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    Clinical Trial Results:
    A Phase 4, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in Subjects With Early, Oligoarticular Psoriatic Arthritis Despite Initial Stable Treatment With Either NSAIDS and/or ≤ 1 Conventional Synthetic DMARD

    Summary
    EudraCT number
    		 2018-002735-26
    Trial protocol
    		 DE   FR   ES   BE   NL   GB   IT  
    Global end of trial date
    05 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2024
    First version publication date
    05 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-10004-PSA-013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03747939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of apremilast 30 mg BID with or without NSAIDs and/or csDMARDs versus placebo with or without NSAIDs and/or csDMARDs in subjects with early oligoarticular psoriatic arthritis (PsA), assessed by modified MDA-Joints.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation Good Clinical Practice regulations/guidelines and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    United States: 163
    Country: Number of subjects enrolled
    Russian Federation: 66
    Worldwide total number of subjects
    308
    EEA total number of subjects
    55
    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)
    259
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 80 study centers in Austria, Belgium, Canada, France, Germany, Italy, Spain, the United Kingdom, and the United States from 31 December 2018 to the last participant's last study visit on 05 July 2023. Of the 310 enrolled participants, 2 were enrolled in error and did not receive any dose of investigational product.

    Pre-assignment
    Screening details
    		 Participants with PsA were randomized in a 2:1 ratio to receive apremilast or placebo. At week 16, participants with no swollen joint count (SJC) improvement could have escaped early to receive apremilast 30 mg twice daily (BID). At week 24, eligible participants entered the extension phase to receive apremilast 30 mg BID up to week 48.

    Period 1
    Period 1 title
    Placebo-controlled Phase (Weeks 0 - 24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo-controlled Phase: Placebo
    Arm description
    		 Participants were randomized to receive placebo BID from day 1. Participants could also have received stable doses of non-steroidal anti-inflammatory drugs (NSAIDs) and 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily for 24 weeks

    Arm title
    		 Placebo-controlled Phase: Apremilast 30 mg
    Arm description
    		 Participants were randomized to receive apremilast 30 mg BID from day 1. Participants could also have received stable doses of NSAIDs and 1 csDMARD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg twice daily ± NSAID and/or ≤ 1 csDMARD

    Number of subjects in period 1
    		Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Started
    105
    203
    Full analysis set
    105
    203
    Escaped early at week 16
    24 [1]
    21 [2]
    Completed week 16 and continued
    92
    172
    Safety analysis set
    104
    203
    Completed
    87
    162
    Not completed
    18
    41
         Consent withdrawn by subject
    4
    7
         Adverse Event
    8
    19
         Death
    -
    1
         Pregnancy
    -
    1
         Miscellaneous
    -
    2
         Non-compliance with study drug
    1
    1
         Lost to follow-up
    -
    3
         Lack of efficacy
    4
    7
         Protocol deviation
    1
    -
    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: This is the number of participants that at week 16 did not have SJC improvement and escaped early to receive apremilast 30 mg BID.
    [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: The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected the number of subjects will be greater than, or equal to the number that completed minus those that left.
    Period 2
    Period 2 title
    Apremilast-Extension (Weeks 24 - 48)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Apremilast-extension Phase: Placebo then Apremilast 30 mg
    Arm description
    		 Participants were randomized to receive placebo in the placebo-controlled phase, and entered the open-label apremilast-extension phase to receive apremilast 30 mg BID from week 24 to week 48.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg twice daily ± NSAIDs and/or ≤ 1 csDMARD

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily for 24 weeks

    Arm title
    		 Apremilast-extension Phase: Continued Apremilast 30 mg
    Arm description
    		 Participants were randomized to receive apremilast 30 mg BID in the placebo-controlled phase, and entered the open-label apremilast-extension phase to continue on apremilast 30 mg BID from week 24 to week 48.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg twice daily ± NSAIDs and/or ≤ 1 csDMARD

    Number of subjects in period 2
    		Apremilast-extension Phase: Placebo then Apremilast 30 mg Apremilast-extension Phase: Continued Apremilast 30 mg
    Started
    87
    162
    Received 1 dose of apremilast
    86
    160
    Completed
    77
    133
    Not completed
    10
    29
         Consent withdrawn by subject
    1
    7
         Adverse Event
    2
    6
         Not specified
    -
    7
         Lost to follow-up
    4
    1
         Lack of efficacy
    3
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo-controlled Phase: Placebo
    Reporting group description
    		 Participants were randomized to receive placebo BID from day 1. Participants could also have received stable doses of non-steroidal anti-inflammatory drugs (NSAIDs) and 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD).

