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    Clinical Trial Results:
    A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis.

    Summary
    EudraCT number
    2014-002981-64
    Trial protocol
    CZ   BG   IT  
    Global end of trial date
    03 Jun 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Mar 2020
    First version publication date
    13 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-10004-UC-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02289417
    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
    Denesh Chitkara, Celgene Corporation, 01 908-897-5751, dchitkara@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
    03 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of apremilast (30 mg twice daily [BID] and 40 mg BID), compared with placebo, in subjects with active ulcerative colitis (UC).
    Protection of trial subjects
    Patient Confidentiality, Informed Consent, Archiving of Essential Documents
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 13
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Russian Federation: 2
    Worldwide total number of subjects
    170
    EEA total number of subjects
    99
    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)
    158
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 61 sites in Australia (3 sites) and New Zealand (1 site); Bulgaria (6 sites), Czech Republic (2 sites), Hungary (3 sites), Poland (9 sites), Russia (1 site), and Ukraine (10 sites); Canada (2 sites) and United States (13 sites); and France (4 sites), Germany (1 site), Italy (4 sites), and the Netherlands (2 sites).

    Pre-assignment
    Screening details
    A total of 170 participants were randomized in a 1:1:1 ratio and received apremilast (30 mg BID or 40 mg BID), or identically appearing placebo and stratified based on concomitant use of oral corticosteroids and previous exposure to immunosuppressants.

    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
    Carer, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The blind was not to be broken during the study unless, in the opinion of the investigator, it was necessary to safely treat the subject. The decision to break the blind in emergency situations was the responsibility of the treating physician, which was not be delayed or refused by the sponsor. However, the investigator could contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the interest of the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules (identical in appearance to apremilast) BID.

    Arm title
    Apremilast 30 mg
    Arm description
    Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.
    Arm type
    Experimental

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

    Arm title
    Apremilast 40 mg
    Arm description
    Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID

    Number of subjects in period 1
    Placebo Apremilast 30 mg Apremilast 40 mg
    Started
    58
    57
    55
    Completed
    51
    53
    52
    Not completed
    7
    4
    3
         Lack of efficacy
    3
    -
    -
         Adverse event, non-fatal
    3
    -
    1
         Consent withdrawn by subject
    1
    3
    2
         Lost to follow-up
    -
    1
    -
    Period 2
    Period 2 title
    Active Treatment Phase Weeks 12-52
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    The blind was not to be broken during the study unless, in the opinion of the investigator, it was necessary to safely treat the subject. The decision to break the blind in emergency situations was the responsibility of the treating physician, which was not be delayed or refused by the sponsor. However, the investigator could contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the interest of the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Apremilast 30 mg
    Arm description
    Participants initially randomized to placebo capsules in the placebo-controlled period were re-randomized at week 12 to receive 30 mg apremilast capsules BID for 40 weeks during the active treatment phase.
    Arm type
    Experimental

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

    Arm title
    Placebo/Apremilast 40 mg
    Arm description
    Participants initially randomized to placebo in the placebo-controlled period were re-randomized at week 12 to receive 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID.

    Arm title
    Apremilast 30 mg/Apremilast 30 mg
    Arm description
    Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase. At week 12, participants who achieved at least a 20% decrease from baseline in the total Mayo score (TMS) continued to receive 30 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase.
    Arm type
    Experimental

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

    Arm title
    Apremilast 30 mg/ Apremilast 40 mg
    Arm description
    Participants initially randomized to 30 mg apremilast capsules BID in the placebo-controlled phase who did not achieve at least 20% decrease in the TMS were re-assigned to 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID.

    Arm title
    Apremilast 40 mg/Apremilast 40 mg
    Arm description
    Participants initially randomized to 40 mg apremilast capsules BID in the placebo-controlled phase continued to receive 40 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase, regardless of achieving a 20% decrease in TMS or not.
    Arm type
    Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID.

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID.

