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    Clinical Trial Results:
    A Phase 3B, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Double-Dummy, Study Of The Efficacy And Safety Of Apremilast (CC-10004), Etanercept, And Placebo, In Subjects With Moderate To Severe Plaque Psoriasis

    Summary
    EudraCT number
    2012-000859-14
    Trial protocol
    BE   DE   GB   NL   CZ   LV   EE   HU  
    Global end of trial date
    04 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Apr 2017
    First version publication date
    16 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-10004-PSOR-010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01690299
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, NJ, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Kristine Nograles, Celgene Corporation, KNograles@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
    26 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy and safety of oral apremilast (APR) 30 mg twice a day (BID) compared with placebo, in subjects with moderate to severe plaque psoriasis at Week 16.
    Protection of trial subjects
    Patient Confidentiality and Personal Data Protection
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 80
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Latvia: 73
    Country: Number of subjects enrolled
    Netherlands: 2
    Worldwide total number of subjects
    250
    EEA total number of subjects
    145
    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)
    225
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 65 study centers in 11 countries.

    Pre-assignment
    Screening details
    Participants were randomized 1:1:1 to the three treatment groups. Participants were stratified according to their calculated body mass index (BMI) categories at Screening (BMI < 30 or BMI ≥ 30).

    Period 1
    Period 1 title
    Placebo-controlled Phase (Weeks 0-16)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received identically matching placebo tablets orally (PO), twice a day (BID) and 2-1 milliliter (ml) placebo subcutaneous (SC) saline injections once weekly (QW) during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo tablets BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Investigational medicinal product name
    Placebo Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2-1ml placebo SC saline injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Arm title
    Apremilast
    Arm description
    Participants received apremilast 30 mg PO BID plus 2-1ml placebo SC saline injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase
    Arm type
    Experimental

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

    Investigational medicinal product name
    Placebo Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2-1ml placebo SC saline injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Arm title
    Etanercept
    Arm description
    Participants received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.
    Arm type
    Active Control

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept 50 mg by SC injection QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo tablets BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Number of subjects in period 1
    Placebo Apremilast Etanercept
    Started
    84
    83
    83
    Safety population
    84
    83
    83
    Completed
    75
    77
    81
    Not completed
    9
    6
    2
         Lack of efficacy
    4
    -
    -
         Adverse event, non-fatal
    2
    2
    1
         Unspecified
    2
    1
    1
         Consent withdrawn by subject
    1
    3
    -
    Period 2
    Period 2 title
    Apremilast Extension Phase-Weeks 16-104
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Apremilast
    Arm description
    Participants who received placebo tablets PO BID and SC saline (placebo) injections (1mL x 2 injections SC) QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase week were switched to 30 mg Apremilast PO BID and remained on this dose through week 104.
    Arm type
    Experimental

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

    Arm title
    Apremilast/Apremilast
    Arm description
    Participants who received apremilast 30 mg PO BID plus saline (placebo) injections (1mL x 2 injections SC) QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase continued on to receive apremilast 30mg PO BID through week 104.
    Arm type
    Experimental

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

    Arm title
    Etanercept/Apremilast
    Arm description
    Participants who received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase, were switched at week 16 to apremilast 30 mg PO BID through week 104.
    Arm type
    Experimental

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

    Number of subjects in period 2 [1]
    Placebo/Apremilast Apremilast/Apremilast Etanercept/Apremilast
    Started
    73
    74
    80
    Received Treatment
    73
    74
    79
    Completed
    47
    41
    50
    Not completed
    26
    33
    30
         Protocol deviation
    -
    -
    1
         Non-compliance to study drug
    -
    1
    1
         Lack of efficacy
    9
    10
    8
         Adverse event, non-fatal
    3
    4
    3
         Consent withdrawn by subject
    8
    5
    11
         Lost to follow-up
    6
    13
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: There are fewer participants in this period because some patients discontinued the study at or prior to Week 16. Six subjects completed Period 1 but did not continue into Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo tablets orally (PO), twice a day (BID) and 2-1 milliliter (ml) placebo subcutaneous (SC) saline injections once weekly (QW) during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.

