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    Clinical Trial Results:
    A Phase 2b, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Finding, Multi-Center Study to Evaluate the Safety and Efficacy of ASP015K in Moderate to Severe Rheumatoid Arthritis Subjects Who Have Had an Inadequate Response to Methotrexate

    Summary
    EudraCT number
    2011-006018-15
    Trial protocol
    BE   CZ   PL   HU   BG  
    Global end of trial date
    11 Feb 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Feb 2017
    First version publication date
    02 Jul 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    015K-CL-RA21
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01554696
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), Astellas.resultsdisclosure@astellas.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
    11 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the safety and efficacy of ASP015K in moderate to severe Rheumatoid Arthritis (RA) patients who were methotrexate-inadequate responders (MTX-IRs).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    At screening, patients were currently taking oral Methotrexate (MTX), taken MTX for at least the past 90 days and at a stable dose (single, unchanging dose) between 15 to 25 mg/week for at least 28 days prior to the first dose of study drug. Lower doses (≥ 7.5 to < 15 mg/week) were accepted if patients had intolerance to higher doses of MTX, provided the same duration and stability requirements were met. Previous use of a non-anti-TNF (Tumor necrosis factor) biologic Disease-modifying antirheumatic drug (DMARD) (e.g., anakinra, abacept, rituximab, tocilizumab) was prohibited and concurrent use of biologic DMARDs was prohibited during the study. Up to 25% of the total number of patients randomized were allowed to be antitumor necrosis factor (TNF) experienced patients, which were defined as patients who have previously been exposed to an approved anti-TNF medication, provided the specified protocol criteria were met. Potential patients who previously used anti-TNF therapy were eligible to participate provided the following washout periods were met and fewer than 25% of the randomized patients had taken anti-TNF therapy: ● Etanercept – 28 days ● Certolizumab, adalimumab, golimumab and infliximab – 60 days ● Cyclophosphamide – 180 days ● Gold, azathioprine, minocycline and penicillamine – 28 days ● Leflunomide – 60 days; if the patient has undergone a cholestyramine washout, then the period is reduced to 30 days prior to day 1 dosing
    Evidence for comparator
    Placebo was used as comparative drug. The ASP015K matching placebo tablets contained the same ingredients as the test drug except for active drug substance and hydroxy-propyl cellulose.
    Actual start date of recruitment
    06 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 92
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Colombia: 25
    Country: Number of subjects enrolled
    Mexico: 43
    Country: Number of subjects enrolled
    United States: 147
    Worldwide total number of subjects
    379
    EEA total number of subjects
    164
    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)
    316
    From 65 to 84 years
    62
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This multi-center study was conducted at 43 sites in a total of 8 countries and 3 regions. The Principal Investigator at each site was a licensed clinician with experience in the therapeutic area of rheumatoid arthritis (RA).

    Pre-assignment
    Screening details
    Patients with prior anti-TNF use were eligible if the following washout periods were met: Etanercept-28 days, Certolizumab/adalimumab/golimumab/infliximab-60 days, Cyclophosphamide-180 days, Gold/azathioprine/minocycline/penicillamine-28 days, Leflunomide-60 days; if cholestyramine washout was met this was reduced to 30 days prior to day 1 dosing.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    This was a double-blind study. The investigator, patient, clinical staff and Sponsor’s study management team were blinded to treatment assignments. The Data and Safety Monitoring Board (DSMB) was provided access to the dosing assignment for periodic review of the unblinded data as documented in the DSMB Charter.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + weekly oral dose of MTX
    Arm description
    This arm consisted of matching ASP015K placebo taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.
    Arm type
    Placebo

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate was not provided by the Sponsor, all patients continued to take MTX orally as concomitant medication on a weekly basis.

    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
    ASP015K matching placebo tablets contained the same ingredients as the test drug except for active drug substance and hydroxy-propyl cellulose. Placebo was to be taken orally with food, daily for 12 weeks (days 1-84) after randomization.

