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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Apremilast (CC-10004) in Subjects with Moderate to Severe Plaque Psoriasis

    Summary
    EudraCT number
    2010-019991-55
    Trial protocol
    DE   BE   GB   IT  
    Global end of trial date
    22 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Dec 2017
    First version publication date
    08 Dec 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-PSOR-008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01194219
    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
    Wendy Zhang, MD, Celgene Corporation, 01 9085149788, WeiZhang@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
    22 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the clinical efficacy of apremilast 30 mg BID, compared with placebo, in subjects with moderate to severe plaque psoriasis.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    66 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 116
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 317
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 294
    Worldwide total number of subjects
    844
    EEA total number of subjects
    117
    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)
    772
    From 65 to 84 years
    72
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 76 study centers in 8 countries

    Pre-assignment
    Screening details
    Subjects were eligible who had moderate to severe plaque psoriasis.

    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
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Treatment assignment blinding remained in effect; the blind was broken when all subjects completed their week 52 visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast
    Arm description
    Participants were initially randomized to apremilast (APR) 30 mg tablets twice daily (BID) during the Placebo-controlled Phase (Weeks 0-16)
    Arm type
    Experimental

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

    Arm title
    Placebo
    Arm description
    Participants were initially randomized to identically matching placebo (PBO) tablets twice daily BID during the Placebo-controlled Phase (Weeks 0-16)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo tablets BID

    Number of subjects in period 1
    Apremilast Placebo
    Started
    562
    282
    Received apremilast
    560
    282
    Completed
    503
    249
    Not completed
    59
    33
         Protocol deviation
    7
    1
         Miscellaneous
    1
    1
         Noncompliance with study drug
    7
    -
         Lack of efficacy
    2
    7
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    23
    5
         Consent withdrawn by subject
    12
    9
         Lost to follow-up
    7
    9
    Period 2
    Period 2 title
    Maintenance Phase Weeks 16-32
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Treatment assignment blinding remained in effect; the blind was broken when all subjects completed their week 52 visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast-Apremilast
    Arm description
    Participants who were initially randomized to apremilast 30 mg tablets BID during the Placebo-controlled Phase (Weeks 0-16) remained on apremilast 30 mg BID during the Maintenance Phase (Weeks 16-32).
    Arm type
    Experimental

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

    Arm title
    Placebo-Apremilast
    Arm description
    Participants who were initially randomized to identically matching placebo tablets BID during the Placebo-controlled Phase (Weeks 0-16) were switched after 16 weeks of treatment to apremilast 30 mg tablets BID and continued dosing with apremilast 30 mg BID during the Maintenance Phase (weeks 16-32)
    Arm type
    Experimental

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

    Number of subjects in period 2 [1]
    Apremilast-Apremilast Placebo-Apremilast
    Started
    494
    245
    Received apremilast
    493
    244
    Completed
    424
    215
    Not completed
    70
    30
         Protocol deviation
    -
    1
         Non-compliance with Study Drug
    2
    1
         Lack of efficacy
    37
    15
         Adverse event, non-fatal
    8
    9
         Unspecified
    2
    1
         Consent withdrawn by subject
    12
    3
         Lost to follow-up
    9
    -
    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: The Study PSOR-008 protocol allowed subjects to withdraw from the clinical trial at any time. Of the 752 subjects who completed the Placebo-controlled Phase, 13 subjects withdrew from the study for diverse reasons including adverse events, lack of efficacy, non-compliance and withdrawal by subject. Consequently, a total of 739 subjects entered the Maintenance Phase of the trial.
    Period 3
    Period 3 title
    Randomized Withdrawal Phase-Weeks 32-52
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Treatment assignment blinding remained in effect; the blind was broken when all subjects completed their week 52 visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    APR-APR-Re-randomized to PBO
    Arm description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (Weeks 16-32). At Week 32, those participants who were considered responders [ie, having a ≥ Psoriasis Area and Severity Index score of 75 (PASI-75) response] were re-randomized to PBO during the Randomized Withdrawal Phase (Weeks 32-52). Those participants who retained their ≥PASI-75 response through the Randomized Withdrawal Phase remained on PBO until week 52. Those participants who lost their PASI-75 improvement achieved at week 32, were switched back to APR 30 mg BID at the time loss of effect was observed. All participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension Phase from weeks 52-260, and received APR 30 mg BID for the remainder of their participation.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Identically matching placebo tablets BID

    Arm title
    APR-APR-Re-randomized to APR
    Arm description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (Weeks 16-32). At Week 32, those participants who were considered responders (ie, having a ≥PASI-75 response) were re-randomized to APR during the Randomized Withdrawal Phase (Weeks 32-52). Those participants who completed the Randomized Withdrawal Phase at Week 52 were eligible to participate in the Long-term Extension Phase from weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.
    Arm type
    Experimental

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

    Arm title
    APR-APR-APR + optional topicals/UVB
    Arm description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (weeks 16-32). At week 32, those participants who were considered partial responders (ie, having a response of PASI-50 to PASI-74) and those participants who were considered non-responders (ie, having a response of <PASI-50), remained on APR 30 mg BID and were given the option of adding topical therapies and/or phototherapy to their regimen. Those participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension (LTE) Phase from Weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.
    Arm type
    Experimental