    Reporting group title
    Placebo-controlled Phase: Apremilast 30 mg
    Reporting group description
    		 Participants were randomized to receive apremilast 30 mg BID from day 1. Participants could also have received stable doses of NSAIDs and 1 csDMARD.

    Reporting group values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg Total
    Number of subjects
    		 105 203 308
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 87 172 259
        From 65-84 years
    		 18 31 49
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.2 ( 13.03 ) 51.3 ( 12.25 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 51 118 169
        Male
    		 54 85 139
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 3 3
        Asian
    		 1 4 5
        Black or African American
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 99 192 291
        Not Collected or Unknown
    		 2 3 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 16 29
        Not Hispanic or Latino
    		 91 185 276
        Not Reported
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo-controlled Phase: Placebo
    Reporting group description
    		 Participants were randomized to receive placebo BID from day 1. Participants could also have received stable doses of non-steroidal anti-inflammatory drugs (NSAIDs) and 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD).

    Reporting group title
    Placebo-controlled Phase: Apremilast 30 mg
    Reporting group description
    		 Participants were randomized to receive apremilast 30 mg BID from day 1. Participants could also have received stable doses of NSAIDs and 1 csDMARD.
    Reporting group title
    Apremilast-extension Phase: Placebo then Apremilast 30 mg
    Reporting group description
    		 Participants were randomized to receive placebo in the placebo-controlled phase, and entered the open-label apremilast-extension phase to receive apremilast 30 mg BID from week 24 to week 48.

    Reporting group title
    Apremilast-extension Phase: Continued Apremilast 30 mg
    Reporting group description
    		 Participants were randomized to receive apremilast 30 mg BID in the placebo-controlled phase, and entered the open-label apremilast-extension phase to continue on apremilast 30 mg BID from week 24 to week 48.

    Primary: Percentage of Participants who Achieved a Clinical State of Minimal Disease Activity (MDA-Joints) Response at Week 16

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    End point title
    		 Percentage of Participants who Achieved a Clinical State of Minimal Disease Activity (MDA-Joints) Response at Week 16
    End point description
    MDA is defined as tender joint counts (TJC) ≤ 1 and SJC ≤ 1 plus 3 of the following 5 criteria: 1. psoriasis body surface area (BSA) ≤ 3% 2. patient's pain visual analogue scale (VAS) on a 100 mm scale ≤ 15; where 0 indicates 'no pain' and 100 indicates 'pain as severe as can be imagined' 3. patient's global assessment of disease activity on a 100 mm scale ≤ 20, where 0 represents the lowest level of disease activity and 100 represents the highest. 4. physical function assessed by Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5; where 0 represents normal or no difficulty and 3 represents an inability to perform 5. enthesitis count ≤ 1 based on the Leeds Enthesitis Index; where 0 means nontender and 6 indicates 6 tender tendon insertions. The full analysis set included all participants who were randomized as specified in the protocol.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    16.0
    33.9
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per Interactive Web Response System (IWRS) data, using Cochran-Mantel-Haenszel (CMH) weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.9
         upper limit
    		 28.1
    Notes
    [1] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Secondary: Percentage of Participants who Achieved Remission or Low Disease Activity at Week 16 Based on Clinical Activity in Psoriatic Arthritis (cDAPSA)

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    End point title
    		 Percentage of Participants who Achieved Remission or Low Disease Activity at Week 16 Based on Clinical Activity in Psoriatic Arthritis (cDAPSA)
    End point description
    The cDAPSA score is based on the numerical summation of 4 disease activity variables: tender and swollen joints, patient's global assessments of Disease Activity and Assessment of Pain (VAS). The cDAPSA score ranges from 0 to 154, with a higher score indicating more disease activity. cDAPSA remission is defined as a DAPSA score ≤ 4 and low disease activity is defined as a cDAPSA score > 4 but ≤ 13). The full analysis set included all participants who were randomized as specified in the protocol.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    51.8
    70.2
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    18.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 30.2
    Notes
    [2] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Secondary: Percentage of Participants with SJC ≤ 1 at Week 16

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    End point title
    		 Percentage of Participants with SJC ≤ 1 at Week 16
    End point description
    The SJC was based on 66 joints and at week 16 is based on the sentinel joints (i.e., the joints that were affected at baseline). A SJC response is defined as a count ≤ 1.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    69.0
    74.0
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3539 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 16
    Notes
    [3] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation

    Secondary: Percentage of Participants with TJC ≤ 1 at Week 16

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    End point title
    		 Percentage of Participants with TJC ≤ 1 at Week 16
    End point description
    The TJC was based on 68 joints and at week 16 was based on the sentinel joints (i.e., the joints that were affected at baseline). A TJC response is defined as a count ≤ 1.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    44.4
    66.2
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    22.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.4
         upper limit
    		 33.7
    Notes
    [4] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Secondary: Percentage of Participants with an Assessment of Pain Score ≤ 15 mm in VAS at Week 16

