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    Clinical Trial Results:
    A 24-Week Randomized, Double Blind, Parallel Group, Active Comparator, Multicenter Study to Assess the Efficacy and Safety of PF-06650833, PF-06651600 (Ritlecitinib) and Tofacitinib Alone and in Combination in Participants With Moderately Severely Active Rheumatoid Arthritis (RA) With an Inadequate Response to Methotrexate

    Summary
    EudraCT number
    		 2019-002676-14
    Trial protocol
    		 SE   HU   SK   CZ   BG  
    Global end of trial date
    07 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2023
    First version publication date
    22 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B7921023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04413617
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, 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
    23 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of each of 2 combinations (PF-06650833 [zimlovisertib]+ PF-06651600 [ritlecitinib] and PF-06650833 [zimlovisertib]+ tofacitinib) individually to tofacitinib alone at Week 12 in participants with moderately - severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate.
    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 for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jul 2020
    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
    Bulgaria: 32
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Chile: 42
    Country: Number of subjects enrolled
    Czechia: 72
    Country: Number of subjects enrolled
    Georgia: 28
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Poland: 128
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Ukraine: 68
    Worldwide total number of subjects
    460
    EEA total number of subjects
    319
    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)
    403
    From 65 to 84 years
    57
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects with moderately to severely active RA were enrolled. Up to 25% of subjects were permitted to have a prior history of exposure to 1 and only 1 blocker of tumor necrosis factor (TNF) alpha; no other prior biologic disease modifying antirheumatic drug or Janus kinase inhibitor exposure was permitted.

    Pre-assignment
    Screening details
    		 A total of 626 subjects were screened, of which 460 subjects were randomized to treatment and received at least 1 dose of study intervention.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tofacitinib 11mg MR
    Arm description
    		 Subjects received tofacitinib 11mg as modified release (MR) tablets once daily (QD).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tofacitinib 11mg as MR tablets QD.

    Arm title
    		 PF-06651600 100mg
    Arm description
    		 Subjects received PF-06651600 100mg tablets QD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06651600
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06651600 50mg*2 tablets QD.

    Arm title
    		 PF-06650833 400mg MR
    Arm description
    		 Subjects received PF-06650833 400mg as MR tablets QD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06650833
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06650833 200mg*2 as MR tablets QD.

    Arm title
    		 PF-06650833 400mg MR + tofacitinib 11mg MR
    Arm description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with tofacitinib 11mg MR tablets QD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tofacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06650833 200*2mg MR tablets coadministered with tofacitinib 11mg MR tablets QD.

    Investigational medicinal product name
    PF-06650833
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06650833 200mg*2 MR tablets coadministered with tofacitinib 11mg MR tablets QD.

    Arm title
    		 PF-06650833 400mg MR + PF-06651600 100mg
    Arm description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with PF-06651600 100mg tablets QD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06651600
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06650833 200mg*2 MR tablets coadministered with PF-06651600 50mg*2 tablets QD.

    Investigational medicinal product name
    PF-06650833
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received PF-06650833 200mg*2 MR tablets coadministered with PF-06651600 50mg*2 tablets QD.

    Number of subjects in period 1
    		Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Started
    102
    77
    77
    103
    101
    Completed
    95
    71
    73
    95
    96
    Not completed
    7
    6
    4
    8
    5
         Adverse event, serious fatal
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    3
    4
    2
    5
    3
         Adverse event, non-fatal
    1
    -
    -
    1
    1
         COVID-19
    -
    1
    -
    -
    -
         Lack of efficacy
    2
    -
    2
    1
    -
         Protocol deviation
    -
    1
    -
    -
    1
         Refused to come for FU visit
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tofacitinib 11mg MR
    Reporting group description
    		 Subjects received tofacitinib 11mg as modified release (MR) tablets once daily (QD).

    Reporting group title
    PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06651600 100mg tablets QD.

    Reporting group title
    PF-06650833 400mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg as MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + tofacitinib 11mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with tofacitinib 11mg MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with PF-06651600 100mg tablets QD.

