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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study Followed by an Active Treatment Phase to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in the Treatment of Subjects With Active Behçet’s Disease

    Summary
    EudraCT number
    		 2014-002108-25
    Trial protocol
    		 DE   IT   GR  
    Global end of trial date
    17 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2021
    First version publication date
    18 Jul 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-BCT-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02307513
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 20200054: Amgen Study ID
    Sponsors
    Sponsor organisation name
    Amgen, Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of apremilast (APR) in the treatment of oral ulcers in active Behçet’s disease (BD).
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice (GCP), according to the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline and in accordance with the general ethical principles outlined in the Declaration of Helsinki. The protocol, amendments, and informed consent form (ICF) were reviewed and approved by each study site’s Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the start of the study. The investigator obtained informed consent of a subject and/or a subject’s legal representative prior to any study-related procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Lebanon: 4
    Country: Number of subjects enrolled
    Turkey: 54
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    207
    EEA total number of subjects
    52
    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)
    200
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 53 sites in Europe, Asia, the United States, Israel, Lebanon, and Turkey. The study included a 12-week placebo-controlled phase and a 52-week active treatment phase. Participants in Germany had the opportunity to enter an optional open-label extension phase at week 64.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to receive either apremilast or placebo in the placebo-controlled treatment phase. After completion of 12 weeks, all participants were to receive apremilast for 52 weeks in the active treatment phase. Participants were stratified by gender, history of uveitis and region (Japan and Other Regions).

    Period 1
    Period 1 title
    Placebo Controlled Phase (Weeks 0-12)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received identically appearing placebo tablets twice a day (BID) from weeks 0 to 12 during the placebo-controlled treatment phase.
    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
    Tablets taken orally twice a day

    Arm title
    		 Apremilast 30 mg BID
    Arm description
    		 Participants received apremilast 30 mg tablets BID from weeks 0 to 12 during the placebo-controlled treatment phase.
    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
    Tablets taken orally twice a day

    Number of subjects in period 1
    		Placebo Apremilast 30 mg BID
    Started
    103
    104
    Completed
    83
    96
    Not completed
    20
    8
         Consent withdrawn by subject
    5
    4
         Non-Compliance with Study Drug
    1
    -
         Adverse event, non-fatal
    4
    3
         Lost to follow-up
    1
    -
         Lack of efficacy
    8
    -
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Active Treatment Phase (Weeks 13-64)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Apremilast 30 mg BID
    Arm description
    		 Participants who received placebo during the placebo-controlled treatment phase were switched at week 12 to apremilast 30 mg tablets BID for 52 weeks up to week 64 in the active treatment phase.
    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
    Tablets taken orally twice a day

    Arm title
    		 Apremilast 30 mf BID / Apremilast 30 mg BID
    Arm description
    		 Participants who received apremilast during the placebo-controlled treatment phase continued to receive apremilast 30 mg BID for 52 weeks up to week 64 in the active treatment phase.
    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
    Tablets taken orally twice a day

    Number of subjects in period 2 [1]
    		Placebo / Apremilast 30 mg BID Apremilast 30 mf BID / Apremilast 30 mg BID
    Started
    83
    95
    Completed
    68
    75
    Not completed
    15
    20
         Consent withdrawn by subject
    7
    7
         Adverse event, non-fatal
    4
    9
         Pregnancy
    1
    -
         Miscellaneous
    -
    1
         Lost to follow-up
    1
    1
         Lack of efficacy
    2
    2
    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: One participant completed Week 12 but did not enter into active treatment.
    Period 3
    Period 3 title
    Long-term Extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Placebo / Apremilast 30 mg BID
    Arm description
    		 Participants in Germany had the option to continue receiving apremilast 30 mg BID in the open-label extension phase.
    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
    Tablets taken orally twice a day

    Number of subjects in period 3 [2]
    		Placebo / Apremilast 30 mg BID
    Started
    2
    Completed
    1
    Not completed
    1
         Physician decision
    1
    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: Only participants in Germany had the option to continue receiving apremilast 30 mg BID in the extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received identically appearing placebo tablets twice a day (BID) from weeks 0 to 12 during the placebo-controlled treatment phase.

