 0 to 10 unit numerical rating scale (NRS) that BASFI is a composite score based on a self-administered survey of 10 questions using a 0 to 10 unit numerical rating scale (NRS) that assesses the degree of mobility and functional ability. The survey consists of 8 questions regarding function in AS and the last 2 reflect the ability to manage everyday life. The patient marks a box with an X on a 0 to 10 unit NRS for 10 questions; the left-hand box of 0 = easy; the right-hand box = impossible.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 5.76 ( 2.194 ) 5.75 ( 2.061 ) 5.65 ( 2.100 ) -
    Baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score (0 - 10 NRS)
    The BASDAI is a composite score based on a self-administered survey of 6 questions using a 0 to 10 unit NRS that assesses for 5 major symptoms of AS: fatigue; spinal pain; peripheral joint pain/swelling; areas of localized tenderness; morning stiffness severity upon wakening; morning stiffness duration upon wakening. To give each of the 5 symptoms equal weighting, the mean of the 2 scores relating to morning stiffness is taken. The resulting 0 to 50 score is divided by 5 to give a final 0 to 10 BASDAI score. A score of ≥4 is considered to be indicative of active
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 6.45 ( 1.319 ) 6.46 ( 1.352 ) 6.37 ( 1.357 ) -
    Baseline Bath Ankylosing Spondylitis Metrology Index (BASMI)-Linear Score (0 - 10 NRS)
    The BASMI-Linear was designed to assess axial status (ie, cervical, dorsal and lumbar spine, hips, and pelvic soft tissue) and to define clinically significant changes in spinal movement. Five dimensions of movement (lateral lumbar flexion, tragus to wall, forward lumbar flexion, maximal intermalleolar distance, and cervical rotation) were measured and normalized on 0 to 10 unit NRS. The average of these scores is the total BASMI score, with a higher value indicating more severe limitation in spinal mobility.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 4.36 ( 1.608 ) 4.63 ( 1.721 ) 4.41 ( 1.700 ) -
    Baseline Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score (0-18)
    The ASQoL is a validated disease specific patient reported outcomes instrument to assess the impact of ankylosing spondylitis on the QoL of individuals with emphasis on the ability of the person to fulfill his or her needs. It consisted of 18 items requesting a yes (score=1) or no (score=0) response to questions related to the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. The summary score ranges 0–18 with higher scores indicating worse quality of life.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 9.10 ( 4.639 ) 8.38 ( 4.548 ) 8.62 ( 4.935 ) -
    Baseline Physical Component Summary Score of Medical Outcome Study Short Form 36-Item Survey
    The SF- 36 is a self-administered instrument that measures the impact of disease and consists of 36 questions in 8 domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Two overall summary scores can also be obtained—a Physical Component Summary score (PCS) and a Mental Component Summary score (MCS). The PCS and MCS scores are transformed to have a mean of 50 and standard deviation of 10, with higher scores indicating better health. Scale scores range from 0 to 100, with higher scores indicating better health.
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    		 32.57 ( 7.821 ) 31.89 ( 8.561 ) 32.16 ( 8.846 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants initially randomized to receive placebo tablets BID in the 24-week placebo-controlled phase.