    Arm title
    ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Arm description
    This arm consisted of ASP015K 25 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The test drug for this study is ASP015K. ASP015K is a round, yellow, film-coated tablet. ASP015K 25 mg once daily was to be taken orally with food, daily for 12 weeks (days 1-84) after randomization.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate was not provided by the Sponsor, all patients continued to take MTX orally as concomitant medication on a weekly basis.

    Arm title
    ASP015K 50 mg qd + weekly oral dose of MTX
    Arm description
    This arm consisted of ASP015K 50 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The test drug for this study is ASP015K. ASP015K is a round, yellow, film-coated tablet. ASP015K 50 mg once daily was to be taken orally with food, daily for 12 weeks (days 1-84) after randomization.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate was not provided by the Sponsor, all patients continued to take MTX orally as concomitant medication on a weekly basis.

    Arm title
    ASP015K 100 mg qd + weekly oral dose of MTX
    Arm description
    This arm consisted of ASP015K 100 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The test drug for this study is ASP015K. ASP015K is a round, yellow, film-coated tablet. ASP015K 100 mg once daily was to be taken orally with food, daily for 12 weeks (days 1-84) after randomization.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate was not provided by the Sponsor, all patients continued to take MTX orally as concomitant medication on a weekly basis.

    Arm title
    ASP015K 150 mg qd + weekly oral dose of MTX
    Arm description
    This arm consisted of ASP015K 150 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.
    Arm type
    Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    MTX
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate was not provided by the Sponsor, all patients continued to take MTX orally as concomitant medication on a weekly basis.

    Investigational medicinal product name
    ASP015K
    Investigational medicinal product code
    ASP015K
    Other name
    Peficitinib (USAN)
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The test drug for this study is ASP015K. ASP015K is a round, yellow, film-coated tablet. ASP015K 150 mg once daily was to be taken orally with food, daily for 12 weeks (days 1-84) after randomization.

    Number of subjects in period 1
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX
    Started
    72
    67
    78
    84
    78
    Completed
    67
    65
    77
    77
    72
    Not completed
    5
    2
    1
    7
    6
         Protocol violation
    -
    -
    1
    -
    -
         Adverse event
    1
    -
    -
    3
    4
         Lack of efficacy
    -
    -
    -
    1
    -
         Withdrawal by subject
    3
    1
    -
    2
    2
         Randomized but never dispensed study drug
    -
    1
    -
    -
    -
         Lost to follow-up
    1
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + weekly oral dose of MTX
    Reporting group description
    This arm consisted of matching ASP015K placebo taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 25 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 50 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 50 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 100 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 100 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 150 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 150 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group values
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX Total
    Number of subjects
    72 67 78 84 78 379
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age values were based on the Safety Analysis Set (SAF) population. The SAF was defined as all patients who received at least 1 dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    52.6 ± 12.2 52.8 ± 11.9 52.3 ± 12.6 54.5 ± 12.8 54.2 ± 12.5 -
    Gender categorical
    Gender values are based on the SAF population.
    Units: Subjects
        Female
    63 55 65 68 64 315
        Male
    9 11 13 16 14 63
        Subject not included in SAF
    0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo + weekly oral dose of MTX
    Reporting group description
    This arm consisted of matching ASP015K placebo taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 25 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 50 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 50 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 100 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 100 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Reporting group title
    ASP015K 150 mg qd + weekly oral dose of MTX
    Reporting group description
    This arm consisted of ASP015K 150 mg qd (once a day) taken orally with food, for 12 weeks (days 1-84) after randomization. All patients continued to take their concomitant oral weekly dose of MTX.

    Subject analysis set title
    H1 Metabolite - ASP015K 25 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the Pharmacokinetic Analysis Set (PKAS). The PKAS consisted of all patients who received at least 1 dose of study drug and who had values of drug concentration for at least 1 time point. The PKAS population included all of the patients treated with ASP015K that were also included in the Full Analysis Set (FAS - all randomized subjects that received at least one study drug dose) and Safety Analysis Set (SAF-all patients who received at least 1 dose of study drug).