    Reporting group title
    Apremilast 30 mg BID
    Reporting group description
    		 Participants received apremilast 30 mg tablets BID from weeks 0 to 12 during the placebo-controlled treatment phase.

    Reporting group values
    		 Placebo Apremilast 30 mg BID Total
    Number of subjects
    		 103 104 207
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 99 101 200
        From 65-84 years
    		 4 3 7
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 40.6 ( 12.66 ) 39.4 ( 12.12 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 63 64 127
        Male
    		 40 40 80
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 30 32 62
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 0 1 1
        White
    		 68 69 137
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 3 2 5
    Region of the World
    Units: Subjects
        Europe
    		 27 25 52
        North America
    		 11 14 25
        Asia
    		 29 32 61
        Rest of World
    		 36 33 69
    Duration of Behcet's Disease
    Units: Years
        arithmetic mean (standard deviation)
    		 6.94 ( 7.966 ) 6.74 ( 7.397 ) -
    Oral Ulcer Count
    Units: Oral ulcers
        arithmetic mean (standard deviation)
    		 3.9 ( 2.70 ) 4.2 ( 3.65 ) -
    Pain of Oral Ulcers Visual Analog Scale (VAS)
    The oral ulcer pain visual analog scale ranges from 0 to 100 mm, with 0 mm representing no pain and 100 mm representing the worst possible pain.
    Units: mm
        arithmetic mean (standard deviation)
    		 60.8 ( 26.92 ) 61.2 ( 27.55 ) -
    Behçet’s Disease Current Activity Index (BDCAI) Score
    The BD Current Activity Index (as measured by the BD Current Activity Form) includes 12 questions regarding disease manifestations over the past 4 weeks, including oral and genital disease activity as well as manifestations involving the skin, joints, gastrointestinal tract, eyes, nervous system, and vascular system. The BDCAI ranges from 0 to 12, where higher scores indicate a higher level of disease activity.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 3.6 ( 1.67 ) 3.7 ( 1.58 ) -
    Behçet’s Syndrome Activity Score (BSAS)
    The Behçet’s Syndrome Activity Score contains 10 questions that assess the number of new oral and genital ulcers and skin lesions, gastrointestinal (GI), central nervous system (CNS), vascular, and ocular involvement, and the participant’s current level of discomfort, each on a scale from 0 to 100 (worst). The item scores are totaled to create a score ranging from 0 to 100, with a higher score indicating a higher level of disease activity.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 44.30 ( 16.862 ) 42.75 ( 16.224 ) -
    Behçet’s Disease Quality of Life (BD QoL)
    The BD QoL consists of 30 self-completed items that measure disease-related restrictions on the participant’s activities and their emotional response to these restrictions. The BD QoL total score ranges from 0 to 30, with 0 representing no influence of BD on quality of life and 30 representing the greatest influence.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 11.24 ( 8.157 ) 10.22 ( 8.245 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received identically appearing placebo tablets twice a day (BID) from weeks 0 to 12 during the placebo-controlled treatment phase.

    Reporting group title
    Apremilast 30 mg BID
    Reporting group description
    		 Participants received apremilast 30 mg tablets BID from weeks 0 to 12 during the placebo-controlled treatment phase.
    Reporting group title
    Placebo / Apremilast 30 mg BID
    Reporting group description
    		 Participants who received placebo during the placebo-controlled treatment phase were switched at week 12 to apremilast 30 mg tablets BID for 52 weeks up to week 64 in the active treatment phase.

    Reporting group title
    Apremilast 30 mf BID / Apremilast 30 mg BID
    Reporting group description
    		 Participants who received apremilast during the placebo-controlled treatment phase continued to receive apremilast 30 mg BID for 52 weeks up to week 64 in the active treatment phase.
    Reporting group title
    Placebo / Apremilast 30 mg BID
    Reporting group description
    		 Participants in Germany had the option to continue receiving apremilast 30 mg BID in the open-label extension phase.

