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    Clinical Trial Results:
    A Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) Monotherapy in Subjects with Active Psoriatic Arthritis

    Summary
    EudraCT number
    		 2013-001590-25
    Trial protocol
    		 HU   CZ   ES   EE  
    Global end of trial date
    17 Nov 2016

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-10004-PSA-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01925768
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07907
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Nikolay Delev, MD, Celgene Corporation, 01 9088975662, NDelev@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
    24 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of apremilast 30 mg BID monotherapy, compared with placebo, over 24 weeks of treatment, with the primary analysis at Week (Wk) 16, in subjects with active psoriatic arthritis
    Protection of trial subjects
    This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents. Patient Confidentiality and Personal Data Protection, Informed Consent and Biomarker Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United States: 66
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Estonia: 25
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 26
    Worldwide total number of subjects
    219
    EEA total number of subjects
    85
    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)
    191
    From 65 to 84 years
    27
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study consisted of a 24-week randomized, double-blind, placebo-controlled treatment phase, followed by a 28-week active treatment phase and a 52-week open-label extension phase, for an overall study duration of 113 weeks. 219 subjects were enrolled from 59 centers across 10 countries.

    Pre-assignment
    Screening details
    		 Randomized participants were stratified by their baseline prednisone use (yes or no) and by their previous disease modifying antirheumatic drug (DMARD) use (excluding biologics). Participants were allowed to take non-steroidal anti-inflammatory agents and/or low dose corticosteroids during the study.

    Period 1
    Period 1 title
    Placebo-controlled Phase (Week 0 - 24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Assessor, Subject
    Blinding implementation details
    Subjects remained blinded to apremilast until week 52 or at discontinuation visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Apremilast (PBO)
    Arm description
    		 Participants were randomized to placebo tablets twice daily (BID) during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape (EE), at the discretion of the investigator and transitioned onto apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape.
    Arm type
    		 Placebo

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

    Arm title
    		 Apremilast (APR)
    Arm description
    		 Participants were randomized to apremilast 30 mg tablets BID during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and continued receiving apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind 24-week treatment phase entered into the blinded active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. All participants who completed the 52-week treatment phase entered into the open-label extension phase (Week 52 to Week 104) for an additional year continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.
    Arm type
    		 Experimental

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

    Number of subjects in period 1
    		Placebo/Apremilast (PBO) Apremilast (APR)
    Started
    109
    110
    Received Treatment
    109
    109
    Completed Week 16
    101
    91
    Escaped Early (EE)
    35 [1]
    13 [2]
    Completed
    98
    87
    Not completed
    11
    23
         Consent withdrawn by subject
    1
    4
         Adverse event, non-fatal
    5
    10
         Non-compliance with study drug
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    2
         Lack of efficacy
    3
    6
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects were assessed for swollen and tender joints; those that met the early escape criteria were allowed to be transitioned to apremilast. Subjects who did not early escape, remained on placebo.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects were assessed for swollen and tender joints; those that met the early escape criteria were allowed to be transitioned to apremilast. Subjects who did not early escape, remained on placebo.
    Period 2
    Period 2 title
    ActiveTreatment/Extension (Weeks 24-104)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Subjects remained blinded to apremilast until week 52 or at discontinuation visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Apremilast
    Arm description
    		 Participants were randomized to placebo tablets twice daily during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and transitioned onto apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind, 24-week treatment phase entered into the blinded, active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. Participants who completed the active treatment phase entered into the open-label extension phase for an additional year (Week 52 to Week 104) continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.
    Arm type
    		 Experimental

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

    Arm title
    		 Apremilast
    Arm description
    		 Participants were randomized to apremilast 30 mg tablets BID during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and continued receiving apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind 24-week treatment phase entered into the blinded active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. All participants who completed the 52-week treatment phase entered into the open-label extension phase (Week 52 to Week 104) for an additional year continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.
    Arm type
    		 Experimental

