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Clinical Trial Results:
A Phase 3B/4 Randomized Double Blind Placebo Controlled Study of Methotrexate (MTX) Withdrawal in Subjects With Rheumatoid Arthritis (RA) Treated With Tofacitinib 11mg Modified Release (MR) Formulation

Summary
EudraCT number	2016-001825-15
Trial protocol	SK BG BE DE GB PL ES CZ HU IT
Global end of trial date	17 Dec 2018

Results information
Results version number	v1(current)
This version publication date	18 Dec 2019
First version publication date	18 Dec 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A3921192

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 May 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Nov 2018

Global end of trial reached?

Yes

Global end of trial date

17 Dec 2018

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of tofacitinib MR 11mg monotherapy to tofacitinib MR 11mg with continued MTX, as measured by the change in the Disease Activity Score utilizing 4 components including erythrocyte sedimentation rate (DAS28-4 [ESR]) from randomization (at Week 24) to the end of the double-blind MTX withdrawal phase (at Week 48).

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 Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 25

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Bulgaria: 49

Country: Number of subjects enrolled

Czech Republic: 60

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Hungary: 30

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 17

Country: Number of subjects enrolled

Philippines: 12

Country: Number of subjects enrolled

Poland: 130

Country: Number of subjects enrolled

Russian Federation: 37

Country: Number of subjects enrolled

Slovakia: 22

Country: Number of subjects enrolled

South Africa: 2

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

United States: 276

Worldwide total number of subjects

694

EEA total number of subjects

318

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

508

From 65 to 84 years

184

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 136 sites in the 16 countries from 01 September 2016 to 17 December 2018.

Screening details

A total of 873 subjects were screened in the open label phase. 694 subjects were treated.

Period 1 title

Open Label Phase (24 Weeks)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Open Label: Tofacitinib 11 mg + Methotrexate

Arm description

Subjects with moderate to severe rheumatoid arthritis (RA) and who were insufficiently responding to their stable dose of methotrexate treatment previous to enrollment in this study, received Tofacitinib modified release (MR) 11 milligram (mg) tablet once daily (QD) with methotrexate (as background therapy) at their previous stable dose for 24 weeks in open label phase (OL).

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 MR 11 mg tablet QD for 24 weeks in open label phase.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received methotrexate at their previous stable dose for 24 weeks in open label phase.

Number of subjects in period 1	Open Label: Tofacitinib 11 mg + Methotrexate
Started	694
Completed	623
Not completed	71
Consent withdrawn by subject	6
Adverse event, non-fatal	39
Insufficient Clinical Response	7
Medication error,no linked adverse event	2
Unspecified	4
Lost to follow-up	8
Protocol deviation	5

Period 2 title

Double Blind Phase (24 Weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo

Arm description

Subjects with low disease activity (LDA) at the end of open label phase were randomized to receive Tofacitinib MR 11 mg tablet once daily with matching placebo to blinded methotrexate at their previously stabilized dose for 24 weeks in double blind phase.

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 MR 11 mg tablet QD for 24 weeks in double blind phase.

Investigational medicinal product name

Methotrexate Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received methotrexate matching placebo at their previous stable dose for 24 weeks in double blind phase.

Double Blind: Tofacitinib 11 mg + Methotrexate

Arm description

Subjects with LDA at the end of open label phase received Tofacitinib MR 11 mg tablet once daily with blinded methotrexate at their previously stabilized dose for 24 weeks in double blind phase.

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 MR 11 mg tablet QD for 24 weeks in double blind phase.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received methotrexate at their previous stable dose for 24 weeks in double blind phase.

Number of subjects in period 2	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Started	267	266
Treated	264	266
Completed	238	247
Not completed	29	19
Adverse event, serious fatal	-	2
Consent withdrawn by subject	5	2
Screen Failure	1	-
Adverse event, non-fatal	6	6
Insufficient Clinical Response	6	1
Randomized but not Treated	3	-
Unspecified	2	5
Lost to follow-up	1	1
Protocol deviation	5	2

Baseline characteristics

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Reporting group title

Open Label: Tofacitinib 11 mg + Methotrexate

Reporting group description

Reporting group values	Open Label: Tofacitinib 11 mg + Methotrexate	Total
Number of subjects	694	694
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	508	508
From 65-84 years	184	184
85 years and over	2	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	56.77 ± 11.83	-
Sex: Female, Male
Units: Subjects
Female	532	532
Male	162	162
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	37	37
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	33	33
White	594	594
More than one race	0	0
Other	30	30
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	59	59
Not Hispanic or Latino	635	635
Unknown or Not Reported	0	0

End points

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Reporting group title

Open Label: Tofacitinib 11 mg + Methotrexate

Reporting group description

Reporting group title

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo

Reporting group description

Reporting group title

Double Blind: Tofacitinib 11 mg + Methotrexate

Reporting group description

Subjects with LDA at the end of open label phase received Tofacitinib MR 11 mg tablet once daily with blinded methotrexate at their previously stabilized dose for 24 weeks in double blind phase.