    Primary: Area Under the Curve (AUC) for the Number of Oral Ulcers from Baseline Through Week 12 (AUC W0-12)

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    End point title
    		 Area Under the Curve (AUC) for the Number of Oral Ulcers from Baseline Through Week 12 (AUC W0-12)
    End point description
    The number of oral ulcers that was counted for the analysis of the primary endpoint included current and recurrent ulcers at each time point; a single oral ulcer could be recounted multiple times if it persisted or recurred at subsequent visits. The intent to treat (ITT) population included all randomized participants who received at least 1 dose of study drug. Multiple imputation (MI) was used to impute missing oral ulcer counts.
    End point type
    Primary
    End point timeframe
    Oral ulcers were assessed at weeks 0 (baseline), 1, 2, 4, 6, 8, 10, and 12 during the placebo-controlled period.
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Ulcers*days
        least squares mean (standard error)
    222.14 ( 15.886 )
    129.54 ( 15.943 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Statistical analysis description
    The AUC W0-12 for oral ulcer counts was compared between the placebo treatment group and the apremilast 30 BID treatment group using a 2-tailed parametric analysis of covariance (ANCOVA) test at the 0.05 significance level.
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -92.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -130.59
         upper limit
    		 -54.6
    Notes
    [1] - ANCOVA model with AUC W0-12 as the response variables; treatment arm, sex, region as factors and the number of oral ulcers at baseline as a covariate.

    Secondary: Change from Baseline in Oral Ulcer Pain as Measured by Visual Analog Scale (VAS) at Week 12

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    End point title
    		 Change from Baseline in Oral Ulcer Pain as Measured by Visual Analog Scale (VAS) at Week 12
    End point description
    Pain of oral ulcers was measured using a 100 mm VAS scale. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was recorded. A negative change from baseline indicates improvement. The analysis was conducted in the the intent to treat population with available baseline data. Last observation carried forward (LOCF) imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    102
    103
    Units: mm
        least squares mean (standard error)
    -15.9 ( 3.31 )
    -40.7 ( 3.34 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -24.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.8
         upper limit
    		 -16.8
    Notes
    [2] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Change from Baseline in Disease Activity as Measured by Behçet’s Syndrome Activity Score (BSAS) at Week 12

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    End point title
    		 Change from Baseline in Disease Activity as Measured by Behçet’s Syndrome Activity Score (BSAS) at Week 12
    End point description
    The Behçet’s Syndrome Activity Score (BSAS) contains 10 questions that assess the number of new oral and genital ulcers and skin lesions, GI, CNS, vascular, and ocular involvement, and the participant’s current level of discomfort. The Behçet’s Syndrome Activity Score ranges from 0 to 100, with a higher score indicating a higher level of disease activity. A negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population with available baseline data. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Units on a scale
        least squares mean (standard error)
    -5.41 ( 1.776 )
    -17.35 ( 1.796 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -11.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.2
         upper limit
    		 -7.67
    Notes
    [3] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Behçet’s Disease Current Activity Index (BDCAI) at Week 12

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    End point title
    		 Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Behçet’s Disease Current Activity Index (BDCAI) at Week 12
    End point description
    The Behçet’s Disease Current Activity Form (BDCAF) consists of 3 component scores: the Behçet’s Disease Current Activity Index (BDCAI) score, the Patient’s Perception of Disease Activity, and the Clinician’s Overall Perception of Disease Activity. The BDCAI consists of 12 questions regarding disease manifestations over the previous 4 weeks, including oral and genital disease activity, as well as other manifestations of BD involving the skin, joints, GI tract, eyes, nervous system, and vascular system. The BDCAI score is the sum score of 12 items and ranges from 0 to 12. A higher score indicates higher level of disease activity (worsening), and a negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population with available baseline data. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    102
    104
    Units: Units on a scale
        least squares mean (standard error)
    -0.4 ( 0.20 )
    -0.9 ( 0.20 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0335 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0
    Notes
    [4] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Patient's Perception of Disease Activity at Week 12