    Number of subjects in period 2
    Placebo/Apremilast 30 mg Placebo/Apremilast 40 mg Apremilast 30 mg/Apremilast 30 mg Apremilast 30 mg/ Apremilast 40 mg Apremilast 40 mg/Apremilast 40 mg
    Started
    26
    25
    41
    12
    52
    Completed
    17
    20
    39
    7
    39
    Not completed
    9
    5
    2
    5
    13
         Miscellaneous
    1
    -
    -
    -
    1
         Lack of efficacy
    6
    2
    1
    3
    5
         Pregnancy
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    2
    2
    1
    1
    4
         Consent withdrawn by subject
    -
    1
    -
    1
    1
         Lost to follow-up
    -
    -
    -
    -
    1
    Period 3
    Period 3 title
    Extension Phase Weeks 52-104
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Extension Phase: Apremilast 30 mg
    Arm description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 30 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12, and participants who entered the extension phase after implementation of Protocol Amendment 4.
    Arm type
    Experimental

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

    Arm title
    Extension Phase Apremilast 40 mg
    Arm description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 40 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12. After implementation of Protocol Amendment 4 participants were switched to 30 mg apremilast BID for the remainder of the extension phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla; CC-10004
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Apremilast 40 mg capsules BID

    Number of subjects in period 3 [1]
    Extension Phase: Apremilast 30 mg Extension Phase Apremilast 40 mg
    Started
    45
    54
    Completed
    38
    48
    Not completed
    7
    6
         Miscellaneous
    1
    -
         Lack of efficacy
    2
    2
         Adverse event, non-fatal
    2
    3
         Consent withdrawn by subject
    2
    1
    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: Not all subjects advanced to the next phase either by choice or due to disease.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 40 mg
    Reporting group description
    Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group values
    Placebo Apremilast 30 mg Apremilast 40 mg Total
    Number of subjects
    58 57 55 170
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    54 54 50 158
        From 65-84 years
    4 3 5 12
        85 years and over
    0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    42.9 ± 14.04 40.1 ± 13.50 43.4 ± 14.92 -
    Sex: Female, Male
    Units: Participants
        Female
    25 18 21 64
        Male
    33 39 34 106
    Race
    Units: Subjects
        Asian
    0 0 1 1
        White
    54 52 45 151
        Other
    1 1 1 3
        Not Reported or Collected
    3 4 8 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 1 5 8
        Not Hispanic or Latino
    55 54 46 155
        Unknown or Not Reported
    1 2 4 7
    Baseline Use of Oral Corticosteroids
    Units: Subjects
        Use of Baseline Corticosteroids
    17 14 12 43
        Non-Use of Corticosteroids
    41 43 43 127
    Previous Exposure to Immunosuppressants
    Units: Subjects
        Previous Exposure to Immunosuppressants
    17 18 16 51
        No Previous Exposure to Immunosuppressants
    41 39 39 119
    Duration of Ulcerative Colitis
    Units: Years
        arithmetic mean (standard deviation)
    6.85 ± 7.043 6.15 ± 5.432 8.63 ± 10.278 -
    Baseline Total Mayo Score (TMS)
    The TMS is an instrument designed to measure disease activity of Ulcerative Colitis (UC). The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease: • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA)
    Units: units on a scale
        arithmetic mean (standard deviation)
    8.2 ± 1.68 8.5 ± 1.62 8.1 ± 1.67 -
    Modified Mayo Score (MMS)
    The MMS was based on the stool frequency, rectal bleeding and endoscopy subscores of the total Mayo score, and excluded the Physician's Global subscore, since this was a global measure that is subjective in nature. The MMS range from 0 to 9 points with zero indicating no symptoms of active ulcerative colitis and 9 indicating the most severe symptoms.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.1 ± 1.51 6.4 ± 1.48 6.0 ± 1.47 -
    Partial Mayo Score (PMS)
    The partial Mayo score is the sum of the rectal bleeding score, the stool frequency score and the physician's global assessment. The partial Mayo score range is from 0 to 9 points with zero indicating no symptoms of active ulcerative colitis and 9 indicating the most severe symptoms and assessment.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.6 ± 1.46 5.8 ± 1.44 5.5 ± 1.57 -
    Mayo Endoscopic Subscore (MES)
    The Mayo endoscopy subscore findings are defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration).
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.6 ± 0.49 2.7 ± 0.45 2.6 ± 0.49 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg
    Reporting group description
    Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 40 mg
    Reporting group description
    Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.
    Reporting group title
    Placebo/Apremilast 30 mg
    Reporting group description
    Participants initially randomized to placebo capsules in the placebo-controlled period were re-randomized at week 12 to receive 30 mg apremilast capsules BID for 40 weeks during the active treatment phase.