Primary: Double Blind Phase: Change From Randomization in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 48

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End point title

Double Blind Phase: Change From Randomization in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 48

End point description

DAS28 is a measure of disease activity in subjects with RA. DAS28-4 (ESR) was calculated from swollen joint count(SJC) and tender/painful joint count (TJC) using 28 joints count, ESR (millimeters per hour [mm/hr]) & subject global assessment of arthritis (PtGA) on a 100 millimeter (mm) visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0(none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) less than or equal to (<=) 3.2 implied low disease activity and greater than (>) 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity & DAS28-4 (ESR) less than (<) 2.6 implied remission. DAS28-4 (ESR) =0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/ hour) + 0.014*PtGA in mm; ln =natural logarithm, sqrt =square root of. FAS-DB. Overall number of subjects analyzed=subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	235	237
Units: units on a scale
least squares mean (standard error)	0.33 ± 0.07	0.03 ± 0.07

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Linear mixed-effect model of repeated measures (MMRM) was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline DAS28-4 (ESR) value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

472

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.0005 ^[2]

Method

MMRM

Parameter type

Least Square (LS) Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.12

upper limit

0.48

Variability estimate

Standard error of the mean

Dispersion value

0.09

Notes
[1] - Non-inferiority of Tofacitinib monotherapy to Tofacitinib with continued MTX treatment was concluded if the upper bound of 95% 2-sided CI for difference between the 2 arms (Tofacitinib monotherapy arm - Tofacitinib with MTX arm) was lower than 0.6.
[2] - The reported p-value (one-sided) is for the non-inferiority test at the margin of 0.6

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 ESR at Week 36

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End point title

Double Blind Phase: Change From Randomization in DAS28-4 ESR at Week 36

End point description

DAS28 is a measure of disease activity in subjects with RA. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition).Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. DAS28-4(ESR) =0.56*sqrt(TJC28) +0.28*sqrt(SJC28) +0.70*In(ESR in mm/hour)+ 0.014*PtGA in mm. Double-blind period full analysis set(FAS-DB) included all subjects who received at least 1 dose of investigational drug during the OL phase,were randomized & received at least 1 dose of the randomized investigational drug regimen during DB phase.Overall number of subjects analyzed=subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	253	253
Units: units on a scale
least squares mean (standard error)	0.40 ± 0.07	0.18 ± 0.07

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD and baseline DAS28-4 (ESR) value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

506

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.41

Variability estimate

Standard error of the mean

Dispersion value

0.1

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 (C-reactive protein [CRP]) at Weeks 36 and 48

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End point title

Double Blind Phase: Change From Randomization in DAS28-4 (C-reactive protein [CRP]) at Weeks 36 and 48

End point description

DAS28 is a measure of disease activity in subjects with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (milligrams per liter [mg/L]) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <= 3.2 implied low disease activity and > 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) < 2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96. FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =250 , 254)	0.38 ± 0.06	0.13 ± 0.06
Change at Week 48 (n =231 , 235)	0.29 ± 0.06	0.01 ± 0.06

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment -by-visit interaction, prior use of a bDMARD and baseline DAS28-4 (CRP) value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.43

Variability estimate

Standard error of the mean

Dispersion value

0.09

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment -by-visit interaction, prior use of a bDMARD and baseline DAS28-4 (CRP) value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.45

Variability estimate

Standard error of the mean

Dispersion value

0.09

Secondary: Double Blind Phase: Change From Randomization in Clinical Disease Activity Index (CDAI) at Weeks 36 and 48

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End point title

Double Blind Phase: Change From Randomization in Clinical Disease Activity Index (CDAI) at Weeks 36 and 48

End point description

CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and physician global assessment of arthritis (PhyGA). PtGA and PhyGA both were assessed on 0-10 centimeter (cm) VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm). FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =254, 259)	3.58 ± 0.49	1.84 ± 0.48
Change at Week 48 (n =238, 244)	2.97 ± 0.48	0.84 ± 0.47

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD and baseline CDAI value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

3.07

Variability estimate

Standard error of the mean

Dispersion value

0.68

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD and baseline CDAI value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

2.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

3.43

Variability estimate

Standard error of the mean

Dispersion value

0.66

Secondary: Double Blind Phase: Change From Randomization in Simplified Disease Activity Index (SDAI) at Weeks 36 and 48

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End point title

Double Blind Phase: Change From Randomization in Simplified Disease Activity Index (SDAI) at Weeks 36 and 48

End point description

SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity. SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity). SDAI score of <=11 indicates low disease activity and a score of <=3.3 indicates remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL). FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =249, 254)	3.83 ± 0.52	1.88 ± 0.51
Change at Week 48 (n =231, 235)	3.16 ± 0.50	0.94 ± 0.49

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD and baseline SDAI value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

3.37

Variability estimate

Standard error of the mean

Dispersion value

0.72

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD and baseline SDAI value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