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

    Number of subjects in period 2 [3]
    		Placebo/Apremilast Apremilast
    Started
    95
    85
    Completed
    75
    67
    Not completed
    20
    18
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    7
    9
         Adverse event, non-fatal
    5
    1
         Lost to follow-up
    2
    1
         Lack of efficacy
    6
    6
    Notes
    [3] - 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: Five subjects from the placebo-controlled period elected not to participate in the active treatment phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Apremilast (PBO)
    Reporting group description
    		 Participants were randomized to placebo tablets twice daily (BID) during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape (EE), at the discretion of the investigator and transitioned onto apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape.

    Reporting group title
    Apremilast (APR)
    Reporting group description
    		 Participants were randomized to apremilast 30 mg tablets BID during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and continued receiving apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind 24-week treatment phase entered into the blinded active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. All participants who completed the 52-week treatment phase entered into the open-label extension phase (Week 52 to Week 104) for an additional year continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.

    Reporting group values
    		 Placebo/Apremilast (PBO) Apremilast (APR) Total
    Number of subjects
    		 109 110 219
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 97 94 191
        From 65-84 years
    		 11 16 27
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.0 ( 13.75 ) 50.7 ( 12.22 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 65 58 123
        Male
    		 44 52 96
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 1 0 1
        White
    		 105 109 214
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 0 2
    Study Specific Characteristic | Duration of Psoriatic Arthritis
    Duration of Psoriatic Arthritis is reported as the time since diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 3.59 ( 5.497 ) 4.04 ( 4.482 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Apremilast (PBO)
    Reporting group description
    		 Participants were randomized to placebo tablets twice daily (BID) during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape (EE), at the discretion of the investigator and transitioned onto apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape.

    Reporting group title
    Apremilast (APR)
    Reporting group description
    		 Participants were randomized to apremilast 30 mg tablets BID during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and continued receiving apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind 24-week treatment phase entered into the blinded active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. All participants who completed the 52-week treatment phase entered into the open-label extension phase (Week 52 to Week 104) for an additional year continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.
    Reporting group title
    Placebo/Apremilast
    Reporting group description
    		 Participants were randomized to placebo tablets twice daily during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and transitioned onto apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind, 24-week treatment phase entered into the blinded, active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. Participants who completed the active treatment phase entered into the open-label extension phase for an additional year (Week 52 to Week 104) continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.

    Reporting group title
    Apremilast
    Reporting group description
    		 Participants were randomized to apremilast 30 mg tablets BID during the double-blind, 24-week placebo-controlled phase. Those whose improvement was less than 10% in both swollen and tender joint counts at Week 16 were eligible for early escape, at the discretion of the investigator and continued receiving apremilast 30 mg BID in a blinded fashion. Those who had a 10% or more improvement in either swollen or tender joint counts at Week 16 were not eligible for early escape. Participants who completed the double-blind 24-week treatment phase entered into the blinded active treatment phase for an additional 28 weeks (Week 24 to Week 52) and continued receiving Apremilast 30 mg tablets BID. All participants who completed the 52-week treatment phase entered into the open-label extension phase (Week 52 to Week 104) for an additional year continuing to receive apremilast 30 mg tablets BID until the end of the study (up to Week 104 visit) or until early discontinuation.

    Subject analysis set title
    Number of subjects with TEAEs in the apremilast-exposure phase
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A TEAE is an AE with a start date on or after the date of the first dose of Investigational Product (IP). An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. Safety population.

    Primary: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Week 16

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    End point title
    		 Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Week 16
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: o Patient's self-assessment of pain (measured on a 0 to 10 unit numeric rating scale [NRS]); o Patient's global self-assessment of disease activity (measured on a 0 to 10 unit NRS); o Physician's global assessment of disease activity (measured on a 0 to 10 unit NRS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); o C-Reactive Protein (CRP) Those who withdrew early or who did not have sufficient data at Week 16 were counted as non-responders. Full Analysis Set (FAS) population consisting of all participants randomized as specified in the protocol.
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    110
    Units: percentage of participants
        number (not applicable)
    20.2
    38.2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.004 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    17.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 29.3
    Notes
    [1] - Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by the 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights. The CI is based on a normal approximation.
    [2] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.