    Reporting group values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg Total
    Number of subjects
    		 102 77 77 103 101 460
    Age Categorical
    Units: Subjects
        18-44
    		 25 17 11 19 21 93
        45-64
    		 68 49 56 71 66 310
        >=65
    		 9 11 10 13 14 57
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.2 ( 10.63 ) 52.8 ( 10.90 ) 53.6 ( 9.87 ) 54.0 ( 10.41 ) 53.0 ( 10.40 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 82 62 61 78 73 356
        Male
    		 20 15 16 25 28 104
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 101 76 77 102 101 457
        Asian
    		 1 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 1 0 1
        Multiracial
    		 0 1 0 0 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tofacitinib 11mg MR
    Reporting group description
    		 Subjects received tofacitinib 11mg as modified release (MR) tablets once daily (QD).

    Reporting group title
    PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06651600 100mg tablets QD.

    Reporting group title
    PF-06650833 400mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg as MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + tofacitinib 11mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with tofacitinib 11mg MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with PF-06651600 100mg tablets QD.

    Primary: Change from baseline (BL) in Disease Activity Score (DAS)28-C Reactive protein (CRP) at Week 12

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    End point title
    		 Change from baseline (BL) in Disease Activity Score (DAS)28-C Reactive protein (CRP) at Week 12
    End point description
    DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale [VAS] scale of 0-100 mm), and CRP (milligram per liter). The lower the DAS28-CRP score is, the better the participant has response (remission = score<2.6, low disease activity = score≤3.2). Modified Intent to Treat (mITT) data set is used, which included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects were analyzed according to the randomized intervention. Subjects with non-missing data at a given visit were included.
    End point type
    Primary
    End point timeframe
    BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    96
    69
    71
    96
    93
    Units: Units on a scale
        least squares mean (confidence interval 90%)
    -2.30 (-2.49 to -2.11)
    -2.20 (-2.43 to -1.98)
    -1.82 (-2.04 to -1.60)
    -2.65 (-2.84 to -2.46)
    -2.35 (-2.54 to -2.15)
    Statistical analysis title
    		 Comparison for DAS28-CRP
    Statistical analysis description
    The primary clinical hypothesis is that mean decrease at Week 12 in DAS28-CRP score in one or both combo arms exceeds the mean decrease in the reference (tofacitinib) treatment arm, regardless of occurrence of intercurrent events. The null hypothesis is that the mean decrease in DAS28-CRP score at Week 12 is identical in the control (tofacitinib arm) and combination arms.
    Comparison groups
    PF-06650833 400mg MR + tofacitinib 11mg MR v Tofacitinib 11mg MR
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0158
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.163
    Notes
    [1] - Mixed Model Repeated Measures used the change from BL value of DAS28-CRP as an outcome and treatment, scheduled study visit, BL value of DAS28-CRP, treatment by visit interaction and BL by visit interaction as fixed effects. The model used the unstructured covariance matrix.
    Statistical analysis title
    		 Comparison for DAS28-CRP
    Statistical analysis description
    The primary clinical hypothesis is that mean decrease at Week 12 in DAS28-CRP score in one or both combo arms exceeds the mean decrease in the reference (tofacitinib) treatment arm, regardless of occurrence of intercurrent events. The null hypothesis is that the mean decrease in DAS28-CRP score at Week 12 is identical in the control (tofacitinib arm) and combination arms.
    Comparison groups
    PF-06650833 400mg MR + PF-06651600 100mg v Tofacitinib 11mg MR
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.3933
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.164
    Notes
    [2] - Mixed Model Repeated Measures used the change from BL value of DAS28-CRP as an outcome and treatment, scheduled study visit, BL value of DAS28-CRP, treatment by visit interaction and BL by visit interaction as fixed effects. The model used the unstructured covariance matrix.

    Secondary: DAS28-CRP remission (<2.6) rates at Week 24

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    End point title
    		 DAS28-CRP remission (<2.6) rates at Week 24
    End point description
    DAS28-CRP is derived using differential weighting given to 4 components: tender joint count, swollen joint count, patient global assessment, and CRP. Remission is defined as DAS28-CRP score <2.6. Remission rate = the number of responders (who had remission) / (number of responders + non-responders + non-responder assigned by non-responder imputation [NRI] after removal of missingness due to COVID-19 and missing components at a given visit). The NRI data set included responders, non-responders, and non-responder assigned by NRI after removal of missingness due to COVID-19 and missing components at a given visit.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    100
    76
    76
    103
    99
    Units: Percentage of subjects
        number (confidence interval 90%)
    24.0 (17.1 to 31.8)
    22.4 (14.8 to 31.3)
    11.8 (6.7 to 19.3)
    40.8 (32.6 to 48.7)
    31.3 (24.1 to 39.8)
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs), and discontinuation (DC) due to TEAEs