2.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

3.59

Variability estimate

Standard error of the mean

Dispersion value

0.69

Secondary: Double Blind Phase: Percentage of Subjects With Low Disease Activity (LDA) Assessed by DAS28-4 (ESR) Less Than or Equal to (<=) 3.2 at Weeks 36 and 48

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End point title

Double Blind Phase: Percentage of Subjects With Low Disease Activity (LDA) Assessed by DAS28-4 (ESR) Less Than or Equal to (<=) 3.2 at Weeks 36 and 48

End point description

DAS28 is a measure of disease activity in subjects with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicated worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. DAS28-4 (ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/ hour) + 0.014*PtGA in mm. Non-responder imputation (NRI) method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	42.42	48.12
Week 48	45.08	49.62

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-5.69

Confidence interval

level

95%

sides

2-sided

lower limit

-14.15

upper limit

2.76

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-4.54

Confidence interval

level

95%

sides

2-sided

lower limit

-13.04

upper limit

3.94

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by DAS28-4 (CRP) <=3.2 at Weeks 36 and 48

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End point title

Double Blind Phase: Percentage of Subjects With LDA Assessed by DAS28-4 (CRP) <=3.2 at Weeks 36 and 48

End point description

DAS28 is a measure of disease activity in subjects with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/dL) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96. NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	65.53	70.68
Week 48	65.91	74.44

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-5.14

Confidence interval

level

95%

sides

2-sided

lower limit

-13.07

upper limit

2.77

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment -by-visit interaction, prior use of a biological DMARD and baseline DAS28-4 (CRP) value as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-8.52

Confidence interval

level

95%

sides

2-sided

lower limit

-16.28

upper limit

-0.76

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by CDAI <=10 at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With LDA Assessed by CDAI <=10 at Weeks 36 and 48

End point description

CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and PhyGA. PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. Percentage of subjects with CDAI <=10 were reported. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm). NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	66.29	73.68
Week 48	65.15	77.07

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-7.39

Confidence interval

level

95%

sides

2-sided

lower limit

-15.17

upper limit

0.38

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-11.91

Confidence interval

level

95%

sides

2-sided

lower limit

-19.56

upper limit

-4.26

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by SDAI <=11 at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With LDA Assessed by SDAI <=11 at Weeks 36 and 48

End point description

SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity. SDAI score of <=11 indicates low disease activity and a score of <=3.3 indicates remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL). NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	66.29	73.31
Week 48	66.29	76.32

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-7.02

Confidence interval

level

95%

sides

2-sided

lower limit

-14.81

upper limit

0.77

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-10.02

Confidence interval

level

95%

sides

2-sided

lower limit

-17.68

upper limit

-2.37

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Weeks 36 and 48

End point description

ACR-EULAR Boolean remission was when a subject satisfied all of the following: tender joint count, swollen joint count (both based on a 28-joint assessment), CRP (in mg/dL), and PtGA (VAS: 0 cm [very well] to 10 cm [worst], higher scores indicated worse health condition) and all scores were <=1. NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	15.53	24.06
Week 48	22.35	23.68

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-8.52

Confidence interval

level

95%

sides

2-sided

lower limit

-15.27

upper limit

-1.78

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-1.33

Confidence interval

level

95%

sides

2-sided

lower limit

-8.5

upper limit

5.83

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (ESR) Less Than [<] 2.6 at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (ESR) Less Than [<] 2.6 at Weeks 36 and 48

End point description

DAS28 is a measure of disease activity in subjects with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity & >3.2 to <=5.1 implied moderate disease activity,>5.1 implied high disease activity, & DAS28-4 (ESR) <2.6 implied remission. DAS28-4 (ESR)=0.56*sqrt(TJC28)+0.28*sqrt(SJC28) + 0.70*In(ESR in mm/ hour) + 0.014*PtGA in mm. Percentage of subjects with DAS remission (DAS28-4-ESR<2.6) were reported in this endpoint. NRI method was used to impute missing data. FAS-DB was analyzed.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	20.45	28.57
Week 48	23.86	30.08

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-8.11

Confidence interval

level

95%

sides

2-sided

lower limit

-15.4

upper limit

-0.82

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-6.21

Confidence interval

level

95%

sides

2-sided

lower limit

-13.74

upper limit

1.32

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (CRP) <2.6 at Weeks 48 and 36

Top of page

End point title

Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (CRP) <2.6 at Weeks 48 and 36

End point description

DAS28 is a measure of disease activity in subjects with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/L) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96. Percentage of subjects with DAS remission (DAS28-4-CRP<2.6) were reported in this endpoint. NRI method was used to impute missing data. FAS-DB was analyzed.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	50.00	55.64
Week 48	50.38	54.51

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-5.63

Confidence interval

level

95%

sides

2-sided

lower limit

-14.12

upper limit

2.84

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-4.13

Confidence interval

level

95%

sides

2-sided

lower limit

-12.62

upper limit

4.36

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by CDAI <=2.8 at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With Remission Assessed by CDAI <=2.8 at Weeks 36 and 48