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

    Arm title
    PBO-APR-APR + optional topicals/ UVB
    Arm description
    Participants who were initially randomized to placebo BID during the 16-week Placebo-controlled Phase (Weeks 0-16) were switched after 16 weeks of treatment to APR 30 mg BID and continued dosing with APR 30 mg BID during the Maintenance Phase (Weeks 16-32). At week 32, all participants continued to receive apremilast 30 mg BID. Those participants who were considered partial responders (ie, having a response of PASI-50 to PASI-74) and non-responders (ie, having a response of < PASI-50), were given the option of adding topical therapies and/or phototherapy to their regimen. All participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension Phase from Weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.
    Arm type
    Experimental

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

    Number of subjects in period 3 [2]
    APR-APR-Re-randomized to PBO APR-APR-Re-randomized to APR APR-APR-APR + optional topicals/UVB PBO-APR-APR + optional topicals/ UVB
    Started
    77
    77
    245
    208
    Received topical + light therapy
    0 [3]
    0 [4]
    126 [5]
    91 [6]
    Completed
    73
    73
    184
    163
    Not completed
    4
    4
    61
    45
         Protocol deviation
    -
    -
    -
    1
         Non-compliance with Study Drug
    1
    -
    2
    -
         Lack of efficacy
    1
    1
    35
    33
         Not specified
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    6
    5
         Consent withdrawn by subject
    1
    -
    12
    6
         Lost to follow-up
    1
    2
    5
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The Study PSOR-008 protocol allowed subjects to withdraw from the clinical trial at any time. Of the 639 subjects who completed the Maintenance Phase, 32 subjects withdrew from the study for diverse reasons including adverse events, lack of efficacy, non-compliance and withdrawal by subject. Consequently, a total of 607 subjects entered the Randomized Withdrawal Phase of the trial.
    [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: Of the 154 subjects who were originally randomized to APR and who achieved a PASI-75 response at Week 32, 77 subjects were re-randomized to placebo and 73 subjects in this group completed the Randomized Withdrawal Phase. Subjects in this treatment group were not permitted to receive topical and/or phototherapy during the Randomization Withdrawal Phase.
    [4] - 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: Of the 154 subjects who were originally randomized to APR and who achieved a PASI-75 response at Week 32, 77 subjects were re-randomized to APR and 73 subjects in this group completed the Randomized Withdrawal Phase. Subjects in this treatment group were not permitted to receive topical and/or phototherapy during the Randomization Withdrawal Phase.
    [5] - 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: During the Randomization Withdrawal Phase, of the 245 subjects in the APR-APR-APR arm, 126 subjects were treated with topical therapy and/or phototherapy, and 119 subjects did not receive topical and/or phototherapy. A total of 184 subjects completed the Randomized Withdrawal Phase, with 105 subjects in the group receiving topical and/or phototherapy, and 79 subjects in the group which did not receive topical and/or phototherapy.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: During the Randomization Withdrawal Phase, of the 208 subjects in the PBO-APR-APR arm, 91 subjects were treated with topical therapy and/or phototherapy, and 117 subjects did not receive topical and/or phototherapy. A total of 163 subjects completed the Randomized Withdrawal Phase, with 73 subjects in the group receiving topical and/or phototherapy, and 90 subjects in the group which did not receive topical and/or phototherapy.
    Period 4
    Period 4 title
    Long-Term Extension Weeks 52 to 260
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Apremilast (Long-term extension)
    Arm description
    Participants who were initially randomized to apremilast 30 mg BID during the 16-week placebo-controlled phase (Weeks 0-16) continued receiving apremilast 30 mg BID through the Maintenance Phase (weeks 16-32) and apremilast 30 mg tablets or placebo during the Randomized Withdrawal Phase then received apremilast 30 mg BID in the Long-term Extension Phase from Weeks 52-260.
    Arm type
    Experimental

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

    Arm title
    Placebo-Apremilast (Long-term extension)
    Arm description
    Participants who were initially randomized to identically matching placebo BID during the placebo-controlled phase (Weeks 0-16) were switched at Week 16 to apremilast 30 mg BID during the Maintenance Phase, received apremilast 30 mg PO BID or placebo during the Randomized Withdrawal Phase and then received apremilast 30 mg tablets BID in the long-term extension phase from weeks 52-260.
    Arm type
    Experimental

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

    Number of subjects in period 4 [7]
    Apremilast (Long-term extension) Placebo-Apremilast (Long-term extension)
    Started
    306
    153
    Received Treatment
    306
    153
    Completed
    86
    41
    Not completed
    220
    112
         Protocol deviation
    3
    -
         Miscellaneous
    11
    2
         Lack of efficacy
    81
    49
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    25
    14
         Noncompliance with IP
    9
    4
         Consent withdrawn by subject
    66
    32
         Lost to follow-up
    24
    10
    Notes
    [7] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The Study PSOR-008 protocol allowed subjects to withdraw from the clinical trial at any time. Of the 493 subjects who completed the Randomized Withdrawal Phase, 34 subjects withdrew from the study for diverse reasons including adverse events, lack of efficacy, non-compliance and withdrawal by subject. Consequently, a total of 459 subjects entered the Long-Term Extension of the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apremilast
    Reporting group description
    Participants were initially randomized to apremilast (APR) 30 mg tablets twice daily (BID) during the Placebo-controlled Phase (Weeks 0-16)