    Reporting group title
    Apremilast
    Reporting group description
    Participants received apremilast 30 mg PO BID plus 2-1ml placebo SC saline injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Reporting group title
    Etanercept
    Reporting group description
    Participants received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.

    Reporting group values
    Placebo Apremilast Etanercept Total
    Number of subjects
    84 83 83 250
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    77 78 70 225
        From 65-84 years
    7 5 13 25
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    43.4 ± 14.91 46 ± 13.59 47 ± 14.07 -
    Gender, Male/Female
    Units: Subjects
        Female
    25 34 34 93
        Male
    59 49 49 157

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo tablets orally (PO), twice a day (BID) and 2-1 milliliter (ml) placebo subcutaneous (SC) saline injections once weekly (QW) during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.

    Reporting group title
    Apremilast
    Reporting group description
    Participants received apremilast 30 mg PO BID plus 2-1ml placebo SC saline injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Reporting group title
    Etanercept
    Reporting group description
    Participants received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase.
    Reporting group title
    Placebo/Apremilast
    Reporting group description
    Participants who received placebo tablets PO BID and SC saline (placebo) injections (1mL x 2 injections SC) QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase week were switched to 30 mg Apremilast PO BID and remained on this dose through week 104.

    Reporting group title
    Apremilast/Apremilast
    Reporting group description
    Participants who received apremilast 30 mg PO BID plus saline (placebo) injections (1mL x 2 injections SC) QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase continued on to receive apremilast 30mg PO BID through week 104.

    Reporting group title
    Etanercept/Apremilast
    Reporting group description
    Participants who received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase, were switched at week 16 to apremilast 30 mg PO BID through week 104.

    Primary: Percentage of Subjects Who Achieved a 75% Improvement (Response) in the Psoriasis Area Severity Index (PASI-75) for the Comparison between Apremilast and Placebo at Week 16 from Baseline

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    End point title
    Percentage of Subjects Who Achieved a 75% Improvement (Response) in the Psoriasis Area Severity Index (PASI-75) for the Comparison between Apremilast and Placebo at Week 16 from Baseline [1]
    End point description
    The PASI was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing. The modified intent to treat population = all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and and at least one post-treatment PASI evaluation. Missing data imputation: Last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint compares placebo with apremilast only and is the reason only two arms are reported. The comparison of placebo and etanercept is a secondary endpoint. The study was not designed to compare apremilast with etanercept.
    End point values
    Placebo Apremilast
    Number of subjects analysed
    84
    83
    Units: Percentage of participants
        number (not applicable)
    11.9
    39.8
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    27.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.9
         upper limit
    40.1
    Notes
    [2] - The confidence interval (CI) is weighted using CMH weights according to the number of participants in the two strata.
    [3] - The two-sided p-value is from a CMH test stratified by the BMI at screening.

    Secondary: Percentage of Subjects who achieved a 75% improvement (response) in the Psoriasis Area and Severity Index (PASI) for the Comparison Between Etanercept 50mg SC QW and Placebo at Week 16

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    End point title
    Percentage of Subjects who achieved a 75% improvement (response) in the Psoriasis Area and Severity Index (PASI) for the Comparison Between Etanercept 50mg SC QW and Placebo at Week 16 [4]
    End point description
    The improvement in PASI score was used as a measure of efficacy. The PASI was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing. mITT population consisted of all participants who were re-randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation. Missing data imputation: LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint compares placebo with Etanercept only and is the reason only two arms are reported. The study was not designed to compare apremilast with etanercept.
    End point values
    Placebo Etanercept
    Number of subjects analysed
    84
    83
    Units: percentage of participants
        number (not applicable)
    11.9
    48.2
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    35.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.3
         upper limit
    48.5
    Notes
    [5] - The two-sided p-value is from a CMH test stratified by the BMI at screening.

