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    Clinical Trial Results:
    A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of Oral CP-690, 550 as an Induction Therapy in Subjects With Moderate to Severe Ulcerative Colitis

    Summary
    EudraCT number
    2011-004579-35
    Trial protocol
    GB   CZ   HU   EE   DK   LV   BE   ES   NL   AT   DE   SK   PL   HR  
    Global end of trial date
    09 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    15 May 2016
    First version publication date
    15 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A3921095
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01458951
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    12 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of tofacitinib in inducing remission in subjects with moderately to severely active Ulcerative Colitis (UC).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    Subjects were permitted to continue stable doses of the following during the study: oral 5-ASA or sulfasalazine, oral corticosteroids up to 25 mg/day prednisone equivalent, and/or chronic antibiotics for UC treatment.
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Jun 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
    Australia: 22
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 58
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Netherlands: 37
    Country: Number of subjects enrolled
    New Zealand: 17
    Country: Number of subjects enrolled
    Poland: 46
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Slovakia: 28
    Country: Number of subjects enrolled
    South Africa: 18
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    547
    EEA total number of subjects
    268
    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)
    517
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects were randomized to tofacitinib 10 milligram (mg) or placebo twice a day (BID) (4:1 ratio) after Protocol Amendment 2, which removed tofacitinib 15 mg BID. Due to low subject numbers, tofacitinib 15 mg BID was excluded from efficacy analyses, but was included in subject disposition, baseline characteristics and adverse events analyses.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tofacitinib 10 mg BID
    Arm description
    Subjects received tofacitinib 10 mg tablets orally BID for 9 weeks of double blind treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib 10 mg BID for 9 weeks of double blind treatment period.

    Arm title
    Tofacitinib 15 mg BID
    Arm description
    Subjects received tofacitinib 15 mg tablets orally BID for 9 weeks of double blind treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib 15 mg tablets orally BID for 9 weeks of double blind treatment period.

    Arm title
    Placebo BID
    Arm description
    Subjects received tofacitinib-matched placebo tablets orally BID for 9 weeks of double blind treatment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Tofacitinib­-matched placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib­ matched placebo tablets orally BID for 9 weeks of double blind treatment period.

    Number of subjects in period 1
    Tofacitinib 10 mg BID Tofacitinib 15 mg BID Placebo BID
    Started
    429
    6
    112
    Completed
    397
    5
    97
    Not completed
    32
    1
    15
         Protocol deviation
    5
    1
    -
         Insufficient Clinical Response
    17
    -
    11
         Consent withdrawn by subject
    2
    -
    2
         Unspecified
    1
    -
    -
         Adverse Event
    7
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    Subjects received tofacitinib 10 mg tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Tofacitinib 15 mg BID
    Reporting group description
    Subjects received tofacitinib 15 mg tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Placebo BID
    Reporting group description
    Subjects received tofacitinib-matched placebo tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group values
    Tofacitinib 10 mg BID Tofacitinib 15 mg BID Placebo BID Total
    Number of subjects
    429 6 112 547
    Age categorical
    Units: Subjects
        18 to 44 Years
    265 5 72 342
        45 to 64 Years
    139 1 35 175
        Greater Than or Equal to (>=) 65 Years
    25 0 5 30
    Gender, Male/Female
    Units: Subjects
        Female
    170 3 57 230
        Male
    259 3 55 317

    End points

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    End points reporting groups
    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    Subjects received tofacitinib 10 mg tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Tofacitinib 15 mg BID
    Reporting group description
    Subjects received tofacitinib 15 mg tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Placebo BID
    Reporting group description
    Subjects received tofacitinib-matched placebo tablets orally BID for 9 weeks of double blind treatment period.