    Reporting group title
    Placebo/Apremilast 40 mg
    Reporting group description
    Participants initially randomized to placebo in the placebo-controlled period were re-randomized at week 12 to receive 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.

    Reporting group title
    Apremilast 30 mg/Apremilast 30 mg
    Reporting group description
    Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase. At week 12, participants who achieved at least a 20% decrease from baseline in the total Mayo score (TMS) continued to receive 30 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase.

    Reporting group title
    Apremilast 30 mg/ Apremilast 40 mg
    Reporting group description
    Participants initially randomized to 30 mg apremilast capsules BID in the placebo-controlled phase who did not achieve at least 20% decrease in the TMS were re-assigned to 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.

    Reporting group title
    Apremilast 40 mg/Apremilast 40 mg
    Reporting group description
    Participants initially randomized to 40 mg apremilast capsules BID in the placebo-controlled phase continued to receive 40 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase, regardless of achieving a 20% decrease in TMS or not.
    Reporting group title
    Extension Phase: Apremilast 30 mg
    Reporting group description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 30 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12, and participants who entered the extension phase after implementation of Protocol Amendment 4.

    Reporting group title
    Extension Phase Apremilast 40 mg
    Reporting group description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 40 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12. After implementation of Protocol Amendment 4 participants were switched to 30 mg apremilast BID for the remainder of the extension phase.

    Subject analysis set title
    Apremilast 30 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    TEAEs during the apremilast 30 mg BID treatment for participants who received 30 mg apremilast capsules BID only and participants who initially received 30 mg apremilast capsules BID and switched to 40 mg apremilast capsules BID at Week 12, and participants who initially received placebo capsules BID and switched to 30 mg apremilast capsules BID at Week 12.

    Subject analysis set title
    Apremilast 40 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    TEAEs during the apremilast 40 mg BID treatment for participants who received 40 mg apremilast capsules BID only, and participants who initially received placebo BID and switched to 40 mg apremilast capsules BID at Week 12.

    Subject analysis set title
    Apremilast 30 mg/Apremilast 40 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    TEAEs during the apremilast 40 mg BID treatment for participants who initially received 30 mg apremilast BID and switched to 40 mg apremilast BID at Week 12.

    Subject analysis set title
    Extension Phase: Apremilast 30 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and received 30 mg apremilast BID for an additional 52 weeks. Includes participants assigned to 30 mg apremilast BID at week 12, and participants who entered the extension phase after implementation of Protocol Amendment 4.

    Subject analysis set title
    Extension Phase Apremilast 40 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and received 40 mg apremilast BID for an additional 52 weeks. After implementation of Protocol Amendment 4 participants were switched to 30 mg apremilast BID for the remainder of the extension phase

    Primary: Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12

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    End point title
    Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12
    End point description
    Clinical remission was defined as a total Mayo score ≤ 2 points, with no individual subscore exceeding 1 point. The TMS is an instrument designed to measure disease activity of UC. The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA). Two-sided 95% confidence intervals (CI) for the within-group proportions are based on the Wilson score method. The intent to treat (ITT) population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    12.1 (6.0 to 22.9)
    31.6 (21.0 to 44.5)
    21.8 (12.9 to 34.4)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0142 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Differences in Percentages
    Point estimate
    19.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    33.6
    Notes
    [1] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [2] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.2689 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified
    Point estimate
    7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    22.9
    Notes
    [3] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method
    [4] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12

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    End point title
    Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12
    End point description
    Clinical response was defined as a decrease from baseline in the TMS of at least 3 points and at least 30%, along with a reduction in the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS of ≤ 1. The TMS is an instrument designed to measure disease activity of UC. The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore • Endoscopy Subscore • Physician’s Global Assessment (PGA) Rectal bleeding (subscore 0-3) was defined as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool 3 = Blood alone passes Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The ITT population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    46.6 (34.3 to 59.2)
    61.4 (48.4 to 72.9)
    67.3 (54.1 to 78.2)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    P-value
    = 0.1224 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    31.5
    Notes
    [5] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [6] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0401 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    19.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    36
    Notes
    [7] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [8] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants who Achieved an Endoscopic Remission at Week 12