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    End point title
    		 Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Patient's Perception of Disease Activity at Week 12
    End point description
    The Behçet’s Disease Current Activity Form (BDCAF) consists of 3 component scores: the Behçet’s Disease Current Activity Index (BDCAI) score, the Patient’s Perception of Disease Activity, and the Clinician’s Overall Perception of Disease Activity. The Patient’s Perception of Disease Activity was assessed on a scale from 1 to 7, where a higher score indicates a higher level of disease activity and a negative change from baseline indicates improvement. The study was conducted in the intent to treat population with available data. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    102
    104
    Units: Units on a scale
        least squares mean (standard error)
    -0.7 ( 0.18 )
    -1.7 ( 0.18 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 -0.6
    Notes
    [5] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Clinician’s Overall Perception of Disease Activity at Week 12

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    End point title
    		 Change from Baseline in Disease Activity as Measured by Behçet’s Disease Current Activity Form (BDCAF): Clinician’s Overall Perception of Disease Activity at Week 12
    End point description
    The Behçet’s Disease Current Activity Form (BDCAF) consists of 3 component scores: the Behçet’s disease Current Activity Index (BDCAI) score, the Patient’s Perception of Disease Activity, and the Clinician’s Overall Perception of Disease Activity. The Clinician’s Overall Perception of Disease Activity was assessed on a scale from 1 to 7, where a higher score indicates a higher level of disease activity and a negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population with available baseline data. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    102
    104
    Units: Units on a scale
        least squares mean (standard error)
    -0.7 ( 0.17 )
    -1.6 ( 0.17 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 -0.5
    Notes
    [6] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Percentage of Participants who Achieved an Oral Ulcer Complete Response (Oral Ulcer-Free) by Week 6 and Remained Oral Ulcer-Free for at Least 6 Additional Weeks

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    End point title
    		 Percentage of Participants who Achieved an Oral Ulcer Complete Response (Oral Ulcer-Free) by Week 6 and Remained Oral Ulcer-Free for at Least 6 Additional Weeks
    End point description
    Participants who were oral ulcer-free by week 6 and remained oral ulcer-free for at least 6 consecutive weeks during the 12-week placebo-controlled treatment phase.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Percentage of participants
        number (not applicable)
    4.9
    29.8
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Statistical analysis description
    The adjusted difference in percentages is the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the CMH weights.
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in percentages
    Point estimate
    25.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.5
         upper limit
    		 34.6
    Notes
    [7] - 2-sided p-value based on the CMH test adjusting for sex and region.

    Secondary: Time to Oral Ulcer Resolution (Complete Response)

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    End point title
    		 Time to Oral Ulcer Resolution (Complete Response)
    End point description
    Time to oral ulcer resolution (defined as oral ulcer-free) was the time between the first dose date and the date when a complete response was achieved for the first time during the placebo-controlled treatment phase. For participants who did not achieve complete response or discontinued treatment before a complete response was achieved during the placebo-controlled treatment phase, time to event was censored at the last oral ulcer assessment date during the placebo-controlled treatment phase or the first dose date if there were no postbaseline ulcer assessments. Median and 95% confidence interval was based on Kaplan-Meier estimates. "99999" indicates values that could not be estimated due to the low number of events at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Weeks
        median (confidence interval 95%)
    8.1 (4.7 to 99999)
    2.1 (2.0 to 4.0)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Stratified Log-Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.692
         upper limit
    		 3.405
    Notes
    [8] - Stratified log-rank test, with sex and region as the stratification factors

    Secondary: Percentage of Participants who Experienced an Oral Ulcer Complete Response at Week 12

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    End point title
    		 Percentage of Participants who Experienced an Oral Ulcer Complete Response at Week 12
    End point description
    A complete response at week 12 was defined as participants who were oral ulcer free at week 12. The analysis was conducted in the intent to treat population; participants with missing data at week 12 were classified as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Percentage of participants
        number (not applicable)
    22.3
    52.9
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Statistical analysis description
    The adjusted difference in percntages was the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the CMH weights.
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in percentages
    Point estimate
    30.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.1
         upper limit
    		 43.1
    Notes
    [9] - 2-sided p-value based on the CMH test adjusting for sex and region.