End point description

CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and PhyGA. PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm). NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	23.48	32.33
Week 48	28.41	30.83

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-8.84

Confidence interval

level

95%

sides

2-sided

lower limit

-16.44

upper limit

-1.24

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-2.41

Confidence interval

level

95%

sides

2-sided

lower limit

-10.18

upper limit

5.35

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by SDAI <=3.3 at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects With Remission Assessed by SDAI <=3.3 at Weeks 36 and 48

End point description

SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity. SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity. SDAI score of <=11 indicates low disease activity and a score of <=3.3 indicates remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL). NRI method was used to impute missing data. FAS-DB included all subjects who received at least 1 dose of investigational drug during the OL phase, were randomized and received at least 1 dose of the randomized investigational drug regimen during DB phase.

End point type

Secondary

End point timeframe

Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	22.73	31.58
Week 48	28.79	31.95

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-8.85

Confidence interval

level

95%

sides

2-sided

lower limit

-16.38

upper limit

-1.31

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-3.16

Confidence interval

level

95%

sides

2-sided

lower limit

-10.99

upper limit

4.65

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 36 and 48

End point description

Subjects with 20% improvement in tender and swollen joint counts and 20% improvement in at least 3 of the 5 measures: PtGA, PhyGA, subject’s assessment of arthritis pain, HAQ-DI and CRP. PtGA: subject assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged subjects’ pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Subject’s assessment of arthritis pain: subject assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1). NRI method was used to impute missing data. FAS-DB was analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	73.86	80.83
Week 48	73.11	79.70

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-6.96

Confidence interval

level

95%

sides

2-sided

lower limit

-14.06

upper limit

0.14

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-6.59

Confidence interval

level

95%

sides

2-sided

lower limit

-13.8

upper limit

0.61

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 50% (ACR50) Response at Week 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 50% (ACR50) Response at Week 36 and 48

End point description

Subjects with 50% improvement in tender and swollen joint counts and 50% improvement in at least 3 of the 5 measures: PtGA, PhyGA, subject’s assessment of arthritis pain, HAQ-DI and CRP. PtGA: subject assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged subjects’ pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Subject’s assessment of arthritis pain: subject assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1). NRI method was used to impute missing data. FAS-DB was analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	53.79	66.54
Week 48	55.30	67.29

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-12.75

Confidence interval

level

95%

sides

2-sided

lower limit

-21.01

upper limit

-4.48

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-11.99

Confidence interval

level

95%

sides

2-sided

lower limit

-20.22

upper limit

-3.75

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 70% (ACR70) Response at Week 36 and 48

Top of page

End point title

Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 70% (ACR70) Response at Week 36 and 48

End point description

Subjects with 70% improvement in tender and swollen joint counts and 70% improvement in at least 3 of the 5 measures: PtGA, PhyGA, subject’s assessment of arthritis pain, health assessment questionnaire-disability index (HAQ-DI) and CRP. PtGA: subject assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged subjects’ pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Subject’s assessment of arthritis pain: subject assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score=more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1). NRI method was used to impute missing data. FAS-DB was analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	35.61	40.98
Week 48	37.88	42.86

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-5.37

Confidence interval

level

95%

sides

2-sided

lower limit

-13.63

upper limit

2.89

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-4.97

Confidence interval

level

95%

sides

2-sided

lower limit

-13.32

upper limit

3.36

Secondary: Double Blind Phase: Change From Randomization in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 36 and 48

Top of page

End point title

Double Blind Phase: Change From Randomization in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 36 and 48

End point description

HAQ-DI assesses the degree of difficulty a subject has experienced during the past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities.. There were total of 30 items distributed in these 8 domains. Each item was scored on a 4-point scale from 0 to 3: 0= no difficulty; 1= some difficulty; 2= much difficulty; 3= unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities. FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =252, 259)	0.10 ± 0.03	0.01 ± 0.03
Change at Week 48 (n =238, 246)	0.01 ± 0.03	0.00 ± 0.03

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological DMARD and baseline HAQ-DI.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.04

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological DMARD and baseline HAQ-DI.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.04

Secondary: Double Blind Phase: Change From Randomization in the Short Form 36 (SF-36) Health Survey 8 Domain Scores at Week 36 and 48

Top of page

End point title

Double Blind Phase: Change From Randomization in the Short Form 36 (SF-36) Health Survey 8 Domain Scores at Week 36 and 48