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

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase, continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Placebo / Apremilast 30 mg Early Escape (EE)
    Reporting group description
    		 Participants initially randomized to receive placebo tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the Assessment of SpondyloArthritis International Society (ASAS) domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Placebo/Apremilast 30 mg Crossover (XO)
    Reporting group description
    		 Participants initially randomized to placebo tablets BID in the 24-week placebo controlled phase were transitioned to 30 mg apremilast tablets BID at Week 24 and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg /Apremilast 30 mg EE
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase who did not have at least 20% improvement or a ≥ 1-unit improvement from baseline in 2 of the 4 ASAS domains at Week 16 continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 20 mg /Apremilast 30 mg EE
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg /Apremilast 30 mg Second Escape (SE)
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains from baseline at Week 24 continued to receive 30 mg apremilast tablets BID (second escape) for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 20 mg/Apremilast 30 mg SE
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 24 were transitioned to 30 mg apremilast tablets BID (second escape) and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.
    Reporting group title
    Apremilast 20 mg
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase, continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Placebo / Apremilast 30 mg Early Escape (EE)
    Reporting group description
    		 Participants initially randomized to receive placebo tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the Assessment of SpondyloArthritis International Society (ASAS) domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Placebo/Apremilast 30 mg Crossover (XO)
    Reporting group description
    		 Participants initially randomized to placebo tablets BID in the 24-week placebo controlled phase were transitioned to 30 mg apremilast tablets BID at Week 24 and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg /Apremilast 30 mg EE
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase who did not have at least 20% improvement or a ≥ 1-unit improvement from baseline in 2 of the 4 ASAS domains at Week 16 continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 20 mg /Apremilast 30 mg EE
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 16 were transitioned to 30 mg apremilast tablets BID and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 30 mg /Apremilast 30 mg Second Escape (SE)
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains from baseline at Week 24 continued to receive 30 mg apremilast tablets BID (second escape) for up to 4.5 years in the long-term extension phase.

    Reporting group title
    Apremilast 20 mg/Apremilast 30 mg SE
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets BID who did not have at least 20% improvement or ≥ 1 unit improvement from baseline in 2 out of 4 of the ASAS domains at Week 24 were transitioned to 30 mg apremilast tablets BID (second escape) and continued to receive 30 mg apremilast tablets BID for up to 4.5 years in the long-term extension phase.

    Subject analysis set title
    Placebo/Apremilast 30 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who initially received placebo tablets BID during the placebo controlled phase were transitioned to 30 mg apremilast tablets BID either at Week 16 or Week 24.

    Subject analysis set title
    Apremilast 20 mg/ Apremilast 30 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who were initially randomized to 20 mg apremilast tablets BID at Week 0 and transitioned to 30 mg apremilast tablets BID at either Week 16 or Week 24.

    Subject analysis set title
    Apremilast 20 mg/Apremilast 20 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who were initially randomized to receive 20 mg apremilast PO BID at Week 0 and continued to receive 20 mg apremilast PO BID without the transition to 30 mg apremilast PO BID.

    Subject analysis set title
    Apremilast 20/30 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants who initially received 20 mg apremilast tablets BID at Week 0 who escaped to 30 mg apremilast BID. Only the TEAEs that occurred during the apremilast 30 mg BID dose were included.

    Subject analysis set title
    Apremilast 20 mg (APR Exposure Period)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received 20 mg apremilast tablets BID only in the study. This also includes participants who initially received APR 20 BID and switched to APR 30 BID treatment. Only the TEAEs that occurred during the 20 mg apremilast BID dose were included.

    Subject analysis set title
    Apremilast 20 mg/30 mg (APR Exposure Period)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who initially received 20 mg apremilast tablets BID at Week 0 who escaped to 30 mg apremilast BID. Only the TEAEs that occurred during the apremilast 30 mg BID dose were included.

    Subject analysis set title
    Apremilast 30 mg (APR Exposure Period)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants initially randomized to 30 mg apremilast tablets BID at Week 0 and participants who received placebo at Week 0 who escaped to 30 mg apremilast BID. Only the TEAEs that occurred during the APR 30 BID dose were included.

    Subject analysis set title
    Apremilast 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants initially randomized to 20 mg apremilast tablets BID in the 24-week placebo-controlled phase, and continued to receive apremilast 20 mg or 30 mg during weeks 24 to 260. The radiograph subset analysis population included randomized participants who received at least one dose of IP and had at least a baseline radiograph available. Includes apremilast participants as treated who had a baseline and at least one post-baseline score. Missing scores were imputed using the LOCF.

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants initially randomized at Week 0 to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase and continued to receive apremilast 30 mg during weeks 24 to 260. The radiograph subset analysis population included randomized participants who received at least one dose of IP and had at least a baseline radiograph available. Includes apremilast participants as treated who had a baseline and at least one post-baseline score. Missing scores were imputed using the LOCF.