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    End point title
    		 Percentage of Participants with an Assessment of Pain Score ≤ 15 mm in VAS at Week 16
    End point description
    The Patients Pain VAS is the participant's assessment of how much pain they had, on average, during the last week in their joints due to psoriatic arthritis. The VAS score ranges from 0 to 100 mm, with a higher score indicating more pain.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    13.1
    29.4
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    16.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.9
         upper limit
    		 25.8
    Notes
    [5] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Secondary: Percentage of Participants with Patient's Global Assessments of Disease Activity Score of ≤ 20 mm in the VAS at Week 16

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    End point title
    		 Percentage of Participants with Patient's Global Assessments of Disease Activity Score of ≤ 20 mm in the VAS at Week 16
    End point description
    The Patient's Global Assessments of Disease Activity is an assessment of how active a participant's psoriatic arthritis was on average during the last week. It was assessed on a VAS ranging from 0 to 100 mm, with a higher score indicating more disease activity. A response is defined as a score ≤ 20 mm.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    19.1
    30.4
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0286 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    11.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 22
    Notes
    [6] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Secondary: Change from Baseline in Psoriatic Arthritis Impact of Disease 12-item for Clinical Trials (PsAID-12) Questionnaire Score at Week 16

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    End point title
    		 Change from Baseline in Psoriatic Arthritis Impact of Disease 12-item for Clinical Trials (PsAID-12) Questionnaire Score at Week 16
    End point description
    The PsAID-12 Questionnaire is a 12-item, self-administered questionnaire that reflects the impact of psoriatic arthritis from the perspective of the participant. The overall score ranges from 0 (best status) to 10 (worst status), with a cut-off ≤ 4 representing patient-acceptable symptom state. Analysis was based on a mixed-effects model for repeated measures (MMRM), which included treatment group, time, treatment group by time interaction, prior/concomitant use of csDMARD (naive, prior use only, both prior and concomitant use) and baseline glucocorticosteroid use (yes/no) per IWRS data as factors, and baseline value as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: score on a scale
        least squares mean (standard error)
    -0.42 ( 0.216 )
    -1.45 ( 0.178 )
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Difference in least square (LS) means is based MMRM of the change from baseline.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Difference in LS means
    Point estimate
    -1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 -0.59

    Secondary: Percentage of Participants with a Good or Moderate Psoriatic Arthritis Disease Activity (PASDAS) Score at Week 16

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    End point title
    		 Percentage of Participants with a Good or Moderate Psoriatic Arthritis Disease Activity (PASDAS) Score at Week 16
    End point description
    The PASDAS is a weighted index comprising assessments of joints, function, acute-phase response, quality of life, and patient and physician VAS. The score range of the PASDAS is 0 - 10, with worse disease activity represented by higher scores. A good response is defined as a PASDAS score of ≤ 3.2 with improvement from baseline ≥ 1.6 points. A moderate response is defined as a PASDAS score > 3.2 with improvement from baseline ≥ 1.6 points; or PASDAS score < 5.4 with improvement from baseline ≥ 0.8 but < 1.6 points.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Placebo-controlled Phase: Placebo Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects analysed
    105
    203
    Units: percentage of participants
        number (not applicable)
    42.7
    59.9
    Statistical analysis title
    		 Apremilast versus Placebo
    Statistical analysis description
    Adjusted difference in proportions is the weighted average of the treatment differences across strata formed by two stratification factors, prior/concomitant use of csDMARD and baseline glucocorticosteroid use per IWRS data, using CMH weights. Two-sided 95% CI is based on a normal approximation to the weighted average.
    Comparison groups
    Placebo-controlled Phase: Placebo v Placebo-controlled Phase: Apremilast 30 mg
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0043 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference in proportions
    Point estimate
    17.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.7
         upper limit
    		 29.7
    Notes
    [7] - Two-sided p-value adjusted for prior/concomitant use of csDMARD and baseline glucocorticosteroid use, normalized via Wilson-Hilferty transformation.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 up to week 48 (end of extension phase), and a 4-week observational follow-up (up to 52 weeks).
    Adverse event reporting additional description
    The safety analysis set included all participants who received at least 1 dose of study medication. For the placebo-controlled phase, participants were included in the treatment group for the treatment they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo-Controlled: Placebo
    Reporting group description
    		 -

    Reporting group title
    Apremilast-Exposure: Apremilast 30 mg BID
    Reporting group description
    		 -