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    End point title
    		 Number of subjects with treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs), and discontinuation (DC) due to TEAEs
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious AE (SAE) was any untoward medical occurrence that: resulted in death; was life-threatening; required inpatient hospitalization/prolongation of hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect; or other serious situations. TEAEs were events between first dose of study drug and up to FU visit that were absent before treatment or worsened after treatment. AEs presented below were TEAEs. The investigator was required to use clinical judgment to assess the potential relationship between investigational product and each AE, to define an treatment-related AE. The safety analysis set is used, which included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From first dose of study intervention (Day 1) to Week 28
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    102
    77
    77
    103
    101
    Units: Subjects
        All-causality TEAEs
    60
    42
    38
    51
    55
        Treatment-related TEAEs
    15
    17
    13
    20
    25
        All-causality TESAEs
    3
    3
    3
    0
    1
        Treatment-related TESAEs
    0
    0
    0
    0
    0
        DC from study due to all-causality AEs
    2
    0
    0
    1
    1
        DC from study due to treatment-related AEs
    1
    0
    0
    1
    0
        Study drug withdrawal due to all-causality AEs
    0
    6
    6
    4
    6
        Study drug withdrawal due to treatment-related AEs
    0
    4
    4
    3
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with clinical laboratory abnormalities (hematology and chemistry, without regard to baseline abnormality)

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    End point title
    		 Number of subjects with clinical laboratory abnormalities (hematology and chemistry, without regard to baseline abnormality)
    End point description
    Clinical laboratory abnormality was determined at the investigator's discretion. The analysis set included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects with evaluable laboratory values were analyzed. Due to system limitation, for some lab parameters, the actual number of subjects analyzed were not 101, 77, 77, 101, 101 and were denoted in the paramter.
    End point type
    Secondary
    End point timeframe
    From BL to Week 28
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    101
    77
    77
    101
    101
    Units: Subjects
        Hemoglobin<0.8xLLN
    2
    2
    0
    2
    2
        Erythrocytes<0.8xLLN
    0
    2
    0
    0
    0
        Ery. Mean Corpuscular Volume <0.9xLLN
    3
    2
    0
    2
    0
        Ery. Mean Corpuscular Volume >1.1xULN
    4
    3
    4
    3
    4
        Ery. Mean Corpuscular HGB<0.9xLLN
    8
    5
    3
    7
    4
        Ery. Mean Corpuscular HGB Conc. <0.9xLLN
    8
    6
    12
    10
    4
        Platelets>1.75xULN
    0
    0
    0
    1
    0
        Reticulocytes/Erythrocytes>1.5xULN
    2
    1
    2
    1
    1
        Leukocytes<0.6xLLN
    0
    1
    0
    0
    1
        Leukocytes>1.5xULN
    2
    2
    1
    1
    3
        Lymphocytes<0.8xLLN
    7
    16
    3
    6
    13
        Lymphocytes>1.2xULN
    3
    2
    1
    1
    2
        Lymphocytes/Leukocytes<0.8xLLN
    6
    11
    9
    6
    10
        Lymphocytes/Leukocytes>1.2xULN
    1
    1
    1
    5
    3
        Neutrophils<0.8xLLN
    2
    2
    3
    5
    4
        Neutrophils>1.2xULN
    11
    16
    8
    5
    14
        Neutrophils/Leukocytes<0.8xLLN
    1
    0
    0
    2
    1
        Neutrophils/Leukocytes>1.2xULN
    5
    9
    6
    3
    7
        Basophils>1.2xULN
    0
    0
    1
    1
    0
        Eosinophils>1.2xULN
    0
    0
    3
    1
    0
        Eosinophils/Leukocytes>1.2xULN
    1
    0
    5
    4
    1
        Monocytes>1.2xULN
    2
    1
    1
    0
    2
        Monocytes/Leukocytes>1.2xULN
    8
    12
    6
    11
    17
        Activated PTT>1.1xULN (n=101,77,77,102,101)
    9
    9
    9
    10
    10
        Prothrombin Time>1.1xULN (n=101,77,77,102,101)
    7
    6
    6
    2
    9
        ESR>1.5xULN (n=101,77,77,102,101)
    72
    59
    58
    71
    63
        Bilirubin>1.5xULN (n=101,77,77,102,101)
    2
    0
    0
    0
    0
        AST>3.0xULN (n=101,77,77,102,101)
    0
    0
    2
    1
    0
        ALT>3.0xULN (n=101,77,77,102,101)
    0
    1
    7
    2
    0
        Urea Nitrogen>1.3xULN (n=101,77,77,102,101)
    4
    1
    5
    4
    2
        Creatinine >1.3xULN (n=101,77,77,102,101)
    0
    0
    0
    1
    0
        Urate>1.2xULN (n=101,77,77,102,101)
    3
    2
    2
    4
    1
        Cholesterol>1.3xULN (n=94,71,73,100,91)
    22
    13
    10
    24
    20
        HDL Cholesterol <0.8xLLN (n=94,70,69,98.90)
    1
    3
    1
    0
    1
        LDL Cholesterol>1.2xULN (n=92,70,68,98,88)
    9
    5
    1
    5
    8
        Sodium<0.95xLLN (n=101,77,77,102,101)
    0
    1
    0
    0
    0
        Potassium<0.9xLLN (n=101,77,77,102,101)
    0
    1
    2
    0
    1
        Potassium>1.1xULN (n=101,77,77,102,101)
    2
    3
    0
    1
    1
        Chloride<0.9xLLN (n=101,77,77,102,101)
    0
    1
    0
    0
    0
        Calcium<0.9xLLN (n=101,77,77,102,101)
    0
    0
    0
    0
    1
        Bicarbonate<0.9xLLN (n=101,77,77,102,101)
    4
    2
    0
    3
    2
        Creatine Kinase>2.0xULN (n=101,77,77,102,101)
    4
    7
    1
    10
    9
        Troponin I>1.0xULN (n=101,77,77,102,101)
    2
    3
    2
    4
    4
        Glucose-FASTING>1.5xULN (n=101,77,77,102,101)
    3
    5
    10
    10
    2
        Triglycerides-FASTING>1.3xULN (n=94,71,73,100,91)
    9
    7
    4
    7
    5
        Apolipoprotein A1>1.5xULN (n=93,68,66,93,87)
    0
    1
    0
    0
    0
        Apolipoprotein B>1.5xULN (n=93,68,66,93,87)
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with change from baseline in vital signs data meeting the pre-defined categorical summarization criteria