    Subject analysis set title
    Placebo/Apremilast 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who initially received placebo tablets BID during the placebo controlled phase were transitioned to 30 mg apremilast tablets BID either at Week 16 or Week 24 through to Week 260. The radiograph subset analysis population included randomized participants who received at least one dose of IP and had at least a baseline radiograph available. Includes apremilast participants as treated who had a baseline and at least one post-baseline score. Missing scores were imputed using the LOCF.

    Subject analysis set title
    Apremilast 20 mg/ Apremilast 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were initially randomized to 20 mg apremilast tablets BID at Week 0 and transitioned to 30 mg apremilast tablets BID at either Week 16 or Week 24 through to Week 260. The radiograph subset analysis population included randomized participants who received at least one dose of IP and had at least a baseline radiograph available. Includes apremilast participants as treated who had a baseline and at least one post-baseline score. Missing scores were imputed using the LOCF.

    Subject analysis set title
    Apremilast 20 mg/Apremilast 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were initially randomized to receive 20 mg apremilast PO BID at Week 0 and continued to receive 20 mg apremilast PO BID through to Week 260 without the transition to 30 mg apremilast PO BID. The radiograph subset analysis population included randomized participants who received at least one dose of IP and had at least a baseline radiograph available. Includes apremilast participants as treated who had a baseline and at least one post-baseline score. Missing scores were imputed using the LOCF.

    Primary: Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS 20) at Week 16

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    End point title
    		 Percentage of Participants Who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS 20) at Week 16
    End point description
    ASAS 20 = achieving an improvement from baseline (BL) of ≥ 20% and ≥ 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from BL of ≥ 20% and ≥ 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains: 1. Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); subject marks an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active, right-hand box = very active 2. Total Back Pain (0 - 10 unit NRS); subject marks an X on a 0 - 10 unit NRS; the left-hand box of 0 = no pain, right-hand box = most severe pain 3. Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); subjects provide a self-administered survey assessing for mobility and functional ability 4. Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit). The mITT population = subjects who were randomized and received at least one dose of study drug
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    164
    163
    163
    Units: Percentage of Participants
        number (not applicable)
    36.6
    35.0
    32.5
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference is the weighted average of the treatment differences across the 4 strata of screening CRP category and baseline BASDAI score category with the Cochran-Mantel-Haenszel weights.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4383 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.3
         upper limit
    		 6.2
    Notes
    [1] - 2 sided p-value was based on CMH test adjusting for C-reactive protein (CRP) category and baseline BASDAI score category
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.7427 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 8.5
    Notes
    [2] - Adjusted difference is the weighted average of the treatment differences across the 4 strata of screening CRP category and baseline BASDAI score category with the Cochran-Mantel-Haenszel weights.
    [3] - 2 sided p-value was based on CMH test adjusting for C-reactive protein (CRP) category and baseline BASDAI score category.

    Secondary: Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24

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    End point title
    		 Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24
    End point description
    The BASFI is a composite score based on a self-administered survey of 10 questions using a 0 to 10 unit numerical rating scale (NRS) that assesses the degree of mobility and functional ability. The survey consists of 8 questions regarding function in AS and the last 2 reflect the ability to manage everyday life. The patient marks a box with an X on a 0 to 10 unit NRS for 10 questions; the left-hand box of 0 = easy; the right-hand box = impossible. The resulting 0 to 100 score is divided by 10 to give a final 0 to 10 BASFI score. The overall score is the mean of the 10 items and ranges from 0 to 10. A higher score correlates to reduced functional ability. The mITT population = those who were randomized and received at least one dose of study drug. Missing data were imputed as baseline carried forward for subjects who escaped early or discontinued early (prior to Week 24) due to lack of efficacy and LOCF for other early discontinuations.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    164
    163
    163
    Units: Units on a Scale
        least squares mean (standard error)
    -0.94 ( 0.136 )
    -1.11 ( 0.137 )
    -0.99 ( 0.138 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8032 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.32
    Notes
    [4] - Based on ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3624 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.19
    Notes
    [5] - Based on ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.