    Reporting group title
    Placebo
    Reporting group description
    Participants were initially randomized to identically matching placebo (PBO) tablets twice daily BID during the Placebo-controlled Phase (Weeks 0-16)

    Reporting group values
    Apremilast Placebo Total
    Number of subjects
    562 282 844
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    514 258 772
        From 65-84 years
    48 24 72
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    45.8 ± 13.07 46.5 ± 12.72 -
    Gender, Male/Female
    Units: Subjects
        Female
    183 88 271
        Male
    379 194 573
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    2 5 7
        Asian
    28 16 44
        Black or African American
    18 10 28
        Native Hawaiian or Other Pacific Islander
    5 1 6
        White
    507 250 757
        Other
    2 0 2
    Duration of Plaque Psoriasis
    All participants enrolled were required to have a diagnosis of plaque psoriasis at least 12 months prior to screening, but the duration was not required for enrollment. Overall baseline population for duration of plaque psoriasis in the apremilast arm were 562 participants and 282 for those in the placebo arm.
    Units: Subjects
        <10 years
    150 85 235
        10 to < 20 years
    159 73 232
        ≥ 20 years
    253 122 375
        Missing
    0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Apremilast
    Reporting group description
    Participants were initially randomized to apremilast (APR) 30 mg tablets twice daily (BID) during the Placebo-controlled Phase (Weeks 0-16)

    Reporting group title
    Placebo
    Reporting group description
    Participants were initially randomized to identically matching placebo (PBO) tablets twice daily BID during the Placebo-controlled Phase (Weeks 0-16)
    Reporting group title
    Apremilast-Apremilast
    Reporting group description
    Participants who were initially randomized to apremilast 30 mg tablets BID during the Placebo-controlled Phase (Weeks 0-16) remained on apremilast 30 mg BID during the Maintenance Phase (Weeks 16-32).

    Reporting group title
    Placebo-Apremilast
    Reporting group description
    Participants who were initially randomized to identically matching placebo tablets BID during the Placebo-controlled Phase (Weeks 0-16) were switched after 16 weeks of treatment to apremilast 30 mg tablets BID and continued dosing with apremilast 30 mg BID during the Maintenance Phase (weeks 16-32)
    Reporting group title
    APR-APR-Re-randomized to PBO
    Reporting group description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (Weeks 16-32). At Week 32, those participants who were considered responders [ie, having a ≥ Psoriasis Area and Severity Index score of 75 (PASI-75) response] were re-randomized to PBO during the Randomized Withdrawal Phase (Weeks 32-52). Those participants who retained their ≥PASI-75 response through the Randomized Withdrawal Phase remained on PBO until week 52. Those participants who lost their PASI-75 improvement achieved at week 32, were switched back to APR 30 mg BID at the time loss of effect was observed. All participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension Phase from weeks 52-260, and received APR 30 mg BID for the remainder of their participation.

    Reporting group title
    APR-APR-Re-randomized to APR
    Reporting group description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (Weeks 16-32). At Week 32, those participants who were considered responders (ie, having a ≥PASI-75 response) were re-randomized to APR during the Randomized Withdrawal Phase (Weeks 32-52). Those participants who completed the Randomized Withdrawal Phase at Week 52 were eligible to participate in the Long-term Extension Phase from weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.

    Reporting group title
    APR-APR-APR + optional topicals/UVB
    Reporting group description
    Participants who were initially randomized to APR 30 mg BID during the 16-week Placebo-controlled Phase (Weeks 0-16) continued dosing with APR 30 mg BID through the Maintenance Phase (weeks 16-32). At week 32, those participants who were considered partial responders (ie, having a response of PASI-50 to PASI-74) and those participants who were considered non-responders (ie, having a response of <PASI-50), remained on APR 30 mg BID and were given the option of adding topical therapies and/or phototherapy to their regimen. Those participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension (LTE) Phase from Weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.

    Reporting group title
    PBO-APR-APR + optional topicals/ UVB
    Reporting group description
    Participants who were initially randomized to placebo BID during the 16-week Placebo-controlled Phase (Weeks 0-16) were switched after 16 weeks of treatment to APR 30 mg BID and continued dosing with APR 30 mg BID during the Maintenance Phase (Weeks 16-32). At week 32, all participants continued to receive apremilast 30 mg BID. Those participants who were considered partial responders (ie, having a response of PASI-50 to PASI-74) and non-responders (ie, having a response of < PASI-50), were given the option of adding topical therapies and/or phototherapy to their regimen. All participants who completed the Randomized Withdrawal Phase at week 52 were eligible to participate in the Long-term Extension Phase from Weeks 52-260 and remained on APR 30 mg BID for the remainder of their participation.
    Reporting group title
    Apremilast (Long-term extension)
    Reporting group description
    Participants who were initially randomized to apremilast 30 mg BID during the 16-week placebo-controlled phase (Weeks 0-16) continued receiving apremilast 30 mg BID through the Maintenance Phase (weeks 16-32) and apremilast 30 mg tablets or placebo during the Randomized Withdrawal Phase then received apremilast 30 mg BID in the Long-term Extension Phase from Weeks 52-260.