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    End point title
    		 Number of subjects with change from baseline in vital signs data meeting the pre-defined categorical summarization criteria
    End point description
    Abnormality in change from BL in vital signs included: sitting/semi-supine diastolic blood pressure (BP) increase and decrease from BL of >=20mmHg, systolic BP increase and decrease from BL of >=30mmHg. The safety analysis set is used, which included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects with evaluable vital signs data were analyzed.
    End point type
    Secondary
    End point timeframe
    From BL to Week 28
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    101
    77
    77
    102
    101
    Units: Subjects
        Diastolic BP increase >=20mmHg
    1
    2
    3
    6
    3
        Diastolic BP decrease >=20mmHg
    0
    0
    0
    0
    0
        Systolic BP increase >=30mmHg
    1
    3
    4
    2
    3
        Systolic BP decrease >=30mmHg
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events of special interest

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    End point title
    		 Number of subjects with adverse events of special interest
    End point description
    These AEs included severe and opportunistic infection AEs; herpes virus infection AEs; clinically significant categorical increases in hepatic enzymes AST, and ALT and total bilirubin, and potential cases meeting Hy’s Law criteria for increased risk of drug induced liver injury (DILI); major adverse cardiovascular events, including pulmonary embolism and deep vein thrombosis, cerebrovascular accident ; AEs for decreased renal function, acute kidney injury, clinically significant increases in serum creatinine (Scr) and decreases in estimated glomerular filtration rate (eGFR). Only subjects with AEs mentioned above were reported. The safety analysis set is used, which included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From first dose of study intervention (Day 1) to Week 28
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    102
    77
    77
    103
    101
    Units: Subjects
        Herpes Zoster
    1
    1
    0
    2
    0
        Oral Herpes
    1
    0
    0
    1
    2
        ALT Increased
    0
    0
    3
    2
    0
        AST Increased
    0
    0
    2
    2
    0
        Hyperbilirubinaemia
    1
    0
    0
    0
    0
        Transaminases Increased
    0
    0
    1
    0
    0
        Hepatic Enzyme Increased
    0
    0
    1
    0
    0
        Liver Injury
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in DAS28-CRP at Week 24