    Secondary: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24

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    End point title
    		 Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24
    End point description
    HAQ-DI is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A higher score indicates worse physical functioning, and a negative change from baseline indicates improvement. Full analysis set; Participants with a baseline and at least 1 postbaseline value during the placebo-controlled phase were included in the analysis (mixed effects model for repeated measure [MMRM])
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    109
    Units: units on a scale
        least squares mean (standard error)
    0.169 ( 0.0581 )
    -0.273 ( 0.0572 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The LS mean (SE) and 2-sided p-value were based on a MMRM analysis for change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD and baseline corticosteroids used as factors and baseline value as a covariate
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1677
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.251
         upper limit
    		 0.044
    Notes
    [3] - Those with a baseline and at least 1 postbaseline value at the PBO controlled phase were counted with mixed effects model for repeated measure (MMRM)

    Secondary: Percentage of participants who Achieved an American College of Rheumatology 20% (ACR20) at Week 24

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    End point title
    		 Percentage of participants who Achieved an American College of Rheumatology 20% (ACR20) at Week 24
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: o Patient's self-assessment of pain (measured on a 0 to 10 unit numeric rating scale [NRS]); o Patient's global self-assessment of disease activity (measured on a 0 to 10 unit NRS); o Physician's global assessment of disease activity (measured on a 0 to 10 unit NRS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); o C-Reactive Protein (CRP) Those who withdrew early or who did not have sufficient data at Week 16 were counted as non-responders. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    110
    Units: percentage of participants
        number (not applicable)
    24.8
    43.6
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by the 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights. The CI is based on a normal approximation.
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.004 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.3
         upper limit
    		 30.6
    Notes
    [4] - Those who withdrew early or who did not have sufficient data at Week 16 were counted as non-responders.
    [5] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.

    Secondary: Change From Baseline in the 28-joint Disease Activity Score using C-reactive protein as the acute-phase reactant (DAS28 [CRP]) at Week 24

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    End point title
    		 Change From Baseline in the 28-joint Disease Activity Score using C-reactive protein as the acute-phase reactant (DAS28 [CRP]) at Week 24
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28 (CRP) scores range from 0 to 9.4. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. A higher value indicates higher disease activity, and a negative change from baseline indicates improvement. Full analysis set; Participants with a baseline value and at least one post-baseline value (after exclusion of data for early escaped participants) during the placebo-controlled phase are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    108
    109
    Units: units on a scale
        least squares mean (standard error)
    -0.76 ( 0.140 )
    -1.26 ( 0.138 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The LS mean (SE) and 2-sided p-value were based on a MMRM analysis for change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD and baseline corticosteroids used as factors and baseline value as a covariate.
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0051
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 -0.15

    Secondary: Change From Baseline in the Medical Outcomes Short Form Health Survey (SF-36) V2 Physical Function Domain Score at Week 24

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    End point title
    		 Change From Baseline in the Medical Outcomes Short Form Health Survey (SF-36) V2 Physical Function Domain Score at Week 24
    End point description
    The SF-36 (v 2.0) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from baseline score indicates an improvement. Full analysis set; Participants with a baseline and at least 1 postbaseline value during the placebo-controlled phase were included in the analysis (mixed effects model for repeated measure [MMRM]).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    106
    107
    Units: units on a scale
        least squares mean (standard error)
    1.26 ( 0.908 )
    3.94 ( 0.888 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The LS mean (SE) and 2-sided p-value were based on a MMRM analysis for change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD and baseline corticosteroids used as factors and baseline value as a covariate
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0167 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 4.88
    Notes
    [6] - Those with a baseline and at least 1 postbaseline value at the PBO controlled phase were counted with mixed effects model for repeated measure (MMRM)