    Secondary: Percentage of subjects who achieved a Static Physician Global Assessment (sPGA) Score of clear (0) or almost clear (1) with at least 2 points reduction for comparison between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Percentage of subjects who achieved a Static Physician Global Assessment (sPGA) Score of clear (0) or almost clear (1) with at least 2 points reduction for comparison between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    The sPGA is an assessment by the Investigator of the overall disease severity at the time of evaluation. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. When making the assessment of overall severity, the Investigator should factor in areas that have already been cleared (ie, have scores of 0) and not just evaluate remaining lesions for severity, ie, the severity of each sign is averaged across all areas of involvement, including cleared lesions. In the event of different severities across disease signs, the sign that is the predominant feature of the disease should be used to help determine the sPGA score. mITT population consisted of all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation. Missing data imputation: LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84
    83
    83
    Units: percentage of participants
        number (not applicable)
    3.6
    21.7
    28.9
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.4
         upper limit
    27.7
    Notes
    [6] - The p-value is from a CMH test stratified by the BMI (Body Mass Index) at screening.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    25.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.8
         upper limit
    35.5
    Notes
    [7] - The Confidence Interval (CI) was weighted using CMH weights according to the number of participants in the two strata.
    [8] - The p-value is from a CMH test stratified by the BMI (Body Mass Index) at screening.

    Secondary: Percent change from baseline in the affected body surface area (BSA) for comparison between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Percent change from baseline in the affected body surface area (BSA) for comparison between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    BSA is a measurement of involved skin. The overall BSA affected by psoriasis was estimated based on the palm area of the participant's hand (entire palmar surface or "handprint" including the fingers), which equates to approximately 1% of total body surface area. BSA percent change from baseline was determined at each visit of the study, which is calculated as 100*(post-baseline BSA - baseline BSA) / baseline BSA. mITT population consisted of all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation. Missing data imputation: LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84
    83
    83
    Units: percent change
        least squares mean (confidence interval 95%)
    -16.3 (-23.71 to -8.81)
    -47.7 (-55.2 to -40.12)
    -56.1 (-63.63 to -48.59)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -31.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -43.33
         upper limit
    -19.46
    Notes
    [9] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -39.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -51.78
         upper limit
    -27.92
    Notes
    [10] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.

    Secondary: Percentage of Subjects Who Achieved a 50% Improvement (Response) in the Psoriasis Area Severity Index (PASI-50) for Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Percentage of Subjects Who Achieved a 50% Improvement (Response) in the Psoriasis Area Severity Index (PASI-50) for Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    The PASI score was a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement). The PASI score was set to missing if any severity score or degree of involvement was missing. mITT population consisted of all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation. Missing data imputation: LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84
    83
    83
    Units: percentage of participants
        number (not applicable)
    33.3
    62.7
    83.1
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.0002 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    29.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.9
         upper limit
    43.9
    Notes
    [11] - The confidence interval (CI) is weighted using CMH weights according to the number of participants in the two strata
    [12] - The two-sided p-value is from a CMH test stratified by the BMI at screening.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.0001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    49.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    36.9
         upper limit
    62.7
    Notes
    [13] - The confidence interval (CI) is weighted using CMH weights according to the number of participants in the two strata.
    [14] - The two-sided p-value is from a CMH test stratified by the BMI at screening.

    Secondary: Change from baseline in the Mental Component Summary (MCS) score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Change from baseline in the Mental Component Summary (MCS) score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    The SF-36 is a 36-item general health status instrument and consists of 8 scales: physical function (PF), role limitations-physical (RP), vitality (VT), general health perceptions (GH), bodily pain (BP), social function (SF), role limitations-emotional (RE), and mental health (MH). Scale scores range from 0 to 100, with higher scores indicating better health. Two overall summary scores were obtained − a Physical Component Summary score (PCS) and a Mental Component Summary score (MCS). Scores from the 8 scales, PCS and MCS were transformed to the norm-based scores using weights from U.S. general population, with higher scores indicating better health. For norm based scores, change from baseline were calculated for the 8 scales and the two summary scales, where change = visit value − baseline value. mITT population consisted of all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    81
    80
    80
    Units: units on a scale
        least squares mean (confidence interval 95%)
    2.6 (0.72 to 4.43)
    3.5 (1.62 to 5.38)
    4.8 (2.92 to 6.67)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.7112 [16]
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.05
         upper limit
    3.9
    Notes
    [15] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.
    [16] - Based on ANCOVA model with treatment and screening BMI category as factors and the change from baseline at week 16 value as a covariate.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.1719 [18]
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    2.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    5.19
    Notes
    [17] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.
    [18] - Based on ANCOVA model with treatment and screening BMI category as factors and the change from baseline at week 16 value as a covariate.