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    End point title
    		 Change from baseline in DAS28-CRP at Week 24
    End point description
    DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale [VAS] scale of 0-100 mm), and CRP (milligram per liter). The lower the DAS28-CRP score is, the better the participant has response (remission = score<2.6, low disease activity = score≤3.2). mITT data set is used, which included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects were analyzed according to the randomized intervention. Subjects with non-missing data at a given visit were included.
    End point type
    Secondary
    End point timeframe
    BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 24
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    80
    54
    49
    84
    73
    Units: Units on a scale
        least squares mean (confidence interval 90%)
    -2.66 (-2.88 to -2.45)
    -2.53 (-2.78 to -2.28)
    -2.26 (-2.51 to -2.00)
    -3.05 (-3.26 to -2.85)
    -2.87 (-3.08 to -2.65)
    No statistical analyses for this end point

    Secondary: American College of Rheumatology (ACR)20, ACR 50, ACR 70, and ACR 90 responder rates at Week 12 and Week 24

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    End point title
    		 American College of Rheumatology (ACR)20, ACR 50, ACR 70, and ACR 90 responder rates at Week 12 and Week 24
    End point description
    The American College of Rheumatology’s definition for calculating improvement in rheumatoid arthritis (ACR20) is calculated as a >=20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and CRP. Similarly, ACR50, ACR70, and ACR 90 were calculated with the respective percent improvement. Responder rate = number of responders (who had ACR20/50/70/90 response)/(number of responders + non-responders + non-responder assigned by NRI after removal of missingness due to COVID-19 and missing components at a given visit). NRI data set is used, which included responders, non-responders, and non-responder assigned by NRI after removal of missingness due to COVID-19 and missing components at a given visit. Due to system limit, the actual number of subjects analyzed for each parameter is denoted beside the parmater.
    End point type
    Secondary
    End point timeframe
    BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    102
    77
    77
    103
    101
    Units: Percentage of subjects
    number (confidence interval 90%)
        ACR20 (Week 12) (n =103,101,101,77,76)
    83.17 (75.94 to 88.98)
    72.73 (63.80 to 80.94)
    75.00 (66.26 to 82.24)
    86.41 (79.94 to 91.59)
    79.21 (71.99 to 85.62)
        ACR50 (Week 12) (n=102,101,101,77,76)
    46.53 (38.04 to 55.19)
    44.16 (34.59 to 54.16)
    38.16 (29.16 to 47.81)
    62.75 (54.69 to 70.75)
    54.46 (45.79 to 62.57)
        ACR70 (Week 12) (n=103,101,101,77,76)
    23.76 (16.96 to 31.42)
    18.18 (11.34 to 26.08)
    10.53 (5.39 to 18.17)
    21.36 (15.35 to 28.95)
    25.74 (19.17 to 33.29)
        ACR90 (Week 12) (n=103,101,101,77,76)
    0.99 (0.10 to 4.12)
    1.30 (0.14 to 5.32)
    1.32 (0.14 to 5.39)
    2.91 (1.07 to 6.86)
    3.96 (1.74 to 8.58)
        ACR20 (Week 24) (n=103,100,101,77,76)
    75.25 (67.64 to 82.11)
    67.53 (57.99 to 76.32)
    55.26 (45.20 to 65.01)
    75.73 (68.31 to 82.41)
    70.00 (61.87 to 77.31)
        ACR50 (Week 24) (n=103,100,101,77,76)
    65.35 (57.14 to 73.21)
    54.55 (44.56 to 63.80)
    43.42 (33.74 to 53.50)
    65.05 (57.08 to 72.34)
    65.00 (56.68 to 72.92)
        ACR70 (Week 24) (n=103,100,101,77,76)
    44.55 (36.60 to 53.22)
    31.17 (22.51 to 40.74)
    27.63 (19.32 to 36.52)
    45.63 (37.25 to 54.20)
    44.00 (35.61 to 52.72)
        ACR90 (Week 24) (n=103,100,101,77,76)
    9.90 (5.58 to 16.09)
    5.19 (2.28 to 11.34)
    1.32 (0.14 to 5.39)
    12.62 (8.05 to 19.19)
    18.00 (12.27 to 25.23)
    No statistical analyses for this end point