    Secondary: Change From Baseline in the 36-item SF-36 Physical Component Summary Score at Week 24

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    End point title
    		 Change From Baseline in the 36-item SF-36 Physical Component Summary Score at Week 24
    End point description
    The SF-36 (v 2.0) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary (PCS) score includes the physical functioning, role physical, bodily pain, and general health domains. Minimum clinically important difference (MCID) for the scale scores, as well as the PCS and MCS, is defined as a 2.5-point improvement (increase) from baseline. Full analysis set. Subjects with a baseline value and at least one post-baseline value (after exclusion of data for early escaped subjects) during the placebo-controlled phase are included in the MMRM model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    106
    106
    Units: units on a scale
        least squares mean (standard error)
    1.60 ( 0.959 )
    5.00 ( 0.949 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    2-sided 95% CI for the difference in LS mean.
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0039 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 5.7
    Notes
    [7] - Based on an MMRM model for the change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD use and baseline Oral Corticosteroids use as factors and the baseline value as a covariate.

    Secondary: Change from Baseline in the Duration of Morning Stiffness at Week 24

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    End point title
    		 Change from Baseline in the Duration of Morning Stiffness at Week 24
    End point description
    Morning stiffness was the participant’s assessment of how long their morning stiffness lasted after first waking up in the morning, on average, during the previous week. A higher value indicates longer duration, and a negative change from baseline indicates improvement. Full Analysis Set; Analysis includes participants with a baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    109
    Units: minutes
        arithmetic mean (standard deviation)
    21.9 ( 137.11 )
    -5.7 ( 83.41 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [8]
    Method
    		 Sign test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.5
         upper limit
    		 10.2
    Notes
    [8] - p-value based on distribution free signed rank test

    Secondary: Percentage of Participants with Improved Change in Severity of Morning Stiffness at Week 24

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    End point title
    		 Percentage of Participants with Improved Change in Severity of Morning Stiffness at Week 24
    End point description
    Morning stiffness severity was the participant’s assessment of how severe their morning stiffness was after first waking up in the morning, on average, during the previous week. The severity was recorded as none, mild, moderate, moderately severe, or very severe. The response of no improvement includes subjects who had no change or worsened. Improvement is defined as the change from baseline of a more severe assessment to less severe assessment. Full Analysis Set; Participants who withdrew early or who did not have sufficient data at Week 24 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    110
    Units: percentage of participants
        number (not applicable)
    20.2
    40.0
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by the 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights. The CI is based on a normal approximation.
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    19.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 31.3
    Notes
    [9] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline oral corticosteroids (prednisone or equivalent) use.

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16

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    End point title
    		 Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 16
    End point description
    HAQ-DI is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A higher score indicates worse physical functioning, and a negative change from baseline indicates improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value during the placebo-controlled phase were included in the mixed effects model for repeated measures (MRMM).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    109
    Units: units on a scale
        least squares mean (standard error)
    0.055 ( 0.0513 )
    -0.205 ( 0.0523 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The LS mean (SE) and 2-sided p-value were based on a MMRM analysis for change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD and baseline corticosteroids used as factors and baseline value as a covariate
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0229
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.279
         upper limit
    		 -0.021

    Secondary: Change From Baseline in the Disease Activity Score DAS28 (CRP) at Week 16

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    End point title
    		 Change From Baseline in the Disease Activity Score DAS28 (CRP) at Week 16
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28 (CRP) scores range from 0 to 9.4. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. A negative change from baseline indicates improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value during the placebo-controlled phase were included in the mixed effects model for repeated measures (MRMM).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    108
    109
    Units: units on a scale
        least squares mean (standard error)
    -0.39 ( 0.129 )
    -1.07 ( 0.133 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Based on an MMRM model for the change from baseline, with treatment group, time, treatment-by-time interaction, and previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use as factors and the baseline value as a covariate
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.35

    Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) V 2 Physical Functioning Domain at Week 16

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    End point title
    		 Change From Baseline in 36-item Short Form Health Survey (SF-36) V 2 Physical Functioning Domain at Week 16
    End point description
    The SF-36 (v 2.0) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value during the placebo-controlled phase were included in the mixed effects model for repeated measures (MRMM).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    106
    107
    Units: units on a scale
        least squares mean (standard error)
    -1.04 ( 0.927 )
    2.43 ( 0.962 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by the 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0039
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 5.8

    Secondary: Mean Change From Baseline in the Duration of Morning Stiffness at Week 16

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    End point title
    		 Mean Change From Baseline in the Duration of Morning Stiffness at Week 16
    End point description
    Morning stiffness was the participant’s assessment of how long their morning stiffness lasted after first waking up in the morning, on average, during the previous week. A higher value indicates longer duration, and a negative change from baseline indicates improvement. Full analysis set; Analysis includes participants with a baseline and at least one post-baseline value; last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    109
    Units: minutes
        arithmetic mean (standard deviation)
    21.7 ( 136.85 )
    -7.2 ( 60.73 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0168 [11]
    Method
    		 Stratified Van Elteren test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 20
    Notes
    [10] - Location shift and 95% CI based on Hodges-Lehmann for between treatment median estimates.
    [11] - p-value based on stratified Van Elteren test, using 2 stratification factors: previous DMARD use and baseline Oral Corticosteroids

    Secondary: Percentage of Participants Whose Severity of Morning Stiffness at Week 16 Improved from Baseline

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    End point title
    		 Percentage of Participants Whose Severity of Morning Stiffness at Week 16 Improved from Baseline
    End point description
    Morning stiffness severity was the participant’s assessment of how severe their morning stiffness was after first waking up in the morning, on average, during the previous week. The severity was recorded as none, mild, moderate, moderately severe, or very severe. Improvement is defined as the change from baseline of a more severe assessment to less severe assessment. Full Analysis Set; Participants who discontinued early prior to Week 16 and those who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    110
    Units: percentage of participants
        number (not applicable)
    25.7
    46.4
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by the 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights.
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    20.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.5
         upper limit
    		 32.8
    Notes
    [12] - 2 sided-p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.

    Secondary: Percentage of participants who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 2, 4, 6, 8, 12 and 20

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    End point title
    		 Percentage of participants who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 2, 4, 6, 8, 12 and 20
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: o Patient's self-assessment of pain (measured on a 0 to 10 unit numeric rating scale [NRS]); o Patient's global self-assessment of disease activity (measured on a 0 to 10 unit NRS); o Physician's global assessment of disease activity (measured on a 0 to 10 unit NRS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); o C-Reactive Protein (CRP). Full analysis set; participants discontinued early prior to the visit and participants who did not have sufficient data for a definitive determination of response status for the visit were counted as nonresponders.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 2, 4, 6, 8, 12 and 20
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    110
    Units: percentage of participants
    number (not applicable)
        Week 2
    6.4
    16.4
        Week 4
    15.6
    24.5
        Week 6
    19.3
    37.3
        Week 8
    22.9
    36.4
        Week 12
    28.4
    40.0
        Week 20
    24.8
    43.6
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0252 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 17.7
    Notes
    [13] - Week 2; 2-sided 95% CI is based on a normal approximation to the weighted average
    [14] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.1121 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    8.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 18.9
    Notes
    [15] - Week 4; 2-sided 95% CI is based on a normal approximation to the weighted average
    [16] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0036 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    17.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 29.3
    Notes
    [17] - Week 6; 2-sided 95% CI is based on a normal approximation to the weighted average
    [18] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0392 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    12.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 24.6
    Notes
    [19] - Week 8; 2-sided 95% CI is based on a normal approximation to the weighted average
    [20] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 12; 2-sided 95% CI is based on a normal approximation to the weighted average
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0884 [21]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 23.2
    Notes
    [21] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across 4 strata by 2 stratification factors: previous DMARD use and baseline Corticosteroids use using CMH weights
    Comparison groups
    Placebo/Apremilast (PBO) v Apremilast (APR)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 = 0.004 [23]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Difference
    Point estimate
    18.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.5
         upper limit
    		 30.7
    Notes
    [22] - Week 20; 2-sided 95% CI is based on a normal approximation to the weighted average
    [23] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for previous DMARD use and baseline Oral Corticosteroids (Prednisone or equivalent) use.