    Reporting group title
    Placebo-Apremilast (Long-term extension)
    Reporting group description
    Participants who were initially randomized to identically matching placebo BID during the placebo-controlled phase (Weeks 0-16) were switched at Week 16 to apremilast 30 mg BID during the Maintenance Phase, received apremilast 30 mg PO BID or placebo during the Randomized Withdrawal Phase and then received apremilast 30 mg tablets BID in the long-term extension phase from weeks 52-260.

    Subject analysis set title
    Number of Subjects with TEAEs During the APR-Exposure Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    An AE was any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. An AE is a treatment emergent AE if the AE start date is on or after the date of the first dose of study drug and no later than 28 days after the last dose.

    Subject analysis set title
    Subjects with a Psoriasis Flare During the APR-Exposure Phase
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Psoriasis flare was defined as a sudden intensification of psoriasis requiring medical intervention, or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. Note categories below. [1] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis) started on or after the first dose date and on or before the last dose date within the phase. [2] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis, Rebound psoriasis) started after the last dose date for participants who discontinued within the phase. [3] PASI >= 125% of baseline score at any visit after the last dose date for participants who discontinued within the phase and were not included in [1] and/or [2]. Apremilast subjects as treated.

    Primary: Percentage of Participants Who Achieved a 75% Improvement (response) in the Psoriasis Area Severity Index (PASI-75) at Week 16 from Baseline

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    End point title
    Percentage of Participants Who Achieved a 75% Improvement (response) in the Psoriasis Area Severity Index (PASI-75) at Week 16 from Baseline
    End point description
    The improvement in PASI score was used as a measure of efficacy. 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 = 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 Full Analysis Set (FAS) consisted of all participants who were randomized. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward (LOCF) imputation was used.
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    562
    282
    Units: percentage of participants
        number (not applicable)
    33.1
    5.3
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    844
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    27.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.1
         upper limit
    32.5

    Secondary: Percentage of Participants Who Achieved a Static Physician Global Assessment (sPGA) Score of Clear (0) or Almost Clear (1) with At Least 2 Points Reduction from Baseline

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    End point title
    Percentage of Participants Who Achieved a Static Physician Global Assessment (sPGA) Score of Clear (0) or Almost Clear (1) with At Least 2 Points Reduction from Baseline
    End point description
    The sPGA was a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), 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 factored in areas that have already been cleared (ie, have scores of 0) and did not just evaluate remaining lesions for severity, ie, the severity of each sign was 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. The Full Analysis Set (FAS) consisted of all participants who were randomized per protocol. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    562
    282
    Units: percentage of participants
        number (not applicable)
    21.7
    3.9
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    844
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    17.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.7
         upper limit
    21.9

    Secondary: Percent Change from Baseline in Percent of Affected Body Surface Area (BSA) at Week 16

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    End point title
    Percent Change from Baseline in Percent of Affected Body Surface Area (BSA) at Week 16
    End point description
    BSA was 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 (Visit 2 Week 0) was determined at each visit of the study, which is calculated as 100*(visit BSA – baseline BSA) / baseline BSA (%). The Full Analysis Set (FAS) consisted of all participants who were randomized per protocol. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Participants with a baseline value and at least 1 postbaseline value were included. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    559
    278
    Units: percent change
        least squares mean (standard error)
    -47.77 ± 1.634
    -6.99 ± 2.317
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    837
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -40.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.34
         upper limit
    -35.21
    Notes
    [1] - The model included treatment group as a factor and the baseline value as a covariate. The estimation and p-value were adjusted by the covariate.

    Secondary: Percent Change from Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 16

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    End point title
    Percent Change from Baseline in the Psoriasis Area Severity Index (PASI) Score at Week 16
    End point description
    The improvement in PASI score was used as a measure of efficacy. 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 = 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 Full Analysis Set (FAS) consisted of all participants who were randomized. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    559
    278
    Units: percent change
        least squares mean (standard error)
    -52.1 ± 1.37
    -16.8 ± 1.94
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    837
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -35.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.9
         upper limit
    -30.6
    Notes
    [2] - The model included treatment group as a factor and the baseline value as a covariate. The estimation and p-value were adjusted by the covariate.

    Secondary: Percentage of Participants Who Achieved a 50% improvement (response) in the PASI score (PASI-50) at Week 16 from Baseline

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    End point title
    Percentage of Participants Who Achieved a 50% improvement (response) in the PASI score (PASI-50) at Week 16 from Baseline
    End point description
    A participant was classified as having at least a 50% improvement in PASI score from baseline, which was equivalent to a percent change from baseline ranging from −100% to −50%. PASI score is based on an assessment of erythema (reddening), induration (plaque thickness), desquamation (scaling), and the percent area affected as observed on the day of examination. The Full Analysis Set (FAS) consisted of all participants who were randomized per protocol. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    562
    282
    Units: Percentage of Participants
        number (not applicable)
    58.7
    17.0
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    844
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    41.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.7
         upper limit
    47.7

    Secondary: Change from Baseline in Pruritus Visual Analog Scale (VAS) Score at Week 16