End point description

SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health perception. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were summarized to derive the 2 component scores (physical component scores [PCS], mental component scores [MCS]) ranging from 0 (worst) to 100 (best), where higher PCS/MCS indicated good health condition. FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36:Physical Functioning(n=252, 259)	-1.32 ± 0.50	-0.88 ± 0.49
Change at Week 36:Role Physical Score(n=252, 259)	-1.69 ± 0.48	-0.02 ± 0.47
Change at Week 36: Social Functioning(n=252, 259)	-0.98 ± 0.50	-0.84 ± 0.49
Change at Week 36: Bodily Pain Score (n=252, 259)	-2.03 ± 0.53	-0.58 ± 0.52
Change at Week 36: Mental Health Score(n=251,259)	-1.22 ± 0.51	-0.32 ± 0.50
Change at Week 36: Role Emotional Score(n=252,259)	-1.80 ± 0.56	-0.69 ± 0.55
Change at Week 36: Vitality Score (n =251, 259)	-1.30 ± 0.50	-0.15 ± 0.50
Change at Week 36: GH Perception Score (n=252,259)	-0.98 ± 0.44	-0.87 ± 0.43
Change at Week 48:Physical Functioning(n=238,246)	-0.46 ± 0.49	-0.97 ± 0.48
Change at Week 48: Role Physical Score(n=238,246)	-0.88 ± 0.51	-0.15 ± 0.50
Change at Week 48: Social Functioning (n=238,246)	-1.06 ± 0.53	-0.55 ± 0.52
Change at Week 48: Bodily Pain Score (n=238,246)	-1.46 ± 0.54	-0.71 ± 0.54
Change at Week 48: Mental Health Score(n=238,246)	-0.34 ± 0.54	0.12 ± 0.54
Change at Week 48:Role Emotional Score(n=238,246)	-0.83 ± 0.54	-0.36 ± 0.54
Change at Week 48: Vitality Score (n =238, 246)	-0.77 ± 0.52	-0.25 ± 0.52
Change at Week 48: GH Perception Score(n=238,246)	-0.43 ± 0.45	-1.05 ± 0.44

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Physical Functioning- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 physical component score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-1.79

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

0.69

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Physical Functioning- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 physical component score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-0.82

upper limit

1.85

Variability estimate

Standard error of the mean

Dispersion value

0.68

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Role Physical Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 role physical score score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-1.67

Confidence interval

level

95%

sides

2-sided

lower limit

-2.97

upper limit

-0.37

Variability estimate

Standard error of the mean

Dispersion value

0.66

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Role Physical Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 role physical score score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.73

Confidence interval

level

95%

sides

2-sided

lower limit

-2.13

upper limit

0.66

Variability estimate

Standard error of the mean

Dispersion value

0.66

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Social functioning- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 Social functioning score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

1.21

Variability estimate

Standard error of the mean

Dispersion value

0.69

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Social functioning- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 social functioning score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.95

upper limit

0.93

Variability estimate

Standard error of the mean

Dispersion value

0.73

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Bodily Pain Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 bodily pain score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-1.45

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.74

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Bodily Pain Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 bodily pain score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.75

Confidence interval

level

95%

sides

2-sided

lower limit

-2.23

upper limit

0.73

Variability estimate

Standard error of the mean

Dispersion value

0.75

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Mental Health Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 mental health score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.29

upper limit

0.49

Variability estimate

Standard error of the mean

Dispersion value

0.71

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Mental Health Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 mental health score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-1.94

upper limit

1.02

Variability estimate

Standard error of the mean

Dispersion value

0.75

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Role Emotional Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 role emotional score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-2.64

upper limit

0.43

Variability estimate

Standard error of the mean

Dispersion value

0.78

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Role Emotional Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 role emotional score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-1.95

upper limit

1.01

Variability estimate

Standard error of the mean

Dispersion value

0.75

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Vitality Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 vitality score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-2.52

upper limit

0.22

Variability estimate

Standard error of the mean

Dispersion value

0.7

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Vitality Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 vitality score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.94

upper limit

0.91

Variability estimate

Standard error of the mean

Dispersion value

0.73

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: General Health Perception Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 general health perception score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

1.08

Variability estimate

Standard error of the mean

Dispersion value

0.61

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: General Health Perception Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 general health perception score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.83

Variability estimate

Standard error of the mean

Dispersion value

0.62

Secondary: Double Blind Phase: Change From Randomization in the SF-36 Health Survey Component Scores at Week 36 and 48

Top of page

End point title

Double Blind Phase: Change From Randomization in the SF-36 Health Survey Component Scores at Week 36 and 48

End point description

SF-36 is a subject reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health perception. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were summarized aggregated to derive the two 2 component scores PCS and MCS ranging from 0 (worst) to 100 (best), where higher PCS/MCS indicated good health condition. FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36: PCS (n =251, 259)	-1.42 ± 0.44	-0.60 ± 0.43
Change at Week 36:MCS (n =251, 259)	-1.25 ± 0.48	-0.43 ± 0.47
Change at Week 48: PCS (n =238, 246)	-0.83 ± 0.44	-0.92 ± 0.43
Change at Week 48: MCS (n =238, 246)	-0.65 ± 0.51	0.03 ± 0.50

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Physical Component Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 physical component score- as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.82