    Secondary: Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 52 and 104

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    End point title
    		 Percentage of Participants Who Achieved an American College of Rheumatology 20% (ACR20) Response at Weeks 52 and 104
    End point description
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: o Patient's self-assessment of pain (measured on a 0 to 10 unit numeric rating scale [NRS]); o Patient's global self-assessment of disease activity (measured on a 0 to 10 unit NRS); o Physician's global assessment of disease activity (measured on a 0 to 10 unit NRS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); o C-Reactive Protein (CRP). Apremilast Participants as Randomized or Transitioned, which includes all participants who randomized or escaped/transitioned (at Week 16 or Week 24) to apremilast, and with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    90
    79
    Units: percentage of partcipants
    number (confidence interval 95%)
        Week 52
    60.0 (49.1 to 70.2)
    67.1 (55.6 to 77.3)
        Week 104, N=74, 69
    66.2 (54.3 to 76.8)
    59.4 (46.9 to 71.1)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 52 and 104

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    End point title
    		 Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 52 and 104
    End point description
    HAQ-DI is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A higher score indicates worse physical functioning, and a negative change from baseline indicates improvement. Apremilast participants as randomized or transitioned; The Placebo/Apremilast 30 mg BID group includes participants initially randomized to placebo and switched to apremilast 30 mg BID at Week 16 or 24 and with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    91
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 52
    -0.323 ( 0.5759 )
    -0.395 ( 0.5297 )
        Week 104, N=75, 69
    -0.382 ( 0.5639 )
    -0.357 ( 0.6102 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 52 and 104

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    End point title
    		 Change From Baseline in the Disease Activity Score (DAS28) at Week 52 and 104
    End point description
    The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28 (CRP) scores range from 0 to 9.4. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. A negative change from baseline indicates improvement. Apremilast participants as randomized or transitioned. The Placebo/Apremilast30 mg BID group includes participants initially randomized to placebo and switched to apremilast 30 mg BID at Week 16 or 24 and with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    90
    79
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 52
    -1.46 ( 0.985 )
    -1.71 ( 1.054 )
        Week 104, N=73, 69
    -1.62 ( 10.86 )
    -1.70 ( 1.035 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in 36-item SF-36 (V2.0) Physical Functioning Domain Score at Weeks 52 and 104

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    End point title
    		 Change From Baseline in 36-item SF-36 (V2.0) Physical Functioning Domain Score at Weeks 52 and 104
    End point description
    The SF-36 (v 2.0) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. Apremilast Subjects as Randomized or Transitioned; The Placebo/30 mg BID group includes participants initially randomized to placebo and switched to apremilast 30 mg BID at Week 16 or 24and with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    91
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 52
    5.11 ( 9.842 )
    6.00 ( 9.990 )
        Week 104, N= 75, 69
    5.78 ( 9.932 )
    5.95 ( 10.827 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Duration of Morning Stiffness at Weeks 52 and 104

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    End point title
    		 Change From Baseline in the Duration of Morning Stiffness at Weeks 52 and 104
    End point description
    Morning stiffness was the participant’s assessment of how long their morning stiffness lasted after first waking up in the morning, on average, during the previous week. A higher value indicates longer duration, and a negative change from baseline indicates improvement. Apremilast participants as randomized or transitioned; The Placebo/ Apremilast 30 mg BID group includes participants initially randomized to placebo and switched to apremilast 30 mg BID at Week 16 or 24 And with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    91
    80
    Units: minutes
    arithmetic mean (standard deviation)
        Week 52
    3.3 ( 174.11 )
    -5.7 ( 93.62 )
        Week 104, N-75, 69
    -11.9 ( 165.36 )
    -7.0 ( 71.34 )
    No statistical analyses for this end point