    Secondary: Change from Baseline in Behçet’s Disease Quality of Life (BD Qol) Scores at Week 12

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    End point title
    		 Change from Baseline in Behçet’s Disease Quality of Life (BD Qol) Scores at Week 12
    End point description
    The Behçet’s Disease Quality of Life questionnaire was developed to measure the influence of BD on a particpant's life. It consists of 30 self-completed itemized questions that measure disease-related restrictions on the participant's activities and their emotional response to these restrictions. The total score is the sum of all 30 items (each yes scores 1 and each no scores 0), with 0 representing no influence of Behçet’s disease on a participant's quality of life and 30 representing the most severe influence. A negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population; LOCF was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Units on a scale
        least squares mean (standard error)
    -0.5 ( 0.66 )
    -3.5 ( 0.67 )
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 -1.4
    Notes
    [10] - Based on an ANCOVA model for the change from baseline with the treatment arm, sex, region as factors and the baseline value as a covariate.

    Secondary: Percentage of Participants who Experienced a Complete Response For Genital Ulcers at Week 12

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    End point title
    		 Percentage of Participants who Experienced a Complete Response For Genital Ulcers at Week 12
    End point description
    A genital ulcer complete response at week 12 was defined as participants who were genital ulcer-free at week 12. The analysis was conducted in the intent to treat population who had genital ulcers at baseline. Participants with missing data at week 12 were classified as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    17 [11]
    17 [12]
    Units: Percentage of participants
        number (not applicable)
    41.2
    70.6
    Notes
    [11] - Participants with genital ulcers at baseline
    [12] - Participants with genital ulcers at baseline
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Statistical analysis description
    The adjusted difference in percentages was the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the CMH weights.
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in percentages
    Point estimate
    28.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 60.4
    Notes
    [13] - Two-sided p-value was based on the CMH test, adjusting for sex and region

    Secondary: Percentage of Participants with no Oral Ulcers Following a Complete Response

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    End point title
    		 Percentage of Participants with no Oral Ulcers Following a Complete Response
    End point description
    The percentage of participants who remained oral ulcer-free through week 12 after achieving a complete response (oral ulcer-free) prior to week 12. The analysis was conducted in the intent to treat population who had a complete response prior to week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    53 [14]
    83 [15]
    Units: Percentage of participants
        number (not applicable)
    13.2
    31.3
    Notes
    [14] - Participants with a complete response prior to week 12
    [15] - Participants with a complete response prior to week 12
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Statistical analysis description
    The adjusted difference in percentages was the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the CMH weights.
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0204 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in percentages
    Point estimate
    17.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 30.7
    Notes
    [16] - Two-sided p-value was based on the CMH test, adjusting for sex and region.

    Secondary: Time to Recurrence of Oral Ulcers Following Loss of Complete Response

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    End point title
    		 Time to Recurrence of Oral Ulcers Following Loss of Complete Response
    End point description
    Time to recurrence of oral ulcers following the loss of complete response (oral ulcer-free) was defined as the first instance when a participant had a reappearance of oral ulcers following a complete response, during the placebo-controlled treatment phase. For participants who did not have oral ulcer recurrence or discontinued treatment before any oral ulcer recurrence during the placebo-controlled treatment phase, time to event was censored at the last oral ulcer assessment during placebo-controlled treatment phase; For participants without any oral ulcer assessment following the first complete response, time to event was censored to the first complete response date. The analysis was conducted in the intent to treat population who had a complete response prior to week 12.
    End point type
    Secondary
    End point timeframe
    Baseline through week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    53 [17]
    83 [18]
    Units: Weeks
        median (confidence interval 95%)
    2.3 (2.1 to 4.1)
    4.6 (3.1 to 6.1)
    Notes
    [17] - Participants with a complete response prior to week 12
    [18] - Participants with a complete response prior to week 12
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0112 [19]
    Method
    		 Stratified Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.611
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.408
         upper limit
    		 0.915
    Notes
    [19] - Stratified log-rank test, with sex and region as the stratification factors.