    Subject analysis set title
    H1 Metabolite - ASP015K 50 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H1 Metabolite - ASP015K 100 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H1 Metabolite - ASP015K 150 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H2 Metabolite - ASP015K 25 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H2 Metabolite - ASP015K 50 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H2 Metabolite - ASP015K 100 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H2 Metabolite - ASP015K 150 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H4 Metabolite - ASP015K 25 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H4 Metabolite - ASP015K 50 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H4 Metabolite - ASP015K 100 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Subject analysis set title
    H4 Metabolite - ASP015K 150 mg + MTX (PKAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The study analysis population consisted of the PKAS.

    Primary: Percentage of participants achieving a response in American College of Rheumatology (ACR) criteria for 20% improvement in disease severity (ACR 20) using the C-reactive protein (CRP) level (ACR20-CRP) at week 12

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    End point title
    Percentage of participants achieving a response in American College of Rheumatology (ACR) criteria for 20% improvement in disease severity (ACR 20) using the C-reactive protein (CRP) level (ACR20-CRP) at week 12
    End point description
    The study analysis population consisted of the Full Analysis Set (FAS), defined as all randomized subjects that received at least one study drug dose. ACR20-CRP responder determined at week 12 if ACR response criteria was met: At least 20% reduction from baseline at week 12 TJC68 count, At least 20% reduction from baseline at week 12 SJC66 count, At least 20% reduction from baseline at week 12 in any 3 of 5 ACR components: subject’s global assessment of arthritis pain SGAP (100mm visual analog scale VAS; score 0=no pain, score 100=very severe pain), subject’s global assessment of arthritis SGA (100mm VAS; score 0=no disease activity, score 100mm=very severe disease activity), PGA (100mm VAS; score 0=no disease activity, score 100mm=very severe disease activity), Health Assessment Questionnaire-Disability Index HAQ-DI (score from 0 to 3, higher score=greater disability), CRP (mg/dL, higher values= >inflammation). Patient defined as a non-responder if the patient was not a responder.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects analysed
    72 [1]
    66 [2]
    78 [3]
    84 [4]
    78 [5]
    Units: percentage of participants
    number (not applicable)
        Responder (R)
    44.4
    43.9
    61.5
    46.4
    57.7
        Non-responder (NR)
    55.6
    56.1
    38.5
    53.6
    42.3
    Notes
    [1] - R (N= 32), NR (N= 40)
    [2] - R (N= 29), NR (N= 37)
    [3] - R (N= 48), NR (N= 30)
    [4] - R (N= 39), NR (N= 45)
    [5] - R (N= 45), NR (N= 33)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    LOCF: Last Observation Carried Forward for missing ACR20 components. NRI: Non-Responder Imputation for missing ACR response. ACR components were LOCFed first and then ACR20 response was calculated. In addition, all subjects with RA rescue therapy prior to or at Week 12 were classified as non-responders for primary analysis of ACR20-CRP response at time of first rescue and until their primary endpoint assessment.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.193 [7]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.9
    Notes
    [6] - ACR components were LOCF first and then the response was calculated. In addition, all patients with RA rescue therapy prior to or at week 12 were classified as non-responders (ACR50-CRP and ACR70-CRP). The total number of subjects in the statistical analysis are the responders in the Placebo group (32) and ASP015K 25 mg (29).
    [7] - Based on logistic regression model: ACR response (responder, non-responder) = Treatment + Prior Anti-TNF Use + Geographic Region. Odds ratio > 1 favors ASP015K.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    LOCF: Last Observation Carried Forward for missing ACR20 components. NRI: Non-Responder Imputation for missing ACR response. ACR components were LOCFed first and then ACR20 response was calculated. In addition, all subjects with RA rescue therapy prior to or at Week 12 were classified as non-responders for primary analysis of ACR20-CRP response at time of first rescue and until their primary endpoint assessment.
    Comparison groups
    ASP015K 50 mg qd + weekly oral dose of MTX v Placebo + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.036 [9]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    3.87
    Notes
    [8] - The total number of subjects in the statistical analysis are the responders in the Placebo group (32) and ASP015K 50 mg (48).
    [9] - Based on logistic regression model: ACR response (responder, non-responder) = Treatment + Prior Anti-TNF Use + Geographic Region. Odds ratio > 1 favors ASP015K.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    LOCF: Last Observation Carried Forward for missing ACR20 components. NRI: Non-Responder Imputation for missing ACR response. ACR components were LOCFed first and then ACR20 response was calculated. In addition, all subjects with RA rescue therapy prior to or at Week 12 were classified as non-responders for primary analysis of ACR20-CRP response at time of first rescue and until their primary endpoint assessment.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 100 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.379 [11]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    2.04
    Notes
    [10] - The total number of subjects in the statistical analysis are the responders in the Placebo group (32) and ASP015K 100 mg (39).
    [11] - Based on logistic regression model: ACR response (responder, non-responder) = Treatment + Prior Anti-TNF Use + Geographic Region. Odds ratio > 1 favors ASP015K.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    LOCF: Last Observation Carried Forward for missing ACR20 components. NRI: Non-Responder Imputation for missing ACR response. ACR components were LOCFed first and then ACR20 response was calculated. In addition, all subjects with RA rescue therapy prior to or at Week 12 were classified as non-responders for primary analysis of ACR20-CRP response at time of first rescue and until their primary endpoint assessment.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.186 [13]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    3.26
    Notes
    [12] - The total number of subjects in the statistical analysis are the responders in the Placebo group (32) and ASP015K 150 mg (45).
    [13] - Based on logistic regression model: ACR response (responder, non-responder) = Treatment + Prior Anti-TNF Use + Geographic Region. Odds ratio > 1 favors ASP015K.