    Secondary: Percentage of participants whose severity of morning stiffness at Week 52 and 104 improved from baseline

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    End point title
    		 Percentage of participants whose severity of morning stiffness at Week 52 and 104 improved from baseline
    End point description
    Morning stiffness severity was the participant’s assessment of how severe their morning stiffness was after first waking up in the morning, on average, during the previous week. The severity was recorded as none, mild, moderate, moderately severe, or very severe. Improvement is defined as the change from baseline of a more severe assessment to less severe assessment. Apremilast participants as randomized or transitioned. The Placebo/30 mg BID group includes subjects initially randomized to placebo and switched to apremilast 30 mg BID at Week 16 or 24 and with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 52 and 104
    End point values
    		 Placebo/Apremilast Apremilast
    Number of subjects analysed
    91
    80
    Units: percentage of participants
    number (not applicable)
        Week 52
    57.1
    57.5
        Week 104, N= 75, 69
    50.7
    59.4
    No statistical analyses for this end point

    Secondary: Number of participants with Treatment Emergent Adverse Events (TEAE) during the 24 week placebo controlled phase

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    End point title
    		 Number of participants with Treatment Emergent Adverse Events (TEAE) during the 24 week placebo controlled phase
    End point description
    A TEAE is an AE with a start date on or after the date of the first dose of IP. An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. A serious AE (SAE) is any untoward AE that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. Safety population = participants who were randomized and received at least one dose of IP.
    End point type
    Secondary
    End point timeframe
    Date of first dose of study drug to Week 24; median duration of exposure during placebo controlled phase was 24.14 weeks
    End point values
    		 Placebo/Apremilast (PBO) Apremilast (APR)
    Number of subjects analysed
    109
    109
    Units: Participants
        Any TEAE
    69
    73
        Any drug-related TEAE
    18
    30
        Any severe TEAE
    4
    2
        Any serious TEAE
    5
    3
        Any serious drug-related TEAE
    0
    0
        Any TEAE leading to study drug withdrawal
    5
    10
        Any TEAE leading to study dose interruption
    7
    10
        Any TEAE leading to death
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with Treatment Emergent Adverse Events (TEAE) during the apremilast-exposure period

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    End point title
    		 Number of participants with Treatment Emergent Adverse Events (TEAE) during the apremilast-exposure period
    End point description
    A TEAE is an AE with a start date on or after the date of the first dose of Investigational Product (IP). An AE is any noxious, unintended, or untoward medical occurrence, that may appear or worsen in a participant during the course of study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. SAE is any untoward adverse event that is fatal, life-threatening, results in persistent or significant disability or incapacity, requires or prolongs existing in-patient hospitalization, is a congenital anomaly or birth defect, or a condition that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. Safety population
    End point type
    Secondary
    End point timeframe
    Start of first dose of IP up to week 104: Weeks 0 to104 for those initially randomized to APR 30 mg BID, Weeks 16 -104 for PBO-treated patients who EE to APR at Week 16 and from Weeks 24-104 for PBO-treated patients who transitioned to APR at Week 24.
    End point values
    		 Number of subjects with TEAEs in the apremilast-exposure phase
    Number of subjects analysed
    206
    Units: particpants
    number (not applicable)
        Any TEAE
    157
        Any drug-related TEAE
    52
        Any severe TEAE
    8
        Any serious TEAE
    15
        Any serious drug-related TEAE
    0
        Any TEAE leading to study dose interruption
    28
        Any TEAE leading to study drug withdrawal
    17
        Any TEAE leading to death
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE's are reported: 1. Placebo-controlled phase (Weeks 0-24) 2. Up to 104 weeks for all participants randomized or transitioned onto apremilast at any time during the study (apremilast-exposure phase). AEs were monitored for 37 months
    Adverse event reporting additional description
    Median duration of exposure during the placebo-controlled phase was 24.14 weeks and 81 weeks during the apremilast exposure phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    V14.0
    Reporting groups
    Reporting group title
    Placebo-Controlled Phase: Placebo (Weeks 0-24)
    Reporting group description
    		 Participants who were randomized to placebo tablets twice daily (BID) during the double-blind, 24-week placebo-controlled phase.