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    End point title
    Change from Baseline in Pruritus Visual Analog Scale (VAS) Score at Week 16
    End point description
    The Pruritus Visual Analog Scores (VAS) were used to measure the amount of itching and discomfort a participant experiences. Participant's Assessment of Pruritus (Itch) asked: On average, how much itch have you had because of your condition in the past week? All VAS values range from 0 to 100. Higher scores correspond to more severe symptom or disease. Change from baseline was calculated for the VAS scale, where change = visit value − baseline value. The Full Analysis Set (FAS) consisted of all participants who were randomized per protocol. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward imputation was used. Participants with a baseline value and at least 1 postbaseline value are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    559
    277
    Units: units on a scale
        least squares mean (standard error)
    -31.5 ± 1.30
    -7.3 ± 1.85
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -24.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.7
         upper limit
    -19.8
    Notes
    [3] - Based on an analysis of variance model for the change from baseline at Week 16, with treatment group as a factor (an ANOVA model).

    Secondary: Change from Baseline in the Dermatology Life Quality Index (DLQI) total score at Week 16

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    End point title
    Change from Baseline in the Dermatology Life Quality Index (DLQI) total score at Week 16
    End point description
    DLQI is a questionnaire that contains 10 items dealing with the subjects skin. With the exception of Item Number 7, the subject responds on a 4-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, part 1 ascertains whether the subject’s skin prevented them from working or studying and if “No,” then the subject is asked how much of a problem the skin has been at work or study over the past week, with responses of: A lot, A little, or Not at all (scores 2, 1, or 0 respectively). The DLQI total score is derived by summing scores, which have a possible range of 0 to 30, with 30 corresponding to the worst quality of life, and 0 corresponding to the best. The FAS consisted of all subjects who were randomized. Subjects were included in the treatment group which they were randomized APR 30 BID or placebo for the FAS. LOCF imputation was used. Subjects with a baseline value and at least 1 postbaseline value are included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    556
    274
    Units: units on a scale
        least squares mean (standard error)
    -6.6 ± 0.27
    -2.1 ± 0.38
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    830
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Difference in LS Mean
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    -3.6

    Secondary: Change from Baseline in the Mental Component Summary (MSC) Score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 at Week 16

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    End point title
    Change from Baseline in the Mental Component Summary (MSC) Score of the Medical Outcome Study Short Form 36-item (SF-36) Health Survey Version 2.0 at Week 16
    End point description
    The SF-36 was a 36-item general health status instrument consisting of 8 scales: physical function, role limitations–physical, vitality, health perceptions, bodily pain, social function, role limitations–emotional, and mental health. Scale scores range from 0 to 100, with higher scores = better health. 2 overall summary scores were used; a Physical Component Summary (PCS) score and a Mental Component Summary (MSC) score. Scores from the 8 scales, PCS and MCS were transformed to a norm-based scores using weights from the U.S. general population, with 50 as the average and 10 as the standard deviation, higher scores = better health. For norm based scores, change from baseline were calculated for the 8 scales and the 2 summary scales, where change = visit value − baseline value. FAS = all subjects who were randomized. Subjects were included in the treatment to which they were randomized for the FAS. LOCF imputation was used; those with a baseline and 1 postbaseline value were included.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    556
    273
    Units: units on a scale
        least squares mean (standard error)
    2.28 ± 0.371
    -0.81 ± 0.529
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    829
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    3.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.81
         upper limit
    4.35
    Notes
    [4] - The model included treatment group as a factor and the baseline value as a covariate. The estimation and p-value were adjusted by the covariate.

    Secondary: Percentage of Participants Who Achieved both a 75% improvement (response) in the PASI and sPGA Score of Clear (0) or Almost Clear (1) with at Least 2 Points Reduction from baseline at Week 16 from Baseline

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    End point title
    Percentage of Participants Who Achieved both a 75% improvement (response) in the PASI and sPGA Score of Clear (0) or Almost Clear (1) with at Least 2 Points Reduction from baseline at Week 16 from Baseline
    End point description
    PASI-75 response was the percentage of participants who achieved at least a 75% reduction (improvement) from baseline in PASI score at Week 16. The improvement in PASI score was used as a measure of efficacy. See Outcome Measure #1 for further description. sPGA is a 5-point scale ranging from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), to 4 (severe), incorporating an assessment of the severity of the three primary signs of the disease: erythema, scaling and plaque elevation. See OCM #2 for further description. The Full Analysis Set (FAS) consisted of all participants who were randomized per protocol. Participants were included in the treatment group to which they were randomized APR 30 BID or placebo for the FAS. Last observation carried forward imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    562
    282
    Units: percentage of participants
        number (not applicable)
    20.3
    3.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    844
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    16.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.8
         upper limit
    20.7

    Secondary: Kaplan Meier Estimate of Time to loss of PASI-75 response (loss of effect) at Week 32 during the Re-Randomized Treatment Withdrawal Phase