    Primary: Trough plasma concentration of ASP015K and metabolites

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    End point title
    Trough plasma concentration of ASP015K and metabolites [14] [15]
    End point description
    The study analysis population consisted of the Pharmacokinetic Analysis Set (PKAS). The PKAS consisted of all patients who received at least 1 dose of study drug and who had values of drug concentration for at least 1 time point. N= number of participants.
    End point type
    Primary
    End point timeframe
    Up to week 12.
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This pharmacokinetic (PK) endpoint pertained to only those arms/subject analysis sets with ASP015K treatment since it measured the trough plasma concentration of ASP015K and metabolites. This was not applicable to the placebo treatment arm.
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics have been summarized for trough plasma concentrations of ASP015K, and metabolites by active treatment group and time point for each analyte.
    End point values
    ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX H1 Metabolite - ASP015K 25 mg + MTX (PKAS) H1 Metabolite - ASP015K 50 mg + MTX (PKAS) H1 Metabolite - ASP015K 100 mg + MTX (PKAS) H1 Metabolite - ASP015K 150 mg + MTX (PKAS) H2 Metabolite - ASP015K 25 mg + MTX (PKAS) H2 Metabolite - ASP015K 50 mg + MTX (PKAS) H2 Metabolite - ASP015K 100 mg + MTX (PKAS) H2 Metabolite - ASP015K 150 mg + MTX (PKAS) H4 Metabolite - ASP015K 25 mg + MTX (PKAS) H4 Metabolite - ASP015K 50 mg + MTX (PKAS) H4 Metabolite - ASP015K 100 mg + MTX (PKAS) H4 Metabolite - ASP015K 150 mg + MTX (PKAS)
    Number of subjects analysed
    66 [16]
    78 [17]
    84 [18]
    78 [19]
    66 [20]
    78 [21]
    84 [22]
    78 [23]
    66 [24]
    78 [25]
    84 [26]
    78 [27]
    66 [28]
    78 [29]
    84 [30]
    78 [31]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline
    0.164 ± 1.3235
    0.448 ± 3.8524
    0.045 ± 0.4094
    0 ± 0
    0 ± 0
    0 ± 0
    0.053 ± 0.3776
    0 ± 0
    0.049 ± 0.3944
    0.554 ± 4.765
    0.213 ± 1.7174
    0 ± 0
    0 ± 0
    0 ± 0
    0.026 ± 0.2393
    0 ± 0
        Week 1
    1.8 ± 5.0241
    3.618 ± 16.1845
    8.177 ± 37.8132
    6.989 ± 7.3098
    2.096 ± 3.2356
    3.37 ± 5.8755
    6.469 ± 6.293
    10.665 ± 14.6867
    4.48 ± 8.4518
    7.92 ± 29.2576
    21.478 ± 96.7487
    21.15 ± 26.1555
    1.425 ± 2.1349
    2.109 ± 3.292
    4.992 ± 6.8523
    6.921 ± 8.6144
        Week 2
    2.538 ± 9.4912
    2.233 ± 2.7951
    3.853 ± 3.1801
    12.025 ± 45.1589
    1.981 ± 3.318
    3.575 ± 4.1641
    5.889 ± 5.6506
    9.137 ± 8.6281