    Reporting group title
    Apremilast Exposure Period: Apremilast (Weeks 0-104)
    Reporting group description
    		 Participants who received apremilast any point during the course of the study, on Day 0, 16 or Day 24 and continued to receive apremilast 30 mg tablets BID up to week 104.

    Reporting group title
    Placebo-Controlled Phase: Apremilast (Weeks 0-24)
    Reporting group description
    		 Participants who were randomized to apremilast tablets twice daily during the double-blind, 24-week placebo-controlled phase.

    Serious adverse events
    		 Placebo-Controlled Phase: Placebo (Weeks 0-24) Apremilast Exposure Period: Apremilast (Weeks 0-104) Placebo-Controlled Phase: Apremilast (Weeks 0-24)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 109 (4.59%)
    15 / 206 (7.28%)
    3 / 109 (2.75%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory papilloma
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy alcoholic
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 206 (0.97%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 206 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureteric obstruction
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis infective
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 206 (0.49%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo-Controlled Phase: Placebo (Weeks 0-24) Apremilast Exposure Period: Apremilast (Weeks 0-104) Placebo-Controlled Phase: Apremilast (Weeks 0-24)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 109 (33.94%)
    83 / 206 (40.29%)
    41 / 109 (37.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 109 (6.42%)
    13 / 206 (6.31%)
    7 / 109 (6.42%)
         occurrences all number
    7
    13
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 109 (3.67%)
    13 / 206 (6.31%)
    8 / 109 (7.34%)
         occurrences all number
    5
    16
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 109 (11.01%)
    34 / 206 (16.50%)
    16 / 109 (14.68%)
         occurrences all number
    13
    52
    22
    Nausea
         subjects affected / exposed
    2 / 109 (1.83%)
    18 / 206 (8.74%)
    9 / 109 (8.26%)
         occurrences all number
    2
    21
    10
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 109 (2.75%)
    11 / 206 (5.34%)
    5 / 109 (4.59%)
         occurrences all number
    3
    11
    5
    Nasopharyngitis
         subjects affected / exposed
    7 / 109 (6.42%)
    17 / 206 (8.25%)
    9 / 109 (8.26%)
         occurrences all number
    7
    24
    11
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 109 (10.09%)
    17 / 206 (8.25%)
    5 / 109 (4.59%)
         occurrences all number
    13
    19
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2013
    •Inclusion Criterion 7 was changed to reflect hsCRP ≥ 0.2 mg/dL at Screening •The analysis of the secondary endpoint of SF-36v2 physical component summary score was described in the SAP •Visit windows were removed from the footnotes and incorporated into the header of the Table of Events •Reflex test was added if hepatitis C antibody test was positive •Bristol Stool Scale and Stool Diary were removed from the protocol •TEAEs of Special Interest were added for TEAEs of diarrhea and similar events •ESR was added to calculate DAS28 for exploratory analysis •Clarification was made on the calculation of DAS28 •Exclusion Criterion 12 was revised to add “no new or recurrent infections prior to baseline visit” •Overdose reporting in drug exposure eCRF page was removed •Modification was made on Section 8.6, Investigational Product Accountability and Disposal •Correction on NSAIDs or narcotic analgesics use was made •Use of topical corticosteroids as background therapy was changed from “all” to “low potency” topical corticosteroids •TEAEs of diarrhea were added to the Monitoring, Recording and Reporting of TEAE section •Citations were updated •Administrative and spelling corrections were made

    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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