    Secondary: Change from Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24

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    End point title
    		 Change from Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24
    End point description
    The BASDAI is a composite score based on a subjects self-administered survey of six questions using a 0 - 10 unit NRS that assesses the subjects' 5major symptoms of AS: 1) fatigue; 2) spinal pain; 3) peripheral joint pain/swelling; 4) areas of localized tenderness; 5a) morning stiffness severity upon wakening; 5b) morning stiffness duration upon wakening. The subject was asked to mark the box with a X on a 0 - 10 unit NRS for each of the 6 questions. To give each of the 5 symptoms equal weighting, the mean of the 2 scores relating to morning stiffness is taken. The resulting 0 - 50 score was divided by 5 to give a final 0 to 10 BASDAI score. A BASDAI score of ≥4 is considered to be indicative of active AS disease. The mITT population = those who were randomized and received at least one dose of study drug. Missing data were imputed as baseline carried forward for subjects who EE or discontinued early (prior to Week 24) due to lack of efficacy and LOCF for other early discontinuations
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    164
    162
    160
    Units: Units on a Scale
        least squares mean (standard error)
    -1.21 ( 0.136 )
    -1.30 ( 0.136 )
    -1.18 ( 0.137 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8618 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.4
    Notes
    [6] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6262 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 0.27
    Notes
    [7] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.

    Secondary: Percentage of Participants who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS) at Week 24

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    End point title
    		 Percentage of Participants who Achieved an Assessment of SpondyloArthritis International Society 20 (ASAS) at Week 24
    End point description
    ASAS 20 = achieving an improvement from baseline (BL) of ≥ 20% and ≥ 1 unit in at least 3 of 4 ASAS domains on a scale of 0 to 10 units and no worsening from BL of ≥ 20% and ≥ 1 unit in the remaining ASAS domain on a scale of 0 to 10 units. The 4 ASAS domains: 1. Patient Global Assessment of Disease (0 - 10 unit Numerical Rating Scale [NRS]); subject marks an X on a 0 - 10 unit NRS; the left-hand box of 0 = not active, right-hand box = very active 2. Total Back Pain (0 to 10 unit NRS); subject marks an X on a 0 - 10 unit NRS; the lefthand box of 0 = no pain, right-hand box = most severe pain 3. Function (Bath AS Functional Index [BASFI] NRS 0 - 10 unit); subjects provides a self-administered survey assessing for mobility and functional ability 4. Inflammation domain is determined by the mean of 2 Bath AS Disease Activity Index NRS Questions #5 and #6 for morning stiffness) (0 - 10 unit). The mITT population = subjects who were randomized and received at least one dose of study dru
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    164
    163
    163
    Units: Percentage of Participants
        number (not applicable)
    31.7
    36.2
    33.7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.6958 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 12.2
    Notes
    [8] - Adjusted difference is the weighted average of the treatment differences across the 4 strata of screening CRP category and baseline BASDAI score category with the Cochran-Mantel-Haenszel (CMH) weights
    [9] - 2 sided p-value was based on CMH test adjusting for C-reactive protein (CRP) category and baseline BASDAI score category
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.4051 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 14.5
    Notes
    [10] - Adjusted difference is the weighted average of the treatment differences across the 4 strata of screening CRP category and baseline BASDAI score category with the Cochran-Mantel-Haenszel (CMH) weights
    [11] - 2 sided p-value was based on CMH test adjusting for C-reactive protein category and baseline BASDAI score category.

    Secondary: Change from Baseline in the Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score at Week 24

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    End point title
    		 Change from Baseline in the Ankylosing Spondylitis Quality of Life (ASQoL) Summary Score at Week 24
    End point description
    The ASQoL is a validated disease specific patient reported outcomes instrument to assess the impact of ankylosing spondylitis on the quality of life of individuals with emphasis on the ability of the person to fulfill his or her needs. It consisted of 18 items requesting a yes (score=1) or no (score=0) response to questions related to the impact of pain on sleep, mood, motivation, ability to cope, activities of daily living, independence, relationships, and social life. The summary score ranges 0–18 with higher scores indicating worse quality of life. The mITT population included those who were randomized and received at least one dose of study drug. Missing data were imputed as baseline carried forward for participants who escaped early or discontinued early (prior to Week 24) due to lack of efficacy and LOCF for other early discontinuations.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    160
    161
    156
    Units: Units on a Scale
        least squares mean (standard error)
    -1.77 ( 0.278 )
    -1.50 ( 0.278 )
    -1.52 ( 0.281 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5126 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.99
    Notes
    [12] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4624 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 1.01
    Notes
    [13] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.