    4.694 ± 12.2919
    6.627 ± 9.5277
    10.532 ± 9.3593
    28.032 ± 64.5609
    1.163 ± 1.4283
    2.266 ± 2.0518
    4.332 ± 3.7518
    6.18 ± 5.207
        Week 4
    0.901 ± 1.0425
    3.144 ± 9.0971
    4.02 ± 7.1763
    7.042 ± 7.0535
    1.677 ± 1.9554
    3.676 ± 5.0981
    5.927 ± 7.7267
    7.833 ± 7.616
    2.747 ± 3.8714
    8.032 ± 18.8903
    10.833 ± 15.9375
    21.29 ± 30.0176
    1.07 ± 0.8048
    2.455 ± 2.9556
    4.309 ± 5.8932
    5.48 ± 3.3805
        Week 8
    1.063 ± 1.6138
    3.351 ± 9.1165
    7.79 ± 25.824
    9.838 ± 17.3091
    2.206 ± 3.8035
    4.359 ± 11.4328
    7.94 ± 17.7368
    10.949 ± 17.9865
    3.835 ± 9.989
    8.747 ± 21.557
    22.766 ± 93.0472
    29.495 ± 56.2249
    1.336 ± 2.0418
    2.589 ± 3.5547
    5.263 ± 9.7618
    7.067 ± 8.1225
        Week 12
    0.753 ± 0.6513
    5.909 ± 19.295
    5.256 ± 7.1434
    11.7 ± 39.9558
    1.997 ± 3.1006
    3.825 ± 4.6887
    6.924 ± 8.2874
    8.413 ± 10.5487
    2.832 ± 5.1774
    12.311 ± 34.0951
    13.252 ± 16.8922
    35.453 ± 114.0364
    1.414 ± 2.365
    2.937 ± 4.1479
    5.55 ± 8.8286
    6.483 ± 7.3158
    Notes
    [16] - [N= Baseline/65, Week 1/50, Week 2/56, Week 4/52, Week 8/51, Week 12/49]
    [17] - [N= Baseline/74, Week 1/56, Week 2/58, Week 4/59, Week 8/58, Week 12/57]
    [18] - [N= Baseline/83, Week 1/67, Week 2/65, Week 4/67, Week 8/64, Week 12/57]
    [19] - [N= Baseline/77, Week 1/65, Week 2/66, Week 4/65, Week 8/61, Week 12/62]
    [20] - [N= Baseline/65, Week 1/50, Week 2/55, Week 4/52, Week 8/52, Week 12/53]
    [21] - [N= Baseline/74, Week 1/58, Week 2/58, Week 4/59, Week 8/62, Week 12/58]
    [22] - [N= Baseline/83, Week 1/68, Week 2/64, Week 4/67, Week 8/63, Week 12/57]
    [23] - [N= Baseline/77, Week 1/68, Week 2/67, Week 4/66, Week 8/61, Week 12/64]
    [24] - [N= Baseline/65, Week 1/50, Week 2/54, Week 4/51, Week 8/51, Week 12/51]
    [25] - [N= Baseline/74, Week 1/57, Week 2/58, Week 4/59, Week 8/57, Week 12/57]
    [26] - [N= Baseline/83, Week 1/67, Week 2/66, Week 4/67, Week 8/63, Week 12/55]
    [27] - [N= Baseline/77, Week 1/65, Week 2/66, Week 4/65, Week 8/60, Week 12/63]
    [28] - [N= Baseline/65, Week 1/51, Week 2/56, Week 4/51, Week 8/51, Week 12/53]
    [29] - [N= Baseline/74, Week 1/58, Week 2/58, Week 4/59, Week 8/61, Week 12/56]
    [30] - [N= Baseline/83, Week 1/69, Week 2/65, Week 4/67, Week 8/63, Week 12/57]
    [31] - [N= Baseline/77, Week 1/67, Week 2/67, Week 4/67, Week 8/62, Week 12/62]
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving American College of Rheumatology criteria for 50% improvement in disease severity using the c-reactive protein level (ACR50-CRP) response at Week 12