    Secondary: Percentage of Subjects who achieved a Lattice System Physician’s Global Assessment (LS-PGA) score of clear (0) or almost clear at Week 16 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Percentage of Subjects who achieved a Lattice System Physician’s Global Assessment (LS-PGA) score of clear (0) or almost clear at Week 16 in Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    The Lattice System Physician’s Global Assessment is a global assessment performed by the investigator of psoriasis severity. Integrating ranges of BSA involvement with assessments of overall plaque severity (using a 4 point scale, from none to marked for the signs of plaque elevation, erythema and scale), the LS-PGA produces an overall assessment of psoriasis severity on an 8-point scale, ranging from clear to very severe. To determine the final score, the lattice portion is governed by the BSA and among the plaque qualities, weights plaque elevation as most important, erythema next, and scale least. mITT population consisted of all participants who were randomized and received at least one dose of study drug and had both a baseline PASI and at least one post-treatment PASI evaluation. Missing data imputation: LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84
    83
    83
    Units: percentage of participants
        number (not applicable)
    6
    24.1
    22.9
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0011 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    18.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.6
         upper limit
    28.6
    Notes
    [19] - The confidence interval (CI) is weighted using CMH weights according to the number of participants in the two strata.
    [20] - The two-sided p-value is from a CMH test stratified by the BMI at screening.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0021 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Difference
    Point estimate
    16.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    26.9
    Notes
    [21] - The confidence interval (CI) is weighted using CMH weights according to the number of participants in the two strata.
    [22] - The two-sided p-value is from a CMH test stratified by the BMI at screening.

    Secondary: Change from Baseline in Dermatology Life Quality Index (DLQI) Total Score In Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16

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    End point title
    Change from Baseline in Dermatology Life Quality Index (DLQI) Total Score In Comparison Between Apremilast and Placebo and Etanercept and Placebo at Week 16
    End point description
    DLQI is a simple, compact, and practical questionnaire for use in a dermatology clinical setting to assess limitations related to the impact of skin disease. The instrument contains ten items dealing with the participant's skin. With the exception of Item Number 7, the participant responds on a four-point scale, ranging from "Very Much" (score 3) to "Not at All" or "Not relevant" (score 0). Item Number 7 is a multi-part item, the first part of which ascertains whether the participant's skin prevented them from working or studying (Yes or No, scores 3 or 0 respectively), and if "No," then the participant is asked how much of a problem the skin has been at work or study over the past week, with response alternatives being "A lot," "A little," or "Not at all" (scores 2, 1, or 0 respectively). The DLQI total score is derived by summing all item scores, which has a range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 corresponding to the best. mITT population; LOCF
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    81
    79
    80
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -3.9 (-5.34 to -2.42)
    -8.4 (-9.84 to -6.88)
    -7.8 (-9.28 to -6.34)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -4.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.82
         upper limit
    -2.14
    Notes
    [23] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Etanercept
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [24]
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -3.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.27
         upper limit
    -1.6
    Notes
    [24] - Based on ANCOVA model with treatment and screening BMI category as factors and the baseline value as a covariate.

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

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    End point title
    Number of Subjects with Treatment Emergent Adverse Events (TEAEs) During the Placebo Controlled Phase
    End point description
    A TEAE is an AE with a start date on or after the date of the first dose of study drug and no later than 28 days after the last dose of study drug for subjects who discontinued early. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subjects health, including laboratory test values, regardless of etiology. Any worsening (ie, clinically significant adverse change in frequency or intensity of a preexisting condition) should be considered an AE. A serious AE (SAE) is any untoward AE that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly/birth defect, or is a condition that may jeopardize or may require intervention to prevent one of the outcomes above.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16; mean duration of exposure was 14.90 weeks for placebo group, 15.13 weeks for apremilast group and 15.87 weeks for Etanercept group
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84 [25]
    83 [26]
    83 [27]
    Units: participants
        Any TEAE
    45
    59
    44
        Any Drug-related TEAE
    17
    27
    21
        Any Severe TEAE
    2
    3
    3
        Any Serious TEAE
    0
    3
    2
        Any Serious Drug-related TEAE
    0
    2
    1
        Any TEAE Leading to Drug Interruption
    1
    9
    3
        Any TEAE Leading to Drug Withdrawal
    2
    3
    2
        Any TEAE Leading to Death
    0
    0
    0
    Notes
    [25] - Safety population = subjects randomized and received at least one dose of study drug
    [26] - Safety population = subjects randomized and received at least one dose of study drug
    [27] - Safety population = subjects randomized and received at least one dose of study drug
    No statistical analyses for this end point