    Reporting group title
    Placebo-Controlled: Apremilast 30 mg BID
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo-Controlled: Placebo Apremilast-Exposure: Apremilast 30 mg BID Placebo-Controlled: Apremilast 30 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 104 (5.77%)
    15 / 291 (5.15%)
    9 / 204 (4.41%)
         number of deaths (all causes)
    0
    2
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Hypertensive crisis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Sudden cardiac death
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Troponin increased
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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
    1 / 104 (0.96%)
    1 / 291 (0.34%)
    0 / 204 (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
    Pericarditis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 291 (0.69%)
    0 / 204 (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
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 104 (0.00%)
    2 / 291 (0.69%)
    2 / 204 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 291 (0.34%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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
    Sepsis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 291 (0.00%)
    0 / 204 (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
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 291 (0.34%)
    0 / 204 (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: Placebo Apremilast-Exposure: Apremilast 30 mg BID Placebo-Controlled: Apremilast 30 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 104 (17.31%)
    103 / 291 (35.40%)
    72 / 204 (35.29%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 104 (2.88%)
    21 / 291 (7.22%)
    16 / 204 (7.84%)
         occurrences all number
    3
    40
    28
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 104 (10.58%)
    69 / 291 (23.71%)
    47 / 204 (23.04%)
         occurrences all number
    13
    82
    51
    Nausea
         subjects affected / exposed
    4 / 104 (3.85%)
    28 / 291 (9.62%)
    22 / 204 (10.78%)
         occurrences all number
    5
    32
    26
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 104 (2.88%)
    19 / 291 (6.53%)
    7 / 204 (3.43%)
         occurrences all number
    4
    19
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2019
    - Edited exclusion criteria for clarity and to add severe renal disease as a significant laboratory abnormality. - Added creatinine clearance to clinical laboratory evaluations to support edits to the exclusion criteria. - Modified vital signs, height and weight to clarify treatment discontinuation for severe weight loss. Measurement of weight was added for every visit and the table events and safety follow-up period were also revised. - Modified psychiatric evaluation to clarify study discontinuation for psychiatric symptoms. - Added Section 6.5.5 to clarify treatment discontinuation for severe symptoms of diarrhea, nausea and vomiting. - Added Section 8.2 to align with guidance provided in the label regarding co-administration of strong cytochrome P450 3A4 enzyme inducers with apremilast. - Updated inclusion criteria to clarify that contraception, Option 2, may not be acceptable as a highly effective contraception option in all countries per local guidelines/regulations. - Modified Section 6.5.1 Serum and Urine Pregnancy Tests for Females of Childbearing Potential to clarify that additional visits (unscheduled visits) may be done to monitor pregnancy testing.
    04 May 2020
    - Removed all references that include “approved product labeling” and “Prescribing Information” to address feedback from Health Authorities. - Updated exclusion criteria to reflect that prior exposure to tyk2 inhibitors is prohibited.
    17 May 2020
    - Removed all references to “Celgene Corporation” and replaced with “Amgen Inc”. - Updated Cover Pages with Amgen contact information. - Updated Monitoring and Reporting of Adverse Events to align with Amgen Global Drug Safety processes. - Modified Section 10.4 Pregnancy according to Amgen Global Drug Safety processes. - Updated reporting of serious adverse events to include instructions for paper reporting. - Updated with Amgen emergency contact information. - Added Section 15.3 Product Complaint.
    03 Feb 2021
    - Modified the timepoint for the primary endpoint from week 24 to week 16, which is closer to the timeframe in which clinicians assess efficacy in clinical practice. - Modified inclusion criteria to remove requirement that treatment with a maximum of 1 csDMARD (methotrexate or sulfasalazine) begin ≤ 6 months prior to baseline to allow for concomitant use of 1 csDMARD if the subject is on a stable regimen for at least 3 months prior to the baseline visit. - Modified exclusion criteria to allow prior use of > 1 csDMARD to treat conditions other than the study indication, such as psoriasis. - Modified the early diagnosis period from ≥ 3 months and ≤ 24 months to ≥ 3 months and ≤ 5 years. - Modified timepoints for secondary efficacy endpoints from week 24 to week 16.
    12 Jul 2021
    - Updated the total number of subjects to be randomized in the study from 330 subjects (220 on active treatment and 110 on placebo) to 285 subjects (190 on active treatment and 95 on placebo). - Updated the inclusion criterion regarding duration of disease to change "diagnosis" to "signs and symptoms" of PsA and to remove the minimum duration. - Updated the study rationale to include subjects with early diagnosis of PsA (≤ 5 years since signs and symptoms began). - Updated the exclusion criteria to allow prior use of 2 csDMARDs (as opposed to 1). - Updated the exclusion criteria to reflect exclusion of subjects with bacterial infections requiring treatment within 1 week of screening (previously within 4 weeks of screening). - Updated the table of events table to include a window of ± 7 days for the observational follow-up visit.

    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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