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    End point title
    Kaplan Meier Estimate of Time to loss of PASI-75 response (loss of effect) at Week 32 during the Re-Randomized Treatment Withdrawal Phase
    End point description
    Time to loss was the time between the re-randomization date and the date of the first assessment where loss of PASI-75 was observed (event); or the time between the re-randomization date and the date of the last PASI assessment in the Weeks 32-52 interval prior to addition of protocol-prohibited medication/therapy, or resumption of APR 30 BID, or discontinuation, or Week 52 if no loss (censored). Analysis population consisted of participants who were re-randomized to placebo or apremilast 30mg BID at Week 32. “99999” indicates data not available since there were not enough subjects who lost response by the end of the Randomized Withdrawal Phase for the estimation.
    End point type
    Secondary
    End point timeframe
    Week 32 to Week 52
    End point values
    APR-APR-Re-randomized to PBO APR-APR-Re-randomized to APR
    Number of subjects analysed
    77
    77
    Units: Weeks
        median (confidence interval 95%)
    17.7 (13.0 to 99999)
    5.1 (4.1 to 8.1)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    APR-APR-Re-randomized to PBO v APR-APR-Re-randomized to APR
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.649
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.768
         upper limit
    3.969

    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
    An AE was any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a subject 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 cause. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) = untoward AE that is fatal, life-threatening, results in persistent disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the subject or require an intervention to prevent one of the outcomes above. A treatment emergent is an AE if the AE start date is on or after the date of the lst dose of IP and no later than 28 days after the last dose. Safety population = subjects randomized; received one dose of IP.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16; mean duration of exposure was 14.8 weeks and 15.0 weeks for subjects randomized to placebo and apremilast respectively.
    End point values
    Apremilast Placebo
    Number of subjects analysed
    560
    282
    Units: participants
        Any TEAE
    388
    157
        Any Drug-Related TEAE
    224
    58
        Any Severe TEAE
    20
    9
        Any Serious TEAE
    12
    8
        Any Serious Drug-Related TEAE
    4
    0
        Any TEAE leading to Drug Interruption
    37
    13
        ≥ 1 TEAE leading to drug withdrawal
    29
    9
        Any TEAE Leading to Death
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with TEAEs During the Apremilast-exposure Period Through Week 260

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    End point title
    Number of Participants with TEAEs During the Apremilast-exposure Period Through Week 260
    End point description
    The APR-exposure period started on the date of the first dose of APR (Week 0 for participants originally randomized to APR or Wk 16 for subjects originally randomized to placebo) to the last dose of APR. AEs that started after 28 days of initiating PBO and before resuming APR treatment in the Randomized Treatment Withdrawal Phase (Wks 32 to 52) were excluded in the APR-exposure Period. A serious AE (SAE) = untoward AE that is fatal, life-threatening, results in persistent disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the subject or require an intervention to prevent one of the outcomes above. A treatment emergent is an AE if the AE start date is on or after the date of the lst dose of IP and no later than 28 days after the last dose. APR subjects as treated. All subjects randomized to (at Week 0) or treated with (at Wk 16) APR 30 mg BID and received at least 1 dose
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 260; mean exposure to apremilast 30 mg BID during the Apremilast-exposure Period up to Week 260 was 97.83 weeks
    End point values
    Number of Subjects with TEAEs During the APR-Exposure Period
    Number of subjects analysed
    804
    Units: participants
        Any TEAE
    675
        Any Drug-Related TEAE
    372
        Any Severe TEAE
    78
        Any Serious TEAE
    74
        Any Serious Drug-Related TEAE
    12
        Any TEAE Leading to Drug Interruption
    107
        Any TEAE Leading to Drug withdrawal
    98
        Any TEAE Leading to Death
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with a Psoriasis Flare or Rebound during the Placebo-Controlled Phase

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    End point title
    Number of Participants with a Psoriasis Flare or Rebound during the Placebo-Controlled Phase
    End point description
    Psoriasis flare was defined as a sudden intensification of psoriasis requiring medical intervention, or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. Note categories below. [1] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis) started on or after the first dose date and on or before the last dose date within the phase. [2] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis, Rebound psoriasis) started after the last dose date for participants who discontinued within the phase. [3] PASI >= 125% of baseline score at any visit after the last dose date for participants who discontinued within the phase and were not included in [1] and/or [2]. Safety population.
    End point type
    Secondary
    End point timeframe
    Weeks 0 to Week 16
    End point values
    Apremilast Placebo
    Number of subjects analysed
    560
    282
    Units: participants
        Participants with any psoriasis flare [1]
    6
    7
        Participants with any psoriasis rebound [2]
    1
    1
        PASI ≥ 125% of Baseline score after last dose [3]
    3
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with a Psoriasis Flare or Rebound During the During the Apremilast-exposure Period Through Week 260