    Secondary: Change from baseline in the Tender/Painful and Swollen Joint Count at Week 12 and Week 24

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    End point title
    		 Change from baseline in the Tender/Painful and Swollen Joint Count at Week 12 and Week 24
    End point description
    Tender/Painful Joint Count 68 (TJC68) was assessed by a blinded joint assessor to determine the number of joints considered tender/painful in upper body, upper/lower extremity. The response to pressure/motion on each joint was assessed using: Present/Absent/Not Done/Not Applicable (for artificial/missing joints). The 28-joints set is the subset of 68 joints set including the following joints: shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and knees. TJC28 was calculated by Pfizer from TJC68. Higher scores indicate higher level of disability. mITT data set is used, including all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects with non-missing data at a given visit were included and were analyzed according to the randomized intervention. Due to system limit, the actual number of subjects analyzed for each paramter was denoted beside the parmater.
    End point type
    Secondary
    End point timeframe
    BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    102
    77
    77
    103
    101
    Units: Joints
    least squares mean (confidence interval 90%)
        TJC28 (Week 12) (n=100,93,96,69,72)
    -9.84 (-10.63 to -9.05)
    -9.83 (-10.76 to -8.91)
    -8.82 (-9.73 to -7.92)
    -9.87 (-10.65 to -9.09)
    -9.78 (-10.58 to -8.98)
        TJC68 (Week 12) (n=100,93,96,69,72)
    -15.32 (-16.47 to -14.18)
    -14.80 (-16.13 to -13.46)
    -13.76 (-15.07 to -12.46)
    -14.96 (-16.09 to -13.83)
    -15.66 (-16.81 to -14.50)
        SJC28 (Week 12) (n=100,93,96,69,72)
    -7.86 (-8.41 to -7.30)
    -8.30 (-8.95 to -7.65)
    -7.80 (-8.44 to -7.15)
    -8.61 (-9.16 to -8.06)
    -8.16 (-8.73 to -7.60)
        SJC66 (Week 12) (n=100,93,96,69,72)
    -10.34 (-11.05 to -9.63)
    -10.75 (-11.58 to -9.92)
    -10.18 (-11.00 to -9.37)
    -11.29 (-11.99 to -10.59)
    -10.90 (-11.62 to -10.19)
        TJC28 (Week 24) (n=84,74,81,55,49)
    -10.60 (-11.34 to -9.86)
    -10.47 (-11.34 to -9.59)
    -10.31 (-11.20 to -9.42)
    -11.33 (-12.06 to -10.61)
    -11.44 (-12.20 to -10.68)
        TJC68 (Week 24) (n=84,74,81,55,49)
    -16.76 (-17.88 to -15.64)
    -16.69 (-18.02 to -15.36)
    -15.79 (-17.13 to -14.46)
    -16.68 (-17.78 to -15.57)
    -17.68 (-18.82 to -16.53)
        SJC28 (Week 24) (n=84,74,81,55,49)
    -8.76 (-9.29 to -8.24)
    -8.71 (-9.33 to -8.08)
    -8.28 (-8.92 to -7.65)
    -8.83 (-9.34 to -8.31)
    -9.44 (-9.98 to -8.90)
        SJC66 (Week 24) (n=84,74,81,55,49)
    -11.59 (-12.21 to -10.97)
    -11.45 (-12.19 to -10.71)
    -11.10 (-11.86 to -10.34)
    -11.41 (-12.02 to -10.80)
    -12.38 (-13.03 to -11.74)
    No statistical analyses for this end point

    Secondary: Change from baseline in the Physician’s Global Assessment (PhGA) of Arthritis at Week 12 and Week 24