    Secondary: Number of Subjects with TEAEs during the Apremilast-exposure Period

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    End point title
    Number of Subjects with TEAEs during the Apremilast-exposure Period [28]
    End point description
    A TEAE in the apremilast-exposure phase is an AE with a start date on or after the date of the first dose of study drug and no later than 28 days after the last dose of study drug. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. A serious AE (SAE) = untoward AE that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly/birth defect, or is a condition that may jeopardize or require intervention to prevent one of the outcomes listed above. Safety population.
    End point type
    Secondary
    End point timeframe
    From the first dose of apremilast (either at Week 0 for subjects originally randomized to apremilast or Week 16 for those originally randomized to placebo or etanercept who were switched to apremilast at week 16) until 28 days after last apremilast dose
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis were performed.
    End point values
    Placebo/Apremilast Apremilast Etanercept/Apremilast
    Number of subjects analysed
    73
    83 [29]
    79
    Units: participants
        Any TEAE
    45
    71
    54
        Any Drug-related TEAE
    23
    36
    15
        Any Severe TEAE
    4
    7
    7
        Any Serious TEAE
    5
    6
    4
        Any Serious Drug-related TEAE
    2
    2
    1
        Any TEAE Leading to Drug Interruption
    8
    13
    7
        Any TEAE Leading to Drug Withdrawal
    3
    7
    2
        Any TEAE Leading to Death
    0
    0
    0
    Notes
    [29] - From first APR dose at Wk 0 for those randomized to APR or for those first randomized to PBO or ETN
    No statistical analyses for this end point

    Secondary: Number of subjects who experienced psoriasis flare/rebound in placebo-controlled phase

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    End point title
    Number of subjects who experienced psoriasis flare/rebound in placebo-controlled phase
    End point description
    Psoriasis flare is an AE and represents an atypical or unusual worsening of disease during treatment. It is defined as a sudden intensification of psoriasis requiring medical intervention or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is an AE and is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. This exacerbation is characterized by a PASI ≥125% of baseline or a new generalized pustular, erythrodermic, or more inflammatory psoriasis after stopping therapy. Includes safety population.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16; Placebo controlled phase
    End point values
    Placebo Apremilast Etanercept
    Number of subjects analysed
    84
    83
    83
    Units: subjects
        Subjects with psoriasis flare
    3
    1
    0
        Any psoriasis rebound captured as TEAE
    0
    0
    0
        Those with PASI ≥125% baseline score and D/C APR
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects who experienced psoriasis flare/rebound during the apremilast-exposure period

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    End point title
    Number of subjects who experienced psoriasis flare/rebound during the apremilast-exposure period [30]
    End point description
    Psoriasis flare is an AE and represents an atypical or unusual worsening of disease during treatment. It is defined as a sudden intensification of psoriasis requiring medical intervention or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is an AE and is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. This exacerbation is characterized by a PASI ≥125% of baseline or a new generalized pustular, erythrodermic, or more inflammatory psoriasis after stopping therapy. PASI ≥125% of baseline score at any visit after the last dose date for those who discontinued within the phase. Safety population.
    End point type
    Secondary
    End point timeframe
    From the first dose of apremilast (either Week 0 or Week 16 for participants originally randomized to placebo or Etanercept who were switched at Week 16) until 28 days after the last dose of apremilast. Safety population.
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis were performed.
    End point values
    Placebo/Apremilast Apremilast Etanercept/Apremilast
    Number of subjects analysed
    73
    83
    79
    Units: subejcts
        Subjects with psoriasis flare
    1
    4
    0
        Subjects with psoriasis rebound
    1
    2
    7
        Those with PASI ≥125% baseline score and D/C APR
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported for the 16-week placebo-controlled period and up to week 104 during the apremilast exposure period for all participants who were randomized or switched to apremilast at any time during the course of the study.
    Adverse event reporting additional description
    The mean duration of exposure was 14.90 weeks, 15.13 weeks, and 15.87 weeks for participants randomized to the placebo, apremilast 30 BID, and etanercept 50 mg every week treatment groups, respectively during the placebo controlled phase. The mean duration of exposure to apremilast 30 mg BID during the apremilast exposure period was 69.13 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo (week 0-16)
    Reporting group description
    Participants received placebo tablets PO BID and 2-1 milliliter (ml) SC saline (placebo) injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Reporting group title
    Apremilast plus placebo injection (Week 0-16)
    Reporting group description
    Participants received Apremilast 30 mg PO BID plus 2-1ml SC saline (placebo) injections QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Reporting group title
    Etanercept plus placebo tablets (Week 0-16)
    Reporting group description
    Participants received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase