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    End point title
    Percentage of Participants who Achieved an Endoscopic Remission at Week 12
    End point description
    An endoscopic remission was defined as a Mayo endoscopic subscore (MES) of 0 at Week 12. The MES subscore findings were defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration) The endoscopy subscores consisted of findings that were centrally read through proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    3.4 (1.0 to 11.7)
    8.8 (3.8 to 18.9)
    7.3 (2.9 to 17.3)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.2472 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    16.7
    Notes
    [9] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [10] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.4628 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.5
         upper limit
    14.6
    Notes
    [11] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [12] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants who Achieved an Endoscopic Response at Week 12

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    End point title
    Percentage of Participants who Achieved an Endoscopic Response at Week 12
    End point description
    An endoscopic response is defined as a decrease from baseline of at least 1 point in the MES at Week 12. The Mayo endoscopy subscore findings were defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration). The endoscopy subscores consisted of findings that were centrally read through proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    41.4 (29.6 to 54.2)
    73.7 (61.0 to 83.4)
    47.3 (34.7 to 60.2)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.0005 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.8
         upper limit
    47.4
    Notes
    [13] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [14] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.6878 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.4
         upper limit
    21.5
    Notes
    [15] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [16] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12

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    End point title
    Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12
    End point description
    The RBS was measured as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes The daily bleeding score represents the most severe bleeding of the day. Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    72.4 (59.8 to 82.2)
    84.2 (72.6 to 91.5)
    87.3 (76.0 to 93.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.1388 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    11.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    26.1
    Notes
    [17] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [18] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0788 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    13.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    27.7
    Notes
    [19] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [20] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12

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    End point title
    Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12
    End point description
    Clinical remission was defined as a modified Mayo score of ≤ 2, with no individual subscore > 1, at Week 12. The MMS was based on a modification of the total Mayo score (TMS) which included the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the Physician's Global Assessment (PGA) subscore, since this was a global measure that is subjective in nature. The MMS ranges from 0 to 9 points with higher scores indicating greater disease severity. The endoscopy subscores was centrally reviewed. Two-sided confidence intervals for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    19.0 (10.9 to 30.9)
    43.9 (31.8 to 56.7)
    27.3 (17.3 to 40.2)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0046 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    24.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.5
         upper limit
    40.1
    Notes
    [21] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [22] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.4476 [24]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.8
         upper limit
    21.6
    Notes
    [23] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [24] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12

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    End point title
    Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12
    End point description
    Clinical response in the MMS was defined as a decrease from baseline in the MMS of at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS ≤ 1. The MMS was based on the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the PGA subscore. The MMS ranges from 0 to 9 points with higher scores indicating greater disease severity. The RBS was measured as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes. The daily bleeding score represents the most severe bleeding of the day. The endoscopy subscores was centrally reviewed. Two-sided confidence intervals for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    46.6 (34.3 to 59.2)
    63.2 (50.2 to 74.5)
    67.3 (54.1 to 78.2)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0755 [25]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified difference in proportions
    Point estimate
    16.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    33.5
    Notes
    [25] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.037 [27]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified difference in proportions
    Point estimate
    19.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    36.4
    Notes
    [26] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [27] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8

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    End point title
    Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8
    End point description
    Clinical remission in the partial Mayo subscore was defined as a PMS of 2 points or lower, with no individual subscore >1. The PMS is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease). Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    32.8 (22.1 to 45.6)
    47.4 (35.0 to 60.1)
    52.7 (39.8 to 65.3)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.1167 [29]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    31.4
    Notes
    [28] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [29] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.0534 [31]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    18.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    34.9
    Notes
    [30] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [31] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8

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    End point title
    Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8
    End point description
    Clinical response in the PMS was defined as a decrease from baseline in PMS of at least 2 points and at least 25%, with an accompanying decrease in the RBS of at least 1 point or an absolute RBS of 0 or 1. The PMS score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease). Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: Percentage of Participants
        number (confidence interval 95%)
    48.3 (35.9 to 60.8)
    64.9 (51.9 to 76.0)
    81.8 (69.7 to 89.8)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Apremilast 30 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    P-value
    = 0.0758 [33]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    16.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    33.3
    Notes
    [32] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [33] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Apremilast 40 mg
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    = 0.0004 [35]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Stratified Difference
    Point estimate
    32.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.9
         upper limit
    47.5
    Notes
    [34] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
    [35] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