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    End point title
    Percentage of participants achieving American College of Rheumatology criteria for 50% improvement in disease severity using the c-reactive protein level (ACR50-CRP) response at Week 12
    End point description
    The study analysis population consisted of the FAS. ACR components were Last Observation Carried Forwrad (LOCF) first and then the response was calculated. In addition, all patients with RA rescue therapy prior to or at week 12 were classified as non-responders. ACR50-CRP responder is defined as per ACR20 but using 50% instead of 20%.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects analysed
    72 [32]
    66 [33]
    78 [34]
    84 [35]
    78 [36]
    Units: percentage of participants
    number (not applicable)
        Responder (R)
    26.4
    18.2
    33.3
    33.3
    37.2
        Non-responder (NR)
    73.6
    81.8
    66.7
    66.7
    62.8
    Notes
    [32] - R (N= 19), NR (N= 53)
    [33] - R (N= 12), NR (N=54)
    [34] - R (N= 26), NR (N=52)
    [35] - R (N= 28), NR (N=56)
    [36] - R (N= 29), NR (N=49)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (19) and ASP015K 25 mg (12).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.023 [37]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.39
    Notes
    [37] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF (tumor necrosis factor) use and geographic region (North America, Europe, Latin America).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (19) and ASP015K 50 mg (26).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 50 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.401 [38]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    2.8
    Notes
    [38] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (19) and ASP015K 100 mg (28).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 100 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.318 [39]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.86
    Notes
    [39] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (19) and ASP015K 150 mg (29).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.106 [40]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    3.29
    Notes
    [40] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).

    Secondary: Percentage of participants achieving American College of Rheumatology criteria for 70% improvement in disease severity (ACR70) response at Week 12

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    End point title
    Percentage of participants achieving American College of Rheumatology criteria for 70% improvement in disease severity (ACR70) response at Week 12
    End point description
    The study analysis population consisted of the FAS. ACR components were LOCF first and then the response was calculated. In addition, all patients with RA rescue therapy prior to or at week 12 were classified as non-responders. ACR70-CRP responder is defined as per ACR20 but using 70% instead of 20%.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects analysed
    72 [41]
    66 [42]
    78 [43]
    84 [44]
    78 [45]
    Units: percentage of participants
    number (not applicable)
        Responder (R)
    11.1
    9.1
    15.4
    16.7
    19.2
        Non-responder (NR)
    88.9
    90.9
    84.6
    83.3
    80.8
    Notes
    [41] - R (N= 8), NR (N= 64)
    [42] - R (N= 6), NR (N= 60)
    [43] - R (N= 12), NR (N= 66)
    [44] - R (N= 14), NR (N= 70)
    [45] - R (N= 15), NR (N= 63)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (8) and ASP015K 25 mg (6).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.202 [46]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    2.47
    Notes
    [46] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (8) and ASP015K 50 mg (12).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 50 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.723 [47]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    3.74
    Notes
    [47] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America)..
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (8) and ASP015K 100 mg (14).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 100 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.364 [48]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    4.23
    Notes
    [48] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    The total number of subjects in the statistical analysis are the responders in the Placebo group (8) and ASP015K 150 mg (15).
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.183 [49]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    4.7
    Notes
    [49] - The odds ratio (odds ratio > 1 favors ASP015K) and P value were based on a logistic regression model with effects for treatment group, prior anti-TNF use and geographic region (North America, Europe, Latin America).