    Reporting group title
    Placebo/APR 30mg (Apremilast Exposure Phase) Weeks 16-104
    Reporting group description
    Participants received identically matching placebo tablets by mouth (PO), twice a day (BID) and subcutaneous (SC) saline (placebo) injections (1mL x 2 injections SC) weekly (QW) during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase; at week 16, participants were switched to 30 mg Apremilast PO BID and remained on this dose through week 104.

    Reporting group title
    APR/APR 30 mg (Apremilast Exposure Phase) Weeks 0-104
    Reporting group description
    Participants received apremilast 30 mg PO BID plus saline (placebo) injections (1mL x 2 injections SC) QW during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase; at week 16, participants continued on apremilast 30mg PO BID through week 104.

    Reporting group title
    Etanercept/Apremilast 30mg (Apremilast Exposure Phase) 16-104
    Reporting group description
    Participants received etanercept 50 mg by SC injection QW plus placebo tablets PO BID during the 16-week randomized, double-blind, double-dummy, placebo-controlled phase; at week 16, participants were switched to apremilast 30mg PO BID through week 104.

    Serious adverse events
    Placebo (week 0-16) Apremilast plus placebo injection (Week 0-16) Etanercept plus placebo tablets (Week 0-16) Placebo/APR 30mg (Apremilast Exposure Phase) Weeks 16-104 APR/APR 30 mg (Apremilast Exposure Phase) Weeks 0-104 Etanercept/Apremilast 30mg (Apremilast Exposure Phase) 16-104
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 83 (3.61%)
    2 / 83 (2.41%)
    5 / 73 (6.85%)
    6 / 83 (7.23%)
    4 / 79 (5.06%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Atrioventricular block complete
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    1 / 83 (1.20%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Pneumocephalus
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (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
    Syncope
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (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
    Deafness unilateral
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
    1 / 83 (1.20%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Appendicitis perforated
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Salpingitis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    0 / 83 (0.00%)
    1 / 79 (1.27%)
         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
    Mastoiditis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    0 / 79 (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
    Anogenital warts
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    0 / 83 (0.00%)
    0 / 79 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (week 0-16) Apremilast plus placebo injection (Week 0-16) Etanercept plus placebo tablets (Week 0-16) Placebo/APR 30mg (Apremilast Exposure Phase) Weeks 16-104 APR/APR 30 mg (Apremilast Exposure Phase) Weeks 0-104 Etanercept/Apremilast 30mg (Apremilast Exposure Phase) 16-104
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 84 (29.76%)
    41 / 83 (49.40%)
    27 / 83 (32.53%)
    30 / 73 (41.10%)
    52 / 83 (62.65%)
    32 / 79 (40.51%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 83 (3.61%)
    4 / 83 (4.82%)
    1 / 73 (1.37%)
    6 / 83 (7.23%)
    2 / 79 (2.53%)
         occurrences all number
    3
    3
    5
    1
    6
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 84 (0.00%)
    4 / 83 (4.82%)
    1 / 83 (1.20%)
    1 / 73 (1.37%)
    5 / 83 (6.02%)
    0 / 79 (0.00%)
         occurrences all number
    0
    5
    1
    1
    7
    0