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    End point title
    Number of Participants with a Psoriasis Flare or Rebound During the During the Apremilast-exposure Period Through Week 260
    End point description
    Psoriasis flare was defined as a sudden intensification of psoriasis requiring medical intervention, or a diagnosis of new generalized erythrodermic, inflammatory, or pustular psoriasis. Rebound is defined as a severe and sudden worsening of disease that occurs after treatment has been discontinued. Note categories below. [1] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis) started on or after the first dose date and on or before the last dose date within the phase. [2] Psoriasis adverse events (ie, preferred term as Guttate psoriasis, Psoriasis, Pustular psoriasis, Rebound psoriasis) started after the last dose date for participants who discontinued within the phase. [3] PASI >= 125% of baseline score at any visit after the last dose date for participants who discontinued within the phase and were not included in [1] and/or [2].
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 260
    End point values
    Subjects with a Psoriasis Flare During the APR-Exposure Phase
    Number of subjects analysed
    804
    Units: participants
        Participants with any psoriasis flare [1]
    35
        Participants with any psoriasis rebound [2]
    12
        PASI ≥ 125% of Baseline score after last dose [3]
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are reported as follows: -16-week PBO-controlled phase -Weeks 32-52 participants re-randomized to PBO at Week 32; re-randomized to PBO at Week 32. -Weeks 0-260 APR exposure period = those randomized or switched to APR at any time during the study
    Adverse event reporting additional description
    During the PBO-controlled Phase (Weeks 0-16), the mean duration of treatment for those randomized to APR 30 BID or PBO at Week 0, was 15.0 and 14.8, respectively; for those re-randomized to PBO at Week 32, the mean duration of PBO was 8.1 weeks; during the APR-Exposure Period (Weeks 0-260), the mean duration of exposure to APR was 97.83 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo (Placebo-Controlled Phase) Weeks 0-16
    Reporting group description
    Participants randomized and received identically matching placebo tablets BID during the Placebo-controlled Phase (Weeks 0-16)

    Reporting group title
    Apremilast (Placebo-Controlled Phase) Weeks 0-16
    Reporting group description
    Participants randomized and received apremilast 30 mg tablets BID during the Placebo-Controlled Phase (Weeks 0-16)

    Reporting group title
    APR-APR-PBO Randomized Withdrawal Phase Weeks 32-52
    Reporting group description
    Participants re-randomized and received placebo tablets BID at Week 32. Data from Week 32 up to Week 52 when participants received placebo treatment.

    Reporting group title
    Apremilast (Apremilast Exposure Period) Weeks 0-260
    Reporting group description
    Participants who received apremilast 30 mg tablets BID, regardless of when the apremilast exposure started (at Week 0 or at week 16), up until Week 260. Adverse events associated with apremilast treatment up to Week 260 were included. AEs that started more than 28 days after Placebo treatment and prior to resuming apremilast were excluded for subjects who were re-randomized to Placebo at Week 32.

    Serious adverse events
    Placebo (Placebo-Controlled Phase) Weeks 0-16 Apremilast (Placebo-Controlled Phase) Weeks 0-16 APR-APR-PBO Randomized Withdrawal Phase Weeks 32-52 Apremilast (Apremilast Exposure Period) Weeks 0-260
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 282 (2.84%)
    12 / 560 (2.14%)
    2 / 77 (2.60%)
    74 / 804 (9.20%)
         number of deaths (all causes)
    1
    1
    0
    3
         number of deaths resulting from adverse events
    0
    1
    0
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctival primary acquired melanosis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    1 / 77 (1.30%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical burns of eye
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    1 / 77 (1.30%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heart rate increased
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    4 / 804 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    6 / 804 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 282 (0.35%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukoplakia oesophageal
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    4 / 804 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Ingrowing nail
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 282 (0.00%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    3 / 804 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 282 (0.35%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    0 / 804 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 282 (0.35%)
    1 / 560 (0.18%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    1 / 804 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 282 (0.00%)
    0 / 560 (0.00%)
    0 / 77 (0.00%)
    2 / 804 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Placebo-Controlled Phase) Weeks 0-16 Apremilast (Placebo-Controlled Phase) Weeks 0-16 APR-APR-PBO Randomized Withdrawal Phase Weeks 32-52 Apremilast (Apremilast Exposure Period) Weeks 0-260
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 282 (31.91%)
    260 / 560 (46.43%)
    10 / 77 (12.99%)
    503 / 804 (62.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 282 (2.48%)
    10 / 560 (1.79%)
    0 / 77 (0.00%)
    56 / 804 (6.97%)
         occurrences all number
    7
    10
    0
    57
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 282 (4.61%)
    31 / 560 (5.54%)
    0 / 77 (0.00%)
    62 / 804 (7.71%)
         occurrences all number
    16
    34
    0
    87
    Tension headache
         subjects affected / exposed
    12 / 282 (4.26%)
    41 / 560 (7.32%)
    2 / 77 (2.60%)
    84 / 804 (10.45%)
         occurrences all number
    14
    49
    2
    134
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 282 (7.09%)
    105 / 560 (18.75%)
    0 / 77 (0.00%)
    163 / 804 (20.27%)
         occurrences all number
    23
    123
    0
    211
    Nausea
         subjects affected / exposed
    19 / 282 (6.74%)
    88 / 560 (15.71%)
    0 / 77 (0.00%)
    130 / 804 (16.17%)
         occurrences all number
    21
    93
    0
    153
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 282 (1.77%)
    9 / 560 (1.61%)
    2 / 77 (2.60%)
    51 / 804 (6.34%)
         occurrences all number
    6
    11
    2
    63
    Back pain
         subjects affected / exposed
    2 / 282 (0.71%)
    14 / 560 (2.50%)
    1 / 77 (1.30%)
    50 / 804 (6.22%)
         occurrences all number
    3
    14
    1
    57
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    6 / 282 (2.13%)
    10 / 560 (1.79%)
    0 / 77 (0.00%)
    41 / 804 (5.10%)
         occurrences all number
    6
    10
    0
    50
    Nasopharyngitis
         subjects affected / exposed
    23 / 282 (8.16%)
    41 / 560 (7.32%)
    3 / 77 (3.90%)
    131 / 804 (16.29%)
         occurrences all number
    26
    48
    3
    226
    Sinusitis
         subjects affected / exposed
    5 / 282 (1.77%)
    16 / 560 (2.86%)
    1 / 77 (1.30%)
    45 / 804 (5.60%)
         occurrences all number
    6
    17
    1
    63
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 282 (7.45%)
    57 / 560 (10.18%)
    2 / 77 (2.60%)
    183 / 804 (22.76%)
         occurrences all number
    21
    64
    2
    326