    Secondary: Number of Oral Ulcers Following Loss of Complete Response Through Week 12

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    End point title
    		 Number of Oral Ulcers Following Loss of Complete Response Through Week 12
    End point description
    Number of oral ulcers reported at the time of the first loss of complete response, ie, at the first instance when a participant had a reappearance of oral ulcers following a complete response, during the placebo-controlled treatment phase. The analysis was conducted in the intent to treat population who had a complete response prior to week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    53 [20]
    83 [21]
    Units: oral ulcers
        least squares mean (standard error)
    1.5 ( 0.21 )
    1.1 ( 0.18 )
    Notes
    [20] - Participants with a complete response prior to week 12
    [21] - Participants with a complete response prior to week 12
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0683 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0
    Notes
    [22] - ANCOVA model with treatment group, sex and region as factors and the baseline ulcers number as a covariate.

    Secondary: Change from Baseline in the Total Score of the Static Physician’s Global Assessment (PGA) of BD Skin Lesions at Week 12

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    End point title
    		 Change from Baseline in the Total Score of the Static Physician’s Global Assessment (PGA) of BD Skin Lesions at Week 12
    End point description
    BD-related skin lesions (including acne-like lesions, folliculitis, and erythema nodosum) were evaluated according to the Static Physician’s Global Assessment as follows: Score 0 = clear skin. Score 1 = mild in severity with the presence of 1 to 10 lesions (papules, pustules, cysts) or nodules at any anatomical site. Score 2 = Moderate severity; presence of 11 to 20 nodules or lesions (papules, pustules, cysts) at any anatomical site. Score 3 = Severe; presence of > 20 nodules or lesions (papules, pustules, cysts) at any anatomical site. The total sore was calculated as the sum of the acne-like lesions, folliculitis, and erythema nodosum scores, and therefore ranges from 0 to 9, where a higher score indicates a higher level of activity. A negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population who had BD skin lesions at baseline. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    59 [23]
    58 [24]
    Units: scores on a scale
        least squares mean (standard error)
    -0.8 ( 0.14 )
    -0.9 ( 0.14 )
    Notes
    [23] - Participants with BD skin lesions at baseline
    [24] - Participants with BD skin lesions at baseline
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5944 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.3
    Notes
    [25] - Based on an ANCOVA model for the change from baseline, with treatment arm, sex and region as factors and the baseline score as a covariate.

    Secondary: Change from Baseline in Genital Ulcer Pain as Measured by VAS Score at Week 12

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    End point title
    		 Change from Baseline in Genital Ulcer Pain as Measured by VAS Score at Week 12
    End point description
    Pain of genital ulcers was measured using a 100 mm visual analog scale. The participant was asked to draw a single line perpendicular to the VAS line at the point that represented the severity of their pain during the previous week, with 0 mm (the left-hand end of the scale) representing no pain and 100 mm (the right-hand end of the scale) representing the worst pain imaginable. The distance of the perpendicular line from the left-hand end of the scale was recorded. A negative change from baseline indicates improvement. The analysis was conducted in the intent to treat population who had genital ulcers at baseline. LOCF imputation was used for missing values at week 12.
    End point type
    Secondary
    End point timeframe
    Baseline to week 12
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    17 [26]
    17 [27]
    Units: mm
        least squares mean (standard error)
    -24.5 ( 10.75 )
    -30.0 ( 11.22 )
    Notes
    [26] - Participants with genital ulcers at baseline
    [27] - Participants with genital ulcers at baseline
    Statistical analysis title
    		 Treatment Comparison (Apremilast – Placebo)
    Comparison groups
    Placebo v Apremilast 30 mg BID
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6182 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.6
         upper limit
    		 16.7
    Notes
    [28] - Based on an ANCOVA model for the change from baseline, with treatment arm, sex and region as factors and the baseline score as a covariate.