    Bronchitis
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 83 (2.41%)
    1 / 83 (1.20%)
    1 / 73 (1.37%)
    6 / 83 (7.23%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    2
    1
    6
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 84 (3.57%)
    11 / 83 (13.25%)
    5 / 83 (6.02%)
    5 / 73 (6.85%)
    12 / 83 (14.46%)
    3 / 79 (3.80%)
         occurrences all number
    5
    11
    6
    6
    13
    6
    Tension Headache
         subjects affected / exposed
    4 / 84 (4.76%)
    5 / 83 (6.02%)
    3 / 83 (3.61%)
    3 / 73 (4.11%)
    5 / 83 (6.02%)
    1 / 79 (1.27%)
         occurrences all number
    6
    7
    3
    3
    7
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 84 (1.19%)
    9 / 83 (10.84%)
    4 / 83 (4.82%)
    5 / 73 (6.85%)
    12 / 83 (14.46%)
    5 / 79 (6.33%)
         occurrences all number
    1
    11
    4
    7
    14
    6
    Diarrhoea
         subjects affected / exposed
    3 / 84 (3.57%)
    9 / 83 (10.84%)
    1 / 83 (1.20%)
    13 / 73 (17.81%)
    12 / 83 (14.46%)
    6 / 79 (7.59%)
         occurrences all number
    5
    11
    1
    15
    15
    7
    Toothache
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 83 (4.82%)
    2 / 83 (2.41%)
    2 / 73 (2.74%)
    5 / 83 (6.02%)
    0 / 79 (0.00%)
         occurrences all number
    1
    4
    3
    3
    5
    0
    Vomiting
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 83 (4.82%)
    2 / 83 (2.41%)
    3 / 73 (4.11%)
    6 / 83 (7.23%)
    2 / 79 (2.53%)
         occurrences all number
    2
    4
    2
    3
    6
    2
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    3 / 84 (3.57%)
    1 / 83 (1.20%)
    0 / 83 (0.00%)
    2 / 73 (2.74%)
    5 / 83 (6.02%)
    0 / 79 (0.00%)
         occurrences all number
    3
    1
    0
    2
    5
    0
    Rebound psoriasis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 83 (0.00%)
    0 / 83 (0.00%)
    1 / 73 (1.37%)
    2 / 83 (2.41%)
    7 / 79 (8.86%)
         occurrences all number
    0
    0
    0
    1
    2
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 83 (3.61%)
    3 / 83 (3.61%)
    4 / 73 (5.48%)
    6 / 83 (7.23%)
    3 / 79 (3.80%)
         occurrences all number
    2
    3
    4
    4
    8
    4
    Pain in extremity
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 83 (2.41%)
    1 / 83 (1.20%)
    1 / 73 (1.37%)
    4 / 83 (4.82%)
    4 / 79 (5.06%)
         occurrences all number
    3
    2
    1
    1
    5
    5
    Psoriatic arthropathy
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 83 (4.82%)
    0 / 83 (0.00%)
    3 / 73 (4.11%)
    6 / 83 (7.23%)
    1 / 79 (1.27%)
         occurrences all number
    5
    4
    0
    4
    7
    3
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 83 (7.23%)
    2 / 83 (2.41%)
    5 / 73 (6.85%)
    9 / 83 (10.84%)
    1 / 79 (1.27%)
         occurrences all number
    2
    6
    2
    5
    13
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 84 (9.52%)
    4 / 83 (4.82%)
    8 / 83 (9.64%)
    4 / 73 (5.48%)
    5 / 83 (6.02%)
    5 / 79 (6.33%)
         occurrences all number
    10
    6
    12
    5
    11
    8
    Rhinitis
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 83 (4.82%)
    4 / 83 (4.82%)
    1 / 73 (1.37%)
    6 / 83 (7.23%)
    2 / 79 (2.53%)
         occurrences all number
    1
    4
    5
    1
    6
    2
    Sinusitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 83 (0.00%)
    3 / 83 (3.61%)
    0 / 73 (0.00%)
    1 / 83 (1.20%)
    5 / 79 (6.33%)
         occurrences all number
    1
    0
    3
    0
    1
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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