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2010
    1. Updated the Table of Events at Week 34 for Investigational Product (IP) Dispense and Return, which allowed sites to maintain the study blinding during the Randomized Treatment Withdrawal Phase of the study (Weeks 32-52) 2. Clarified procedures for male subjects while on study in the case of a male subject impregnating a female partner 3. Clarified data collection method to be used to subject-reported data 4. Included PHQ-8 quality of life questionnaire within the context of the full protocol 5. Clarified subject signature was required on a separate page of the ICD for PK and photography assessments
    04 Jan 2011
    1. Clarified the language regarding contraception methods to ensure that acceptable methods of contraception by subjects were used: added a statement to ensure that appropriate education regarding contraception methods was provided by the investigator to the subjects 2. Clarified procedures for subjects who entered the Randomized Treatment Withdrawal Phase at Week 32 3. Clarified that Arthritis VAS only pertained to subjects with psoriatic arthritis 4. Clarified procedures for VAS Exploratory Endpoint regarding intent to compare the proportion of subjects with 10-mm improvement in symptoms (minimal clinically important difference [MCID]) 5. Deleted annual CXRs allowing local treatment guidelines to dictate when CXRs were performed 6. Corrected the order of Health-Related Quality of Life (HRQoL) and VAS assessments to align with what is actually being done on the SitePad instrument 7. Aligned exclusion criteria related to past malignancies across the entire apremilast Phase 3 program in order to give investigators responsibility for determining subject eligibility for previously successfully treated local lesions 8. Clarified Statistical Efficacy Analysis deleting the “per protocol” analysis 9. Modified the Reasons for Discontinuation to align with what is displayed in the InForm database 10. Clarified protocol definition of permitted therapies for partial responders and nonresponders beginning at Week 32
    10 Jun 2011
    1. Clarified the Contraception Education that required the investigator to educate the subject on acceptable birth control any time when a subject’s contraceptive measures or ability to become pregnant changed; modified to direct the investigator to Section 7.2 of the protocol where details regarding the acceptable contraception for this study may be found 2. Modified Inclusion Criterion Number 9 (female birth control) to clearly define single or multiple forms of contraception that were acceptable for this study 3. Added a footnote to Inclusion Criterion Number 9 (female birth control) to clarify that the female subject’s chosen form of contraception must be fully effective by the time the female subject receives the first dose of IP at randomization 4. Modified Inclusion Criterion Number 10 (male birth control) to clarify that male subjects must use a “male” latex or non-latex condom
    19 Apr 2012
    1. Updates made to the contact information for the study medical monitor 2. Clarified in Section 3.2.2, Efficacy, and in Section 3.3, Exploratory Endpoint(s), that the VAS scale endpoints were to be change from baseline rather than percent change 3. Modified Section 4.1, Study Design, to allow the use of topical corticosteroids, retinoids or vitamin D analog preparations and/or phototherapy after the Week 52 visit for partial and nonresponders (< PASI-75) 4. Modified Section 4.1, Study Design, regarding the replacement of the Safety Review Panel with an independent external DMC 5. Added footnote k and h in Table 1 and 2, respectively, to the AEs row that vasculitis assessments and/or psychiatric evaluations were to be performed as needed when AEs were reported 6. Clarification of footnote l and i in Table 1 and 2, respectively, that only subjects with nail disease, scalp psoriasis, palmoplantar psoriasis, and/or psoriatic arthritis at baseline were to be evaluated with the disease activity tools for those respective conditions 7. Revision of the Contraception Education in Section 6.2 and movement of footnote from Section 7.2 to Section 6.2 8. Added Section 6.6.4.1, Vasculitis Assessment 9. Added Section 6.6.4.2, Psychiatric Evaluation, to provide precautionary guidance to physicians for the management of subjects identified as having thoughts of suicide, attempted suicide or having major psychiatric illness 10. Change to the open-label IP package as described in Sections 6.11.1, IP Dispensing and Counting for Compliance, and 8.4, Packaging and Labeling 11. Modified Section 9.1, Permitted Concomitant Medications, and Section 9.2, Prohibited Concomitant Medications, to allow the use of topical corticosteroids, retinoids, or vitamin D analog preparations and/or phototherapy after the Week 52 visit for partial and nonresponders (< PASI-75) 12. Clarified that AE tables were to summarize TEAE only 13. “CRF” changed to “eCRF” to reflect that data captured in the eCRF pages

    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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