    Secondary: The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

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    End point title
    The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase
    End point description
    A TEAE was defined as any adverse event (AE) occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From the first dose of investigational product (IP) and no later than 28 days after the last dose of IP for those who had completed the study or discontinued (D/C) early; maximum duration of exposure to treatment was 12.00 weeks
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: participants
        Any TEAE
    31
    28
    36
        Any IP-related TEAE
    12
    13
    20
        Any Severe TEAE
    4
    0
    1
        Any Serious TEAE
    2
    0
    1
        Any Serious IP-related TEAE
    0
    0
    0
        Any TEAE Leading to IP Withdrawal
    5
    0
    1
        Any TEAE Leading to IP Interruption
    1
    0
    0
        Any TEAE Leading to Death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period

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    End point title
    The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period
    End point description
    A TEAE was defined as any AE occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From the first dose of IP and no later than 28 days after the last dose of IP for those who had completed the study or discontinued early; median duration of exposure to treatment was 12.00 weeks
    End point values
    Placebo Apremilast 30 mg Apremilast 40 mg
    Number of subjects analysed
    58
    57
    55
    Units: participants
    5
    0
    2
    No statistical analyses for this end point

    Secondary: The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52

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    End point title
    The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52
    End point description
    A TEAE was defined as any AE occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.
    End point type
    Secondary
    End point timeframe
    From first dose of IP and no later than 28 days after last dose of IP for those who completed the active treatment phase or D/C early; median duration of exposure = 41.00, 44.15 and 40.00 weeks respectively for 30 mg, 40 mg and 30 mg/40 mg APR arms
    End point values
    Apremilast 30 mg Apremilast 40 mg Apremilast 30 mg/Apremilast 40 mg
    Number of subjects analysed
    83
    80
    11
    Units: participants
        Any TEAE
    60
    67
    8
        Any Severe TEAE
    5
    6
    0
        Any Serious TEAE
    6
    8
    1
        Any TEAE Leading to Drug Withdrawal
    3
    9
    1
        Any TEAE Leading to Drug Interruption
    1
    4
    0
        Any TEAE Leading to Death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)

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    End point title
    The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)
    End point description
    A TEAE was defined as any AE occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain
    End point type
    Secondary
    End point timeframe
    From the first dose of IP at Week 52 and no later than 28 days after the last dose of IP for those who completed the study or had discontinued early; median exposure of apremilast for the total apremilast group was 52 weeks.
    End point values
    Extension Phase: Apremilast 30 mg Extension Phase Apremilast 40 mg
    Number of subjects analysed
    45
    54
    Units: participants
        Any TEAE
    16
    27
        Any Severe TEAE
    1
    0
        Any Serious TEAE
    4
    3
        Any Serious IP-related TEAE
    0
    1
        Any TEAE Leading to IP Withdrawal
    2
    1
        Any TEAE Leading to IP Interruption
    1
    0
        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
    From first dose of IP and no later than 28 days after the last dose of IP for those who had completed the study D/C early. AEs are reported for the placebo-controlled phase from Week 0 to Week 12 and for the APR exposure period from Week 0 to Week 104.
    Adverse event reporting additional description
    Median duration of study drug was 12 weeks in the placebo controlled phase, 41.00, 44.15 and 40.00 weeks respectively for 30 mg, 40 mg and 30 mg/40 mg APR arms in the active treatment phase and 52 weeks in the extension phase; MedDRA Version 20.1 was used in the placebo controlled phase and Version 22 in the active treatment and extension phase.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo (Placebo Controlled Period)
    Reporting group description
    TEAEs for participants who were randomized to identically matching placebo capsules twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg BID (Placebo Controlled Period)
    Reporting group description
    TEAEs for participants who were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 40 mg BID (Placebo Controlled Period)
    Reporting group description
    TEAEs for participants who were randomized to apremilast 40 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

    Reporting group title
    Apremilast 30 mg BID (Apremilast Exposure Period)
    Reporting group description
    TEAEs during the apremilast 30 mg BID treatment for participants who received 30 mg apremilast capsules BID only and participants who initially received 30 mg apremilast capsules BID and switched to 40 mg apremilast capsules BID at Week 12, and participants who initially received placebo capsules BID and switched to 30 mg apremilast capsules BID at Week 12.

    Reporting group title
    Apremilast 40 mg BID (Apremilast Exposure Period)
    Reporting group description
    TEAEs during the apremilast 40 mg BID treatment for participants who received 40 mg apremilast capsules BID only, and participants who initially received placebo BID and switched to 40 mg apremilast capsules BID at Week 12.