    Secondary: Change from Baseline in the Physical Component Summary Score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) at Week 24

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    End point title
    		 Change from Baseline in the Physical Component Summary Score (PCS) of Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) at Week 24
    End point description
    The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) was 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 (based on US general population with mean of 50 and standard deviation of 10) were used in analyses. Higher scores indicate a higher level of functioning. The PCS encompasses physical functioning, role-physical, and bodily pain, as well as general health and vitality. A positive change from baseline score indicates an improvement.The mITT included those who were randomized and received at least one dose of IP. Missing data were imputed as baseline carried forward for participants who escaped early or discontinued early (prior to Week 24) due to lack of efficacy and LOCF for other early discontinuations.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    160
    161
    155
    Units: Units on a Scale
        least squares mean (standard error)
    3.50 ( 0.553 )
    3.46 ( 0.551 )
    3.79 ( 0.559 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6997 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 1.76
    Notes
    [14] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9587 [15]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.42
    Notes
    [15] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.

    Secondary: Change from Baseline in Bath Ankylosing Spondylitis Metrology Index-Linear (BASMI-Linear) at Week 24

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    End point title
    		 Change from Baseline in Bath Ankylosing Spondylitis Metrology Index-Linear (BASMI-Linear) at Week 24
    End point description
    The BASMI-Linear was designed to assess axial status (ie, cervical, dorsal and lumbar spine, hips, and pelvic soft tissue) and to define clinically significant changes in spinal movement. Five dimensions of movement (lateral lumbar flexion, tragus to wall, forward lumbar flexion, maximal intermalleolar distance, and cervical rotation) were measured and normalized on 0 to 10 unit NRS. The average of these scores was the total BASMI score, ranging from 0-10 with higher values indicating more severe limitation in spinal mobility. The mITT population included those who were randomized and received at least one dose of study drug. Missing data were imputed as baseline carried forward for participants who escaped early or discontinued early (prior to Week 24) due to lack of efficacy and LOCF for other early discontinuations.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    163
    162
    158
    Units: Units on a Scale
        least squares mean (standard error)
    -0.19 ( 0.042 )
    -0.16 ( 0.043 )
    -0.13 ( 0.043 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3307 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.17
    Notes
    [16] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 20 mg
    Number of subjects included in analysis
    325
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5938 [17]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.14
    Notes
    [17] - Based on an ANCOVA model for change from baseline with treatment group, CRP and baseline BASDAI score as factors and baseline value as covariate.

    Secondary: Change from Baseline in the Radiographic Score Using the Modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 and Week 260

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    End point title
    		 Change from Baseline in the Radiographic Score Using the Modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 and Week 260
    End point description
    The Modified Stoke Ankylosing Spondylitis Spine Score is a scoring method used to determine the amount or degree of ankylosing spondylitis disease that is in the spine based on x-ray radiographs of the spine. The m-SASSS scores 0-3. 0 = No abnormality, 1 = Erosion, Sclerosis or Squaring, 2 = Syndesmophyte, 3 = Total bony Bridging at each Site. An increase in the m-SASSS indicated a worsening of AS disease.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 104 and Week 260
    End point values
    		 Apremilast 20 mg Apremilast 30 mg Placebo/Apremilast 30 mg Apremilast 20 mg/ Apremilast 30 mg Apremilast 20 mg/Apremilast 20 mg
    Number of subjects analysed
    81 [18]
    81 [19]
    74 [20]
    35 [21]
    46 [22]
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Week 104
    0.99 ( 3.018 )
    0.65 ( 2.453 )
    0.98 ( 3.768 )
    0.82 ( 2.435 )
    1.12 ( 3.417 )
        Week 260
    3.14 ( 8.292 )
    1.76 ( 6.997 )
    1.92 ( 7.363 )
    2.21 ( 5.959 )
    3.83 ( 9.652 )
    Notes
    [18] - N = 81, 83
    [19] - N = 81, 84
    [20] - N = 74, 79
    [21] - N = 35, 35
    [22] - N = 46, 48
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) during the Placebo Controlled Phase