    Secondary: Change from Baseline/Day 1 to Week 12/Early Termination (ET) in Disease Activity Score in 28 Joints score based on the c-reactive protein level (DAS28-CRP) score

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    End point title
    Change from Baseline/Day 1 to Week 12/Early Termination (ET) in Disease Activity Score in 28 Joints score based on the c-reactive protein level (DAS28-CRP) score
    End point description
    The study analysis population consisted of the FAS. DAS28-CRP was used to assess disease activity for RA. The DAS28-CRP score includes the TJC28 (refers to tender joint count based on 28 joints) and SJC28 (refers to swollen joint count based on 28 joints), the CRP level (measured in mg/dL will be converted to mg/L for analysis purposes) and the subject's general health (SGA, measured on 100 mm Visual Analog Scale [VAS]. Higher DAS28-CRP scores indicate greater disease activity. Missing DAS28 component values were imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo + weekly oral dose of MTX ASP015K 25 mg qd (once a day) + weekly oral dose of MTX ASP015K 50 mg qd + weekly oral dose of MTX ASP015K 100 mg qd + weekly oral dose of MTX ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects analysed
    72
    66
    78
    84
    78
    Units: units on a scale
        least squares mean (standard error)
    -1.38 ± 0.163
    -1.35 ± 0.169
    -1.84 ± 0.157
    -1.64 ± 0.151
    -2.01 ± 0.16
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Difference between Placebo vs. ASP015K 25 mg.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 25 mg qd (once a day) + weekly oral dose of MTX
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.894 [50]
    Method
    ANCOVA
    Parameter type
    Least Squares (LS) Mean of Difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.41
         upper limit
    0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.223
    Notes
    [50] - P value was based on an ANCOVA model: DAS28 Change = Treatment + Baseline DAS28 + Prior Anti-TNF Use + Geographic Region.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Difference between Placebo vs. ASP015K 50 mg.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 50 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.033 [51]
    Method
    Regression, Logistic
    Parameter type
    LS Mean of Difference
    Point estimate
    -0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.214
    Notes
    [51] - P value was based on an ANCOVA model: DAS28 Change = Treatment + Baseline DAS28 + Prior Anti-TNF Use + Geographic Region.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Difference between Placebo vs. ASP015K 100 mg.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 100 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.217 [52]
    Method
    ANCOVA
    Parameter type
    LS Mean of Difference
    Point estimate
    -0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.211
    Notes
    [52] - P value was based on an ANCOVA model: DAS28 Change = Treatment + Baseline DAS28 + Prior Anti-TNF Use + Geographic Region.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    Difference between Placebo vs. ASP015K 150 mg.
    Comparison groups
    Placebo + weekly oral dose of MTX v ASP015K 150 mg qd + weekly oral dose of MTX
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [53]
    Method
    ANCOVA
    Parameter type
    LS Mean of Difference
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.215
    Notes
    [53] - P value was based on an ANCOVA model: DAS28 Change = Treatment + Baseline DAS28 + Prior Anti-TNF Use + Geographic Region.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment-emergent AE (TEAE) was defined as any AE that started or worsened in severity after initial dose of study drug through the follow-up period.
    Adverse event reporting additional description
    An adverse event was any untoward medical occurrence in a patient administered a study drug and which did not necessarily have a causal relationship with the treatment. Adverse events were based on the Safety Analysis Set (SAF) population. The SAF was defined as all patients who received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo + MTX
    Reporting group description
    Reporting group 1 description