    Primary: Percentage of Subjects With Remission at Week 8

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    End point title
    Percentage of Subjects With Remission at Week 8 [1]
    End point description
    Remission in subjects was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and physician global assessment (PGA), each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [1] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    16.6
    3.6
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on Cochran-Mantel Haenszel (CMH) chi-square test stratified by prior treatment with anti-tumor necrosis factor (TNF), steroid use at baseline and geographic region. Percentage difference and its 95 percent Confidence interval (CI) was based on normal approximation for the difference in binomial proportions. Missing data were imputed using non-responder imputation (NRI).
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.1
         upper limit
    17.9

    Secondary: Percentage of Subjects Achieving Mucosal Healing at Week 8

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    End point title
    Percentage of Subjects Achieving Mucosal Healing at Week 8 [2]
    End point description
    Mucosal healing in subjects was defined by Mayo endoscopic subscore of 0 or 1. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [2] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    28.4
    11.6
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    16.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.5
         upper limit
    24.1

    Secondary: Percentage of Subjects Achieving Clinical Response at Week 8

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    End point title
    Percentage of Subjects Achieving Clinical Response at Week 8 [3]
    End point description
    Clinical response in subjects was defined by a decrease from baseline in Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the rectal bleeding sub score of at least 1 point or an absolute rectal bleeding sub score of 0 or 1. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible centrally read proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [3] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    55
    28.6
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    26.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.8
         upper limit
    36

    Secondary: Percentage of Subjects With Endoscopic Remission at Week 8

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    End point title
    Percentage of Subjects With Endoscopic Remission at Week 8 [4]
    End point description
    Endoscopic remission in subjects was defined by Mayo endoscopic subscore of 0. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [4] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    7
    1.8
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0425
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    5.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.8
         upper limit
    8.6

    Secondary: Percentage of Subjects With Clinical Remission at Week 8

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    End point title
    Percentage of Subjects With Clinical Remission at Week 8 [5]
    End point description
    Clinical remission in subjects was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible centrally read proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [5] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    16.8
    3.6
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    13.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.3
         upper limit
    18.1

    Secondary: Percentage of Subjects With Symptomatic Remission at Week 8

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    End point title
    Percentage of Subjects With Symptomatic Remission at Week 8 [6]
    End point description
    Symptomatic remission was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and 0 subscore for both rectal bleeding and stool frequency. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible centrally read proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicated more severe disease. Full analysis set indicating all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [6] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    10.7
    2.7
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.9
         upper limit
    12.2

    Secondary: Percentage of Subjects With Deep Remission at Week 8

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    End point title
    Percentage of Subjects With Deep Remission at Week 8 [7]
    End point description
    Deep remission in subjects was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and 0 subscore for both rectal bleeding and endoscopic subscores. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible centrally read proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID.
    End point type
    Secondary
    End point timeframe
    Week 8
    Notes
    [7] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: percentage of subjects
        number (not applicable)
    5.1
    1.8
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    P-value was based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Percentage difference and its 95% CI was based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1408
    Method
    CMH Chi-square Test
    Parameter type
    Percentage difference
    Point estimate
    3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    6.6

    Secondary: Partial Mayo Scores

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    End point title
    Partial Mayo Scores [8]
    End point description
    A partial mayo score (mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) and each grading from 0 to 3 with higher scores indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, ‘n’ signifies those subjects who were evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8
    Notes
    [8] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 428, 112 )
    6.4 ± 1.3
    6.4 ± 1.2
        Week 2 (n= 419, 107 )
    4.4 ± 2.2
    5.4 ± 1.7
        Week 4 (n= 412, 102 )
    3.7 ± 2.3
    4.8 ± 2
        Week 8 (n= 401, 98 )
    3.3 ± 2.3
    4.5 ± 2.1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8