Confidence interval

level

95%

sides

2-sided

lower limit

-2.01

upper limit

0.37

Variability estimate

Standard error of the mean

Dispersion value

0.61

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Physical Component Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 physical component score- as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-1.11

upper limit

1.29

Variability estimate

Standard error of the mean

Dispersion value

0.61

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Mental Component Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 mental component score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.82

Confidence interval

level

95%

sides

2-sided

lower limit

-2.13

upper limit

0.49

Variability estimate

Standard error of the mean

Dispersion value

0.67

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Mental Component Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a biological disease-modifying anti-rheumatic drug (DMARD), and baseline SF-36 mental component score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-2.06

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

0.7

Secondary: Double Blind Phase: Change From Randomization in the Work Productivity and Activity Impairment (WPAI) Scores at Week 36 and 48

Top of page

End point title

Double Blind Phase: Change From Randomization in the Work Productivity and Activity Impairment (WPAI) Scores at Week 36 and 48

End point description

WPAI is 6-question subject rated questionnaire to determine the impact of rheumatoid arthritis and yields 4 types of outcomes: absenteeism (work time missed), presenteeism (impairment while working), work productivity loss (overall work impairment), and daily activity (DA) impairment (activity impairment) for a period of 7 days prior to a visit. These 4 outcomes are expressed as an impairment percentage (range from 0 to 100), with higher numbers indicating greater impairment and less productivity. FAS-DB was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage impairment
least squares mean (standard error)
Change at Week 36: Absenteeism (n =90, 104)	-1.39 ± 1.79	-3.00 ± 1.69
Change at Week 36: DA impairment (n =252, 256)	4.00 ± 1.35	0.81 ± 1.34
Change at Week 36: Presenteeism (n =96, 104)	3.68 ± 2.20	0.67 ± 2.07
Change at Week 36:Work productivity loss(n=90,101)	3.03 ± 2.57	0.19 ± 2.41
Change at Week 48: Absenteeism (n =89, 101)	-2.21 ± 1.70	-1.69 ± 1.61
Change at Week 48: DA impairment (n =238, 243)	2.86 ± 1.47	1.25 ± 1.46
Change at Week 48: Presenteeism (n =93, 101)	2.82 ± 2.78	3.72 ± 2.61
Change at Week 48:Work productivity loss(n=89,98)	2.98 ± 3.09	5.45 ± 2.91

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Absenteeism Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI absenteeism score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-3.14

upper limit

6.37

Variability estimate

Standard error of the mean

Dispersion value

2.41

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Absenteeism Score- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI absenteeism score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-5.01

upper limit

3.99

Variability estimate

Standard error of the mean

Dispersion value

2.28

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Daily activity impairment- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI daily activity impairment score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

3.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

6.89

Variability estimate

Standard error of the mean

Dispersion value

1.88

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Daily activity impairment- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI daily activity impairment score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.41

upper limit

5.61

Variability estimate

Standard error of the mean

Dispersion value

2.04

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Presenteeism- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI presenteeism score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

3.01

Confidence interval

level

95%

sides

2-sided

lower limit

-2.84

upper limit

8.87

Variability estimate

Standard error of the mean

Dispersion value

2.97

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Presenteeism- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI presenteeism score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-8.34

upper limit

6.54

Variability estimate

Standard error of the mean

Dispersion value

3.77

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Work productivity loss- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI work productivity loss score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

2.84

Confidence interval

level

95%

sides

2-sided

lower limit

-3.97

upper limit

9.65

Variability estimate

Standard error of the mean

Dispersion value

3.45

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Work productivity loss- Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline WPAI work productivity loss score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-2.46

Confidence interval

level

95%

sides

2-sided

lower limit

-10.72

upper limit

5.8

Variability estimate

Standard error of the mean

Dispersion value

4.19

Secondary: Double Blind Phase: Change From Randomization in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Week 36 and 48

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End point title

Double Blind Phase: Change From Randomization in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Week 36 and 48

End point description

EQ-5D was a subject completed instrument designed to assess impact on quality of life in terms of a single utility score in 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. 3 possible answers for mobility: 1=no problem in walking, 2=moderate problems in walking, 3= confined to bed; self-care: 1=no problem, 2=moderate problems, 3= unable to wash/dress; usual activities: 1=no problem, 2=moderate problems, 3= unable to do usual activities; pain and discomfort: 1=no pain or discomfort, 2=moderate pain or discomfort, 3= extreme pain or discomfort; anxiety and depression: 1=not anxious or depressed, 2=moderately anxious or depressed, 3= extremely anxious or depressed. The 5-dimensional systems are converted into a single index utility score between 0 and 1, where higher score indicated a better health state. FAS-DB population was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =251, 258)	-0.05 ± 0.01	-0.01 ± 0.01
Change at Week 48 (n =237, 245)	-0.02 ± 0.01	0.00 ± 0.01

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline EQ-5D score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.02

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline EQ-5D score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.02

Secondary: Double Blind Phase: Change From Randomization in the Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Scale Scores at Week 36 and 48

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End point title

Double Blind Phase: Change From Randomization in the Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Scale Scores at Week 36 and 48

End point description

The FACIT-Fatigue scale was a subject completed questionnaire consisted of 13 items that assessed fatigue. Each item was scored on a scale of 0 (maximum fatigue) to 4 (no fatigue), higher scores indicate less fatigue. Total FACIT-fatigue score was obtained by addition of scores from 13 items, giving a possible overall range from 0 (maximum fatigue) to 52 (no fatigue). Higher FACIT-fatigue scores indicated lower level of fatigue, better subject status. FAS-DB population was analyzed. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.