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) during the Placebo Controlled Phase
    End point description
    A TEAE was an adverse event (AE) with a start date on or after the date of the first dose of investigational product and no later than 28 days after the last dose of IP for subjects who discontinued early. A serious AE = 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; constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort. Safety population included all subjects who were randomized and received at least one dose of IP. Includes data through Week 16 for placebo-treated and apremilast 20 mg BID treated subjects who EE and data up to Week 24 for all other subjects.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 24; the median duration of exposure was 23.57 weeks for the placebo arm, 23.71 weeks for the apremilast 20 mg arm and 24.00 weeks for the apremilast 30 mg arm.
    End point values
    		 Placebo Apremilast 20 mg Apremilast 30 mg
    Number of subjects analysed
    164
    163
    163
    Units: participants
        Any Treatment Emergent Adverse Event
    83
    91
    88
        Any Drug-related TEAE
    24
    44
    51
        Any Severe TEAE
    0
    2
    5
        Any Serious TEAE
    1
    3
    6
        Any Serious Drug-related TEAE
    0
    0
    3
        Any TEAE Leading to Drug Interruption
    14
    13
    14
        Any TEAE Leading to Drug Withdrawal
    7
    11
    13
        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 was an adverse event (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 of IP for subjects who discontinued early. A serious AE = 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; constitutes an important medical event. The severity of AEs was assessed based on the following scale: Mild = asymptomatic or mild symptoms, clinical or diagnostic observations only; Moderate = symptoms cause moderate discomfort; Severe = symptoms causing severe pain discomfort.Apremilast Subjects as Treated were those who 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 actually 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; the median duration of treatment was 24, 163, and 216 weeks in the Apremilast 20 mg, Apremilast 20/30 mg and Apremilast 30 mg treatment groups respectively.
    End point values
    		 Apremilast 20 mg (APR Exposure Period) Apremilast 20 mg/30 mg (APR Exposure Period) Apremilast 30 mg (APR Exposure Period)
    Number of subjects analysed
    163
    72
    305
    Units: Participants
        Any Treatment Emergent Adverse Event
    114
    47
    239
        Any Severe TEAE
    5
    8
    23
        Any Serious TEAE
    12
    8
    41
        Any TEAE Leading to Drug Interruption
    22
    11
    51
        Any TEAE Leading to Drug Withdrawal
    18
    4
    34
        Any TEAE Leading to Death
    0
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported for the placebo-controlled phase from Week 0 to Week 16 for placebo participants who entered EE at Week 16 and up to Week 24 for all other participants.
    Adverse event reporting additional description
    AEs were reported for the apremilast (APR) exposure period from Week 0 to Week 260, irrespective of when the APR started (Week 0, 16 or 24). The median duration of treatment was 24, 163, and 216 weeks in the Apremilast 20 mg, Apremilast 20/30 mg and Apremilast 30 mg treatment groups respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo (Weeks 0-24) Placebo-Controlled Phase
    Reporting group description
    		 Participants randomized to placebo tablets twice daily (BID) in the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast 20 mg BID (Weeks 0-24) Placebo-Controlled Phase
    Reporting group description
    		 Participants initially randomized to 20 mg apremilast tablets (APR) BID in the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg BID (Weeks 0-24) Placebo-Controlled Phase
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID in the 24-week placebo-controlled phase.

    Reporting group title
    Apremilast 20 mg BID (APR Exposure Period)
    Reporting group description
    		 Participants who initially received 20 mg apremilast tablets BID at Week 0 who escaped to 30 mg apremilast BID. Only the TEAEs that occurred during the 20 mg apremilast BID dose were included.