    Reporting group title
    ASP015K 25 mg + MTX
    Reporting group description
    Reporting group 2 description

    Reporting group title
    ASP015K 50 mg + MTX
    Reporting group description
    Reporting group 3 description

    Reporting group title
    ASP015K 100 mg + MTX
    Reporting group description
    Reporting group 4 description

    Reporting group title
    ASP015K 150 mg + MTX
    Reporting group description
    Reporting group 5 description

    Serious adverse events
    Placebo + MTX ASP015K 25 mg + MTX ASP015K 50 mg + MTX ASP015K 100 mg + MTX ASP015K 150 mg + MTX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 66 (0.00%)
    0 / 78 (0.00%)
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Pulmonary mass
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 66 (0.00%)
    0 / 78 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 66 (0.00%)
    0 / 78 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 66 (0.00%)
    0 / 78 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + MTX ASP015K 25 mg + MTX ASP015K 50 mg + MTX ASP015K 100 mg + MTX ASP015K 150 mg + MTX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 72 (18.06%)
    9 / 66 (13.64%)
    14 / 78 (17.95%)
    11 / 84 (13.10%)
    15 / 78 (19.23%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 66 (1.52%)
    4 / 78 (5.13%)
    2 / 84 (2.38%)
    2 / 78 (2.56%)
         occurrences all number
    1
    1
    4
    2
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 66 (6.06%)
    2 / 78 (2.56%)
    1 / 84 (1.19%)
    5 / 78 (6.41%)
         occurrences all number
    4
    4
    2
    1
    6
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 66 (3.03%)
    3 / 78 (3.85%)
    4 / 84 (4.76%)
    3 / 78 (3.85%)
         occurrences all number
    4
    2
    3
    5
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 66 (3.03%)
    5 / 78 (6.41%)
    4 / 84 (4.76%)
    6 / 78 (7.69%)
         occurrences all number
    5
    2
    5
    4
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2012
    The changes included in Amendment 1 are summarized below: ● Dosing instructions revised to state “take with food” ● Screening period extended to 4 weeks (28 days) ● The follow-up period for patient not rolling-over into the extension study extended to 30 days ● Clarifications and other administrative changes made. These changes to the protocol were included prior to the randomization of any patients.
    12 Jun 2012
    The changes included in Amendment 2 are summarized below: ● “Monotherapy” removed from trial design ● Allowed and prohibited concomitant medications updated ● Required washout periods for previous DMARDs updated ● Stratification by geographic region added ● Supine blood pressure requirement removed ● Estimated glomerular filtration rate (GFR) calculation added ● Use of dosing diary added ● Clarifications and other administrative changes made These changes to the protocol were included prior to the randomization of any patients.
    05 Dec 2012
    The changes included in Amendment 3 (Czech Republic-specific amendment) are summarized below: ● Age limitation to only enroll patients under the age of 65 years added ● Language regarding compliance with local practice and guidance for tuberculosis (TB) screening via purified protein derivative skin testing added These changes to the protocol were included prior to the randomization of any patients in this country.
    01 Apr 2013
    The changes included in Amendment 4 are summarized below: ● Number of planned sites revised ● Optional messenger RNA (mRNA) expression profiling included ● Allowed and prohibited concomitant medications updated ● Inclusion criteria revised to add contraception requirements for both men and women ● Exclusion criteria revised to include other malabsorption syndromes. ● Significant (absolute lymphocyte count [ALC] < 750/mm3) or severe (ALC < 500/mm3) lymphopenia added as an exclusion and discontinuation criteria, respectively ● Recording of prior rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) testing results added ● Clarifications and other administrative changes made These changes to the protocol were included after the randomization of 117 patients, but did not affect the overall outcome of the study.
    05 Jun 2013
    The changes included in Amendment 5 (Czech Republic-specific amendment) are summarized below: ● Inclusion criteria revised to include age cap at < 65 years This change to the protocol was included after the randomization of 11 patients in the Czech Republic, but did not affect the overall outcome of the study.

    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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