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During the Placebo-controlled Treatment Period

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) During the Placebo-controlled Treatment Period
    End point description
    A TEAE is an adverse event (AE) with a start date on or after the date of the first dose of study drug and no later than 28 days after the last dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. A serious AE (SAE) is any AE that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or constituted an important medical event. For both AEs and SAEs the investigator assessed the severity of the event according to the grading scale: Mild: asymptomatic or with mild symptoms; Moderate: symptoms causing moderate discomfort and local or noninvasive intervention is indicated; Severe: symptoms causing severe discomfort or pain, symptoms requiring medical/surgical intervention.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug in the placebo-controlled phase to the first dose of apremilast in the active treatment phase (12 weeks) or up to 28 days after last dose for participants who did not receive study drug at week 12, whichever was earlier.
    End point values
    		 Placebo Apremilast 30 mg BID
    Number of subjects analysed
    103
    104
    Units: Participants
        Any TEAE
    74
    82
        Any Drug-related TEAE
    37
    60
        Any Severe TEAE
    6
    6
        Any Serious TEAE
    4
    3
        Any TEAE Leading to Drug Interruption
    6
    9
        Any TEAE Leading to Drug Withdrawal
    5
    3
        Any TEAE Leading to Death
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with TEAEs During the Apremilast-Exposure Period [29]
    End point description
    The apremilast-exposure period started on the date of the first dose of apremilast (week 0 for participants assigned to apremilast or week 12 for participants originally assigned to placebo who switched to apremilast at week 12) and ended 28 days after last dose in the active treatment phase. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. An SAE is any AE that resulted in death; was life-threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or constituted an important medical event. The investigator assessed the severity of each event according to the grading scale: Mild: asymptomatic or mild symptoms; Moderate: symptoms causing moderate discomfort, local or noninvasive intervention indicated; Severe: symptoms causing severe discomfort or pain, requiring medical/surgical intervention.
    End point type
    Secondary
    End point timeframe
    From first dose of apremilast (week 0 for those assigned to apremilast or week 12 for those assigned to placebo) up to 28 days after last dose; up to 56 weeks and 68 weeks in each arm respectively.
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data are reported for the apremilast-exposure period.
    End point values
    		 Placebo / Apremilast 30 mg BID Apremilast 30 mg BID
    Number of subjects analysed
    83
    104
    Units: participants
        Any TEAE
    70
    90
        Any Drug-related TEAE
    29
    64
        Any Severe TEAE
    4
    17
        Any Serious TEAE
    7
    10
        Any TEAE Leading to Drug Interruption
    10
    17
        Any TEAE Leading to Drug Withdrawal
    3
    12
        Any TEAE Leading to Death
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo-controlled phase: Week 0 to 12. Apremilast exposure: From first dose of APR (week 0 or 12) to 28 days after last dose; 56 and 68 weeks in each arm respectively. Extension: From first dose of open-label APR to 28 days after last dose, max 784 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo-controlled Phase: Placebo
    Reporting group description
    		 Participants received identically appearing placebo tablets twice a day from weeks 0 to 12 during the placebo-controlled treatment phase.

    Reporting group title
    Placebo-controlled Phase: Apremilast 30 mg BID
    Reporting group description
    		 Participants received apremilast 30 mg tablets twice a day from weeks 0 to 12 during the placebo-controlled treatment phase.

    Reporting group title
    Apremilast-exposure Period: Apremilast 30 mg BID
    Reporting group description
    		 Participants received apremilast 30 mg BID from week 0 or week 12 up to week 64.

    Reporting group title
    Open-label Extension: Apremilast 30 mg BID
    Reporting group description
    		 Participants in Germany received apremilast 30 mg BID in the open-label extension phase.