    Reporting group title
    Apremilast 20/30 mg BID (APR Exposure Period)
    Reporting group description
    		 Participants who initially received 20 mg apremilast tablets BID at Week 0 who escaped to 30 mg apremilast BID. Only the TEAEs that occurred during the 20 mg apremilast BID dose were included.

    Reporting group title
    Apremilast 30 mg BID (APR Exposure Period)
    Reporting group description
    		 Participants initially randomized to 30 mg apremilast tablets BID at Week 0 and participants who received placebo at Week 0 who escaped to 30 mg apremilast tablets BID. Only the TEAEs that occurred during the 30 mg apremilast BID dose were included.

    Serious adverse events
    		 Placebo (Weeks 0-24) Placebo-Controlled Phase Apremilast 20 mg BID (Weeks 0-24) Placebo-Controlled Phase Apremilast 30 mg BID (Weeks 0-24) Placebo-Controlled Phase Apremilast 20 mg BID (APR Exposure Period) Apremilast 20/30 mg BID (APR Exposure Period) Apremilast 30 mg BID (APR Exposure Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 164 (0.61%)
    3 / 163 (1.84%)
    6 / 163 (3.68%)
    12 / 163 (7.36%)
    8 / 72 (11.11%)
    41 / 305 (13.44%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Malignant melanoma
         subjects affected / exposed
    1 / 164 (0.61%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    0 / 305 (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
    Prostate cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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 cancer
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Lung infiltration
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Pulmonary embolism
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Suicide attempt
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cardiac function disturbance postoperative
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Humerus fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Tibia fracture
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    1 / 72 (1.39%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Sick sinus syndrome
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Anaemia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Strabismus
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Uveitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    2 / 305 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Abdominal pain upper
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 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 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Diverticulum intestinal
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Duodenogastric reflux
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Jejunal perforation
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Pancreatitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Umbilical hernia
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Vomiting
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Alcoholic liver disease
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 72 (1.39%)
    0 / 305 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    2 / 305 (0.66%)
         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
    Calculus urinary
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Renal colic
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 72 (0.00%)
    0 / 305 (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
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Muscular weakness
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Osteoarthritis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    1 / 72 (1.39%)
    1 / 305 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Bronchitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Chronic sinusitis
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Infected bites
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Peritonsillar abscess
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 163 (0.00%)
    0 / 72 (0.00%)
    1 / 305 (0.33%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Weeks 0-24) Placebo-Controlled Phase Apremilast 20 mg BID (Weeks 0-24) Placebo-Controlled Phase Apremilast 30 mg BID (Weeks 0-24) Placebo-Controlled Phase Apremilast 20 mg BID (APR Exposure Period) Apremilast 20/30 mg BID (APR Exposure Period) Apremilast 30 mg BID (APR Exposure Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 164 (22.56%)
    58 / 163 (35.58%)
    57 / 163 (34.97%)
    82 / 163 (50.31%)
    38 / 72 (52.78%)