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    End point title
    Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 [9]
    End point description
    Change in Partial Mayo scores at Weeks 2, 4, 8 relative to baseline were reported. A Partial Mayo Score (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each graded from 0 to 3 with higher scores indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, ‘n’ signifies those subjects who were evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8
    Notes
    [9] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 2 (n= 418, 107 )
    -2 ± 0.1
    -1 ± 0.2
        Change at Week 4 (n= 411, 102 )
    -2.7 ± 0.1
    -1.5 ± 0.2
        Change at Week 8 (n= 400, 98 )
    -3 ± 0.1
    -1.7 ± 0.2
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 2
    Statistical analysis description
    The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and subjects as a random effect.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least square mean difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 4
    Statistical analysis description
    The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and subjects as a random effect.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least square mean difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and subjects as a random effect.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least square mean difference
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2

    Secondary: Change From Baseline in Total Mayo Score at Week 8

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    End point title
    Change From Baseline in Total Mayo Score at Week 8 [10]
    End point description
    Change in total Mayo score at Week 8 relative to baseline was reported. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of flexible centrally read proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher score indicating more severe disease. Full analysis set included all subjects who were randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, ‘n’ signifies those subjects who were evaluable at specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    Notes
    [10] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Tofacitinib 10 mg BID Placebo BID
    Number of subjects analysed
    429
    112
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=428,112)
    9 ± 1.5
    8.9 ± 1.5
        Change at Week 8 (n=396,98)
    -3.7 ± 2.8
    -2 ± 2.4
    Statistical analysis title
    Tofacitinib 10 mg BID vs. Placebo BID at Week 8
    Statistical analysis description
    The change from baseline at Week 8 was analyzed using an analysis of covariance (ANCOVA) model with treatment group, prior treatment with anti-TNF, steroid use at baseline and geographic region as factors and baseline as a covariate based on the observed-case data.
    Comparison groups
    Tofacitinib 10 mg BID v Placebo BID
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    -1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 98
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and an serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non serious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Tofacitinib 10 mg BID
    Reporting group description
    Subjects received tofacitinib 10 mg tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Placebo BID
    Reporting group description
    Subjects received tofacitinib-matched placebo tablets orally BID for 9 weeks of double blind treatment period.

    Reporting group title
    Tofacitinib 15 mg BID
    Reporting group description
    Subjects received tofacitinib 15 mg tablets orally BID for 9 weeks of double blind treatment period.

    Serious adverse events
    Tofacitinib 10 mg BID Placebo BID Tofacitinib 15 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 429 (4.20%)
    9 / 112 (8.04%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Femur fracture
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Hip fracture
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Colon neoplasm
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 112 (0.89%)
    0 / 6 (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
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 112 (0.89%)
    0 / 6 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Chills
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 429 (0.47%)
    0 / 112 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 112 (0.89%)
    0 / 6 (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
    Colitis ulcerative
         subjects affected / exposed
    8 / 429 (1.86%)
    4 / 112 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Crohn’s disease
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Intestinal perforation
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 112 (0.89%)
    0 / 6 (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
    Proctalgia
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 429 (0.00%)
    1 / 112 (0.89%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    0 / 6 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tofacitinib 10 mg BID Placebo BID Tofacitinib 15 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 429 (15.85%)
    20 / 112 (17.86%)
    4 / 6 (66.67%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 429 (0.23%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    Investigations
    Urine analysis abnormal
         subjects affected / exposed
    0 / 429 (0.00%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 429 (2.56%)
    2 / 112 (1.79%)
    1 / 6 (16.67%)
         occurrences all number
    11
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 429 (7.69%)
    9 / 112 (8.04%)
    0 / 6 (0.00%)
         occurrences all number
    41
    9
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 429 (1.63%)
    6 / 112 (5.36%)
    0 / 6 (0.00%)
         occurrences all number
    7
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    7 / 429 (1.63%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 429 (2.56%)
    6 / 112 (5.36%)
    0 / 6 (0.00%)
         occurrences all number
    12
    6
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 429 (1.63%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 429 (0.00%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 429 (0.00%)
    0 / 112 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2012
    Tofacitinib 15 mg BID arm was removed. Prior to this, subjects were randomized to tofacitinib 10 mg BID, tofacitinib 15 mg BID, or placebo BID (2:2:1 ratio).

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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