    Serious adverse events
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg BID Apremilast-exposure Period: Apremilast 30 mg BID Open-label Extension: Apremilast 30 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 103 (3.88%)
    3 / 104 (2.88%)
    17 / 187 (9.09%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 104 (0.96%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Behcet's syndrome
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 104 (0.96%)
    2 / 187 (1.07%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 104 (0.96%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mouth ulceration
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal stricture
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Erythema multiforme
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Skin lesion
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    2 / 187 (1.07%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Genital infection
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Genital infection fungal
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    0 / 2 (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
    Herpes zoster
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         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-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg BID Apremilast-exposure Period: Apremilast 30 mg BID Open-label Extension: Apremilast 30 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 103 (50.49%)
    67 / 104 (64.42%)
    132 / 187 (70.59%)
    2 / 2 (100.00%)
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Behcet's syndrome
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 103 (10.68%)
    15 / 104 (14.42%)
    38 / 187 (20.32%)
    0 / 2 (0.00%)
         occurrences all number
    13
    21
    58
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 103 (2.91%)
    4 / 104 (3.85%)
    12 / 187 (6.42%)
    0 / 2 (0.00%)
         occurrences all number
    3
    4
    13
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 103 (1.94%)
    9 / 104 (8.65%)
    20 / 187 (10.70%)
    0 / 2 (0.00%)
         occurrences all number
    2
    9
    27
    0
    Diarrhoea
         subjects affected / exposed
    21 / 103 (20.39%)
    43 / 104 (41.35%)
    74 / 187 (39.57%)
    1 / 2 (50.00%)
         occurrences all number
    35
    72
    157
    1
    Nausea
         subjects affected / exposed
    11 / 103 (10.68%)
    20 / 104 (19.23%)
    36 / 187 (19.25%)
    1 / 2 (50.00%)
         occurrences all number
    14
    29
    54
    1
    Vomiting
         subjects affected / exposed
    2 / 103 (1.94%)
    9 / 104 (8.65%)
    14 / 187 (7.49%)
    0 / 2 (0.00%)
         occurrences all number
    2
    9
    15
    0
    Constipation
         subjects affected / exposed
    3 / 103 (2.91%)
    0 / 104 (0.00%)
    3 / 187 (1.60%)
    1 / 2 (50.00%)
         occurrences all number
    3
    0
    3
    1
    Impaired gastric emptying
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 103 (1.94%)
    1 / 104 (0.96%)
    12 / 187 (6.42%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    12
    0
    Depression
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 104 (0.00%)
    1 / 187 (0.53%)
    2 / 2 (100.00%)
         occurrences all number
    1
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 103 (2.91%)
    6 / 104 (5.77%)
    18 / 187 (9.63%)
    0 / 2 (0.00%)
         occurrences all number
    3
    8
    24
    0
    Back pain
         subjects affected / exposed
    6 / 103 (5.83%)
    8 / 104 (7.69%)
    16 / 187 (8.56%)
    0 / 2 (0.00%)
         occurrences all number
    6
    9
    18
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 103 (4.85%)
    12 / 104 (11.54%)
    26 / 187 (13.90%)
    0 / 2 (0.00%)
         occurrences all number
    5
    13
    32
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 103 (4.85%)
    7 / 104 (6.73%)
    20 / 187 (10.70%)
    0 / 2 (0.00%)
         occurrences all number
    5
    8
    27
    0
    Eye infection
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Helicobacter infection
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 104 (0.00%)
    0 / 187 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 103 (3.88%)
    1 / 104 (0.96%)
    2 / 187 (1.07%)
    1 / 2 (50.00%)
         occurrences all number
    4
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    - Extended eligibility to subjects previously exposed to biologic therapy. - Revised to allow subjects to receive colchicine until 7 days prior to randomization. - Revised to allow tapering of oral and topical corticosteroids and subsequent discontinuation close to the day of randomization. - Clarified the required number of oral ulcers at screening and baseline to avoid misinterpretation. All subjects must have had at least 2 oral ulcers at the Screening Visit (Visit 1). Once 3 oral ulcers were observed, regardless of the time interval from the Screening Visit (ie, the interval of 2 weeks was not required) a subject was qualified to be randomized, provided all other eligibility criteria were met. If only 2 oral ulcers were present at Visit 2, then at least 14 days must have passed since Visit 1 before the subject could have been randomized. - Revised the static PGA of skin lesions, as described in Appendix G of the protocol. Scoring of the number of nodules/lesions was based NOT on one anatomical site at a time, but at any anatomical site with respect to the whole body.

    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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