    168 / 305 (55.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 164 (2.44%)
    4 / 163 (2.45%)
    6 / 163 (3.68%)
    6 / 163 (3.68%)
    2 / 72 (2.78%)
    21 / 305 (6.89%)
         occurrences all number
    4
    5
    6
    8
    2
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 164 (4.88%)
    9 / 163 (5.52%)
    16 / 163 (9.82%)
    11 / 163 (6.75%)
    5 / 72 (6.94%)
    28 / 305 (9.18%)
         occurrences all number
    9
    13
    22
    18
    5
    58
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    1 / 163 (0.61%)
    2 / 163 (1.23%)
    4 / 72 (5.56%)
    8 / 305 (2.62%)
         occurrences all number
    0
    1
    1
    5
    6
    10
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 164 (2.44%)
    3 / 163 (1.84%)
    9 / 163 (5.52%)
    7 / 163 (4.29%)
    1 / 72 (1.39%)
    16 / 305 (5.25%)
         occurrences all number
    4
    3
    12
    7
    1
    20
    Diarrhoea
         subjects affected / exposed
    7 / 164 (4.27%)
    22 / 163 (13.50%)
    17 / 163 (10.43%)
    26 / 163 (15.95%)
    4 / 72 (5.56%)
    38 / 305 (12.46%)
         occurrences all number
    8
    51
    29
    59
    4
    68
    Frequent bowel movements
         subjects affected / exposed
    2 / 164 (1.22%)
    2 / 163 (1.23%)
    3 / 163 (1.84%)
    3 / 163 (1.84%)
    4 / 72 (5.56%)
    3 / 305 (0.98%)
         occurrences all number
    2
    2
    5
    5
    4
    5
    Nausea
         subjects affected / exposed
    7 / 164 (4.27%)
    10 / 163 (6.13%)
    14 / 163 (8.59%)
    13 / 163 (7.98%)
    6 / 72 (8.33%)
    28 / 305 (9.18%)
         occurrences all number
    8
    17
    16
    20
    10
    44
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 164 (0.00%)
    2 / 163 (1.23%)
    1 / 163 (0.61%)
    6 / 163 (3.68%)
    4 / 72 (5.56%)
    12 / 305 (3.93%)
         occurrences all number
    0
    2
    1
    7
    6
    17
    Muscle spasms
         subjects affected / exposed
    1 / 164 (0.61%)
    4 / 163 (2.45%)
    0 / 163 (0.00%)
    5 / 163 (3.07%)
    4 / 72 (5.56%)
    4 / 305 (1.31%)
         occurrences all number
    1
    6
    0
    7
    7
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 164 (0.00%)
    0 / 163 (0.00%)
    1 / 163 (0.61%)
    2 / 163 (1.23%)
    4 / 72 (5.56%)
    3 / 305 (0.98%)
         occurrences all number
    0
    0
    1
    2
    4
    3
    Osteoarthritis
         subjects affected / exposed
    0 / 164 (0.00%)
    1 / 163 (0.61%)
    0 / 163 (0.00%)
    2 / 163 (1.23%)
    4 / 72 (5.56%)
    5 / 305 (1.64%)
         occurrences all number
    0
    1
    0
    3
    5
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 164 (0.61%)
    4 / 163 (2.45%)
    2 / 163 (1.23%)
    8 / 163 (4.91%)
    6 / 72 (8.33%)
    10 / 305 (3.28%)
         occurrences all number
    1
    5
    2
    14
    9
    12
    Nasopharyngitis
         subjects affected / exposed
    6 / 164 (3.66%)
    9 / 163 (5.52%)
    7 / 163 (4.29%)
    25 / 163 (15.34%)
    10 / 72 (13.89%)
    55 / 305 (18.03%)
         occurrences all number
    6
    10
    8
    35
    13
    100
    Sinusitis
         subjects affected / exposed
    1 / 164 (0.61%)
    2 / 163 (1.23%)
    1 / 163 (0.61%)
    7 / 163 (4.29%)
    5 / 72 (6.94%)
    10 / 305 (3.28%)
         occurrences all number
    1
    2
    1
    10
    8
    12
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 164 (4.88%)
    7 / 163 (4.29%)
    8 / 163 (4.91%)
    17 / 163 (10.43%)
    8 / 72 (11.11%)
    32 / 305 (10.49%)
         occurrences all number
    9
    7
    13
    33
    11
    57

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2012
    Removed 3 subject questionnaires from the study: - Bath Ankylosing Spondylitis Global Score - Functional Assessment of Chronic Illness Therapy – Fatigue, version 4 - Medical Outcomes Study Sleep Scale • Decreased the frequency of certain subject questionnaires and clinical assessments after Year 1 • Moved certain subject questionnaires to visits where there were fewer questionnaires taken • Changed the joint count evaluation from 44 tender/40 swollen to 44 tender/44 swollen • Added the following sections: Study Drug Discontinuation, Early Termination Visit, Observational Follow-up Visit, Lost to Follow up, and Study Completion • Changed the assessments in the Clinical Benefit Evaluation • Changed the sequencing for section numbers and appendix letters due to deletions/additions of the certain sections in the protocol

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

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