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    End point title
    		 Change from baseline in the Physician’s Global Assessment (PhGA) of Arthritis at Week 12 and Week 24
    End point description
    PhGA of Arthritis is an evaluation done by investigator based on the subject's disease signs, functional capacity and physical examination, and should be independent of the Patient’s Global Assessment of Arthritis. The investigator’s response was recorded using a 100 mm visual analog scale (VAS). Higher scores indicate higher level of disability. mITT data set is used, which included all subjects randomly assigned to study intervention and who took at least 1 dose of study intervention. Subjects were analyzed according to the randomized intervention. Subjects with non-missing data at a given visit were included. Due to system limit, the actual number of subjects analyzed for each parameter is denoted beside the parameter.
    End point type
    Secondary
    End point timeframe
    BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
    End point values
    		 Tofacitinib 11mg MR PF-06651600 100mg PF-06650833 400mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg
    Number of subjects analysed
    102
    77
    77
    103
    101
    Units: Units on a scale
    least squares mean (confidence interval 90%)
        PhGA of Arthritis (Week 12) (n=100,93,96,69,72)
    -40.86 (-43.72 to -38.00)
    -38.62 (-41.95 to -35.28)
    -31.56 (-34.82 to -28.30)
    -43.50 (-46.32 to -40.69)
    -41.20 (-44.06 to -38.34)
        PhGA of Arthritis (Week 24) (n=84,74,81,55,49)
    -47.31 (-49.98 to -44.63)
    -43.42 (-46.60 to -40.25)
    -39.27 (-42.49 to -36.05)
    -47.50 (-50.13 to -44.87)
    -48.21 (-50.95 to -45.47)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study intervention (Day 1) to Week 28
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06651600 100mg tablets QD.

    Reporting group title
    Tofacitinib 11mg MR
    Reporting group description
    		 Subjects received tofacitinib 11mg MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + tofacitinib 11mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with tofacitinib 11mg MR tablets QD.

    Reporting group title
    PF-06650833 400mg MR + PF-06651600 100mg
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets coadministered with PF-06651600 100mg tablets QD.

    Reporting group title
    PF-06650833 400mg MR
    Reporting group description
    		 Subjects received PF-06650833 400mg MR tablets QD.

    Serious adverse events
    		 PF-06651600 100mg Tofacitinib 11mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg PF-06650833 400mg MR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 102 (2.94%)
    0 / 103 (0.00%)
    1 / 101 (0.99%)
    3 / 77 (3.90%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin squamous cell carcinoma recurrent
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    1 / 77 (1.30%)
         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
    Uterine polyp
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    1 / 77 (1.30%)
         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
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    1 / 77 (1.30%)
         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
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    1 / 77 (1.30%)
         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
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 101 (0.99%)
    0 / 77 (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
    Coronavirus infection
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 101 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    		 PF-06651600 100mg Tofacitinib 11mg MR PF-06650833 400mg MR + tofacitinib 11mg MR PF-06650833 400mg MR + PF-06651600 100mg PF-06650833 400mg MR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 77 (23.38%)
    24 / 102 (23.53%)
    19 / 103 (18.45%)
    26 / 101 (25.74%)
    11 / 77 (14.29%)
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 77 (1.30%)
    7 / 102 (6.86%)
    4 / 103 (3.88%)
    8 / 101 (7.92%)
    2 / 77 (2.60%)
         occurrences all number
    1
    7
    4
    8
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 102 (3.92%)
    3 / 103 (2.91%)
    7 / 101 (6.93%)
    2 / 77 (2.60%)
         occurrences all number
    4
    4
    3
    7
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 77 (6.49%)
    4 / 102 (3.92%)
    1 / 103 (0.97%)
    3 / 101 (2.97%)
    2 / 77 (2.60%)
         occurrences all number
    5
    4
    3
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 77 (6.49%)
    3 / 102 (2.94%)
    2 / 103 (1.94%)
    2 / 101 (1.98%)
    1 / 77 (1.30%)
         occurrences all number
    5
    3
    2
    2
    1
    Rheumatoid arthritis
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 102 (2.94%)
    1 / 103 (0.97%)
    1 / 101 (0.99%)
    4 / 77 (5.19%)
         occurrences all number
    4
    3
    1
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 77 (2.60%)
    3 / 102 (2.94%)
    3 / 103 (2.91%)
    6 / 101 (5.94%)
    1 / 77 (1.30%)
         occurrences all number
    2
    4
    3
    6
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
    5 / 102 (4.90%)
    7 / 103 (6.80%)
    3 / 101 (2.97%)
    1 / 77 (1.30%)
         occurrences all number
    1
    7
    9
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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