End point type

Secondary

End point timeframe

Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: units on a scale
least squares mean (standard error)
Change at Week 36 (n =252, 258)	-0.99 ± 0.43	-0.80 ± 0.43
Change at Week 48 (n =237, 245)	-0.34 ± 0.46	-0.52 ± 0.45

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 36: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline FACIT - fatigue scale score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-1.37

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.6

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Change at Week 48: Linear MMRM was used that included the fixed effects of treatment, visit, treatment-by-visit interaction, prior use of a bDMARD, and baseline FACIT - fatigue scale score as a covariate.

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

1.44

Variability estimate

Standard error of the mean

Dispersion value

0.64

Secondary: Double Blind Phase: Percentage of Subjects Achieving an Improvement of at Least 0.22 Units in HAQ-DI at Weeks 36 and 48

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End point title

Double Blind Phase: Percentage of Subjects Achieving an Improvement of at Least 0.22 Units in HAQ-DI at Weeks 36 and 48

End point description

HAQ-DI assesses the degree of difficulty a subject has experienced during the past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities.. There were total of 30 items distributed in these 8 domains. Each item was scored on a 4-point scale from 0 to 3: 0= no difficulty; 1= some difficulty; 2= much difficulty; 3= unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities. Percentage of subjects with an improvement of at least 0.22 units in HAQ scores from baseline (Day 1) to Week 36 and 48 were reported in this endpoint. NRI method was used to impute missing data. FAS-DB population was analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1), Week 36 and 48

End point values	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	264	266
Units: percentage of subjects
number (not applicable)
Week 36	67.05	77.07
Week 48	68.56	75.19

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 36

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-10.02

Confidence interval

level

95%

sides

2-sided

lower limit

-17.61

upper limit

-2.42

Variability estimate

Standard error of the mean

Dispersion value

3.87

Tofacitinib + MTX Placebo Vs Tofacitinib + MTX

Statistical analysis description

Week 48

Comparison groups

Double Blind: Tofacitinib 11 mg + Methotrexate Placebo v Double Blind: Tofacitinib 11 mg + Methotrexate

Number of subjects included in analysis

530

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in percentage of subjects

Point estimate

-6.62

Confidence interval

level

95%

sides

2-sided

lower limit

-14.26

upper limit

Variability estimate

Standard error of the mean

Dispersion value

3.89

Other pre-specified: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious AEs

Top of page

End point title

Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious AEs

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to Week 52 (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs. Overall study safety analysis set included all subjects who received at least one dose of study drug during the study.

End point type

Other pre-specified

End point timeframe

For OL Phase: Baseline up to Week 24; For DB Phase: Week 24 up to Week 52 (up to 28 days after last dose)

End point values	Open Label: Tofacitinib 11 mg + Methotrexate	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	694	264	266
Units: subjects
AEs\|	362	107	109
SAEs\|	20	10	5

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Abnormal Laboratory Parameters

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End point title

Number of Subjects With Abnormal Laboratory Parameters

End point description

Hemoglobin (Hb),Hematocrit,Erythrocytes:<0.8*LLN; Ery. mean corpuscular volume <0.9*LLN, >1.1*ULN;Platelets:<0.5*LLN,>1.75*ULN;WBCs:<0.6*LLN,>1.5*ULN; Lymphocytes/WBCs, Neutrophils/WBCs:<0.8*LLN,>1.2x ULN;Basophils/WBCs, Eosinophils/WBCs,Monocytes, Monocytes/WBCs: >1.2*ULN;Prothrombin Time, Prothrombin Intl. Normalized Ratio:>1.1*ULN; ESR:>1.5*ULN; Bilirubin,Direct Bilirubin,Indirect Bilirubin: >1.5*ULN; Aspartate Aminotransferase,Alanine Aminotransferase,Gamma Glutamyl Transferase,Alkaline Phosphatase:>3.0*ULN; Protein,Albumin: <0.8*LLN, >1.2*ULN; Blood Urea Nitrogen, Creatinine,Triglycerides: >1.3*ULN;HDL Cholesterol:<0.8*LLN;Sodium <0.95*LLN, >1.05*ULN;Potassium,Chloride, Calcium, Bicarbonate: <0.9*LLN, >1.1*ULN; Glucose: <0.6*LLN, >1.5*ULN;Creatine Kinase: >2.0*ULN; Cholesterol:>1.3*ULN;Specific Gravity:<1.003;pH:<4.5;urine glucose,Ketones,urine protein,urine Hb,WBCs Esterase:>=1.Overall safety analysis set.Overall number of subjects analyzed=subjects evaluable for this endpoint.