    Reporting group title
    Apremilast 30/40 mg BID (Apremilast Exposure Period)
    Reporting group description
    TEAEs during the apremilast 40 mg BID treatment for participants who initially received 30 mg apremilast BID and switched to apremilast 40 mg BID at Week 12

    Serious adverse events
    Placebo (Placebo Controlled Period) Apremilast 30 mg BID (Placebo Controlled Period) Apremilast 40 mg BID (Placebo Controlled Period) Apremilast 30 mg BID (Apremilast Exposure Period) Apremilast 40 mg BID (Apremilast Exposure Period) Apremilast 30/40 mg BID (Apremilast Exposure Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    9 / 83 (10.84%)
    11 / 80 (13.75%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Epididymal neoplasm
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    3 / 80 (3.75%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis tuberculous
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Placebo Controlled Period) Apremilast 30 mg BID (Placebo Controlled Period) Apremilast 40 mg BID (Placebo Controlled Period) Apremilast 30 mg BID (Apremilast Exposure Period) Apremilast 40 mg BID (Apremilast Exposure Period) Apremilast 30/40 mg BID (Apremilast Exposure Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 58 (34.48%)
    26 / 57 (45.61%)
    25 / 55 (45.45%)
    49 / 83 (59.04%)
    53 / 80 (66.25%)
    11 / 11 (100.00%)
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyolipoma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 57 (5.26%)
    1 / 55 (1.82%)
    5 / 83 (6.02%)
    3 / 80 (3.75%)
    2 / 11 (18.18%)
         occurrences all number
    2
    3
    1
    5
    5
    2
    Influenza like illness
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    1 / 55 (1.82%)
    2 / 83 (2.41%)
    2 / 80 (2.50%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    2
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 57 (1.75%)
    1 / 55 (1.82%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    1
    1
    3
    2
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    2 / 83 (2.41%)
    4 / 80 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    2
    4
    0
    Depression
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 83 (0.00%)
    1 / 80 (1.25%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    Insomnia
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 57 (3.51%)
    1 / 55 (1.82%)
    3 / 83 (3.61%)
    2 / 80 (2.50%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    1
    3
    2
    1
    Investigations
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Faecal calprotectin increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    1 / 55 (1.82%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    4 / 83 (4.82%)
    4 / 80 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    4
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 83 (0.00%)
    5 / 80 (6.25%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    6
    0
    Dysphonia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 58 (6.90%)
    12 / 57 (21.05%)
    14 / 55 (25.45%)
    17 / 83 (20.48%)
    25 / 80 (31.25%)
    2 / 11 (18.18%)
         occurrences all number
    10
    17
    20
    25
    35
    2
    Migraine
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    1 / 55 (1.82%)
    2 / 83 (2.41%)
    3 / 80 (3.75%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    2
    7
    1
    Sciatica
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    Sinus headache
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 57 (5.26%)
    0 / 55 (0.00%)
    4 / 83 (4.82%)
    3 / 80 (3.75%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    0
    4
    3
    1
    Nausea
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 57 (5.26%)
    6 / 55 (10.91%)
    8 / 83 (9.64%)
    9 / 80 (11.25%)
    3 / 11 (27.27%)
         occurrences all number
    6
    3
    7
    8
    10
    4
    Dyspepsia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    2 / 83 (2.41%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    0
    2
    0
    2
    Anorectal discomfort
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Colitis ulcerative
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    2 / 83 (2.41%)
    6 / 80 (7.50%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    2
    7
    0
    Diarrhoea
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    5 / 83 (6.02%)
    6 / 80 (7.50%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    0
    5
    6
    2
    Gastritis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    4 / 80 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Swollen tongue
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 57 (3.51%)
    2 / 55 (3.64%)
    3 / 83 (3.61%)
    3 / 80 (3.75%)
    3 / 11 (27.27%)
         occurrences all number
    1
    2
    2
    3
    4
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    1 / 83 (1.20%)
    2 / 80 (2.50%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    2
    1
    Pruritus
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Rash
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    3 / 55 (5.45%)
    0 / 83 (0.00%)
    3 / 80 (3.75%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    0
    5
    0
    Arthralgia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    5 / 83 (6.02%)
    6 / 80 (7.50%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    1
    6
    7
    1
    Osteochondrosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 57 (3.51%)
    1 / 55 (1.82%)
    2 / 83 (2.41%)
    3 / 80 (3.75%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    1
    2
    3
    1
    Iron deficiency
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 83 (0.00%)
    2 / 80 (2.50%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 57 (7.02%)
    2 / 55 (3.64%)
    7 / 83 (8.43%)
    8 / 80 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    4
    2
    8
    11
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    4 / 83 (4.82%)
    4 / 80 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    0
    4
    5
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    3 / 83 (3.61%)
    3 / 80 (3.75%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    3
    3
    1
    Influenza
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    2 / 83 (2.41%)
    3 / 80 (3.75%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    2
    4
    1
    Periodontitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    1 / 83 (1.20%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    1 / 83 (1.20%)
    1 / 80 (1.25%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    4 / 83 (4.82%)
    0 / 80 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    4
    0
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2014
    • The planned sample size was reduced from 249 to 165 after an internal decision to keep the Study CC-10004-UC-001 design in line with standard proof-of-concept Phase 2 trials. • The assessment of the primary endpoint was changed from Week 8 to Week 12 because cumulative clinical experience in other indications suggests that apremilast may take a longer time to induce a clinical response than initially anticipated in the approved protocol. Clinical remission at Week 8 was planned to be evaluated as one of the key secondary endpoints. • Secondary endpoints based on a modified Mayo score (without inclusion of PGA) were added based on a recommendation by the Food and Drug Administration during review of the original Investigational New Drug application. • Nonresponder criteria were revised to allow patients with an incomplete response (partial responders) at Week 12 to continue blinded treatment, to assess the potential late response of apremilast in this population. • Exclusion criterion 15 was added to clarify the psychiatric conditions that were exclusionary.
    13 Apr 2015
    • A treatment extension phase was added to provide all subjects the opportunity to receive active apremilast during the 40-week Blinded Active-treatment Phase. • Concomitant medication restrictions were changed from a prohibition of background oral corticosteroid treatment to instead allow subjects to receive stable doses of prednisone ≤ 20 mg/day or equivalent or budesonide ≤ 9 mg/day. • Stratification was added based on use of oral corticosteroids. Stratification based on use of aminosalicylates was deleted. • The requirement for chest radiograph was removed. • The psychiatric evaluation was updated based on feedback from the Health Authorities. • Several efficacy-related exploratory endpoints were deleted and time points in the secondary and exploratory endpoints were modified due to the change in study duration. • The definition of clinical remission based on the PMS was changed: “The proportion of subjects achieving clinical remission at Week 12, defined as a PMS of ≤ 2, with no individual subscore ≥ 1”. Changed to > 1. • The description in the sparse PK section was updated for clarity.
    20 Jul 2016
    • An Extension Phase was added for subjects who met the criteria for endoscopic response at Week 52 to allow these subjects to receive blinded, active treatment (apremilast) for an additional 52 weeks (Weeks 52 to 104). • Safety information was updated to reflect the most recent version of the Investigator’s Brochure. • The following exploratory endpoints were added: - The proportion of subjects with endoscopic remission, defined as a Mayo endoscopic subscore ≤ 1, and histological remission at Week 12 - The proportion of subjects achieving a clinical remission in the TMS at Week 12, defined as a TMS ≤ 2 with no individual subscore > 1 and no evidence of friability on the Mayo endoscopic subscore - The exposure-adjusted incidence of UC-related health outcomes (eg, UC-related hospitalizations, emergency room visits, and surgeries)
    08 Aug 2018
    • The apremilast dose in the Extension Phase was adjusted so that all subjects participating in that phase of the study would receive apremilast 30 mg BID (rather than either apremilast 30 mg BID or 40 mg BID). • Overdose for subjects receiving open-label 30 mg BID in the Extension Phase was defined as 4 or more 30-mg tablets in any 24-hour period (on a per-dose basis) or dosing more than 4 times in 24 hours (on a schedule or frequency basis). • The DMC was decommissioned. After a meeting with the external DMC on 27 Oct 2017, Celgene determined that the DMC was no longer needed to support CC-10004-UC-001, as described in Section 6. • Safety information was updated to reflect the most current information in the Investigator’s Brochure. • Clarification was added that subjects who experienced UC-related symptoms after corticosteroid tapering were permitted to receive the same treatment taken prior to tapering, provided that the dose was the same.

    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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