End point type

Other pre-specified

End point timeframe

For OL Phase: Baseline up to Week 24; For DB Phase: Week 24 up to Week 48

End point values	Open Label: Tofacitinib 11 mg + Methotrexate	Double Blind: Tofacitinib 11 mg + Methotrexate Placebo	Double Blind: Tofacitinib 11 mg + Methotrexate
Number of subjects analysed	688	263	263
Units: subjects	682	263	263

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline (Day 1) up to Week 52

Adverse event reporting additional description

Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. AEs were evaluated for subjects with at least 1 dose of the study drug during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Open Label: Tofacitinib 11 mg + Methotrexate

Reporting group description

Subjects with moderate to severe rheumatoid arthritis (RA) and who were insufficiently responding to their stable dose of methotrexate treatment previous to enrollment in this study, received Tofacitinib modified release (MR) 11 milligram (mg) tablet once daily (QD) with methotrexate at their previous stable dose for 24 weeks in open label phase (OL).

Reporting group title

Double Blind: Tofacitinib 11mg + Methotrexate

Reporting group description

Subjects with LDA at the end of open label phase received Tofacitinib MR 11 mg tablet once daily with blinded methotrexate at their previously stabilized dose for 24 weeks in double blind phase.

Reporting group title

Double Blind: Tofacitinib + Methotrexate Placebo

Reporting group description

Serious adverse events	Open Label: Tofacitinib 11 mg + Methotrexate	Double Blind: Tofacitinib 11mg + Methotrexate	Double Blind: Tofacitinib + Methotrexate Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 694 (2.88%)	5 / 266 (1.88%)	10 / 264 (3.79%)
number of deaths (all causes)	0	2	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal adenoma
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Prostate cancer
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Thyroid cancer metastatic
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 694 (0.00%)	2 / 266 (0.75%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Interstitial lung disease
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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 / 694 (0.14%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Patella fracture
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Tibia fracture
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Cardiac disorders
Angina unstable
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Atrial fibrillation
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Nervous system disorders
Nerve root compression
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Umbilical hernia
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Pancreatitis acute
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Peritoneal disorder
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Gallbladder disorder
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Mobility decreased
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 694 (0.00%)	1 / 266 (0.38%)	0 / 264 (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
Encephalitis viral
subjects affected / exposed	0 / 694 (0.00%)	1 / 266 (0.38%)	0 / 264 (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
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 694 (0.00%)	1 / 266 (0.38%)	0 / 264 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 694 (0.00%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 694 (0.43%)	0 / 266 (0.00%)	1 / 264 (0.38%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Respiratory tract infection
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 694 (0.14%)	0 / 266 (0.00%)	0 / 264 (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

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Open Label: Tofacitinib 11 mg + Methotrexate	Double Blind: Tofacitinib 11mg + Methotrexate	Double Blind: Tofacitinib + Methotrexate Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	158 / 694 (22.77%)	31 / 266 (11.65%)	24 / 264 (9.09%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	16 / 694 (2.31%)	10 / 266 (3.76%)	5 / 264 (1.89%)
occurrences all number	20	11	6
Aspartate aminotransferase increased
subjects affected / exposed	0 / 694 (0.00%)	6 / 266 (2.26%)	5 / 264 (1.89%)
occurrences all number	0	6	5
Vascular disorders
Hypertension
subjects affected / exposed	17 / 694 (2.45%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	18	0	0
Nervous system disorders
Headache
subjects affected / exposed	17 / 694 (2.45%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	19	0	0
Dizziness
subjects affected / exposed	15 / 694 (2.16%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	15	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	16 / 694 (2.31%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	17	0	0
Nausea
subjects affected / exposed	20 / 694 (2.88%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	23	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 694 (0.00%)	2 / 266 (0.75%)	7 / 264 (2.65%)
occurrences all number	0	2	7
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 694 (0.00%)	7 / 266 (2.63%)	3 / 264 (1.14%)
occurrences all number	0	8	3
Nasopharyngitis
subjects affected / exposed	35 / 694 (5.04%)	7 / 266 (2.63%)	5 / 264 (1.89%)
occurrences all number	40	7	6
Upper respiratory tract infection
subjects affected / exposed	33 / 694 (4.76%)	6 / 266 (2.26%)	4 / 264 (1.52%)
occurrences all number	41	6	4
Urinary tract infection
subjects affected / exposed	19 / 694 (2.74%)	0 / 266 (0.00%)	0 / 264 (0.00%)
occurrences all number	20	0	0

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3B/4 Randomized Double Blind Placebo Controlled Study of Methotrexate (MTX) Withdrawal in Subjects With Rheumatoid Arthritis (RA) Treated With Tofacitinib 11mg Modified Release (MR) Formulation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Double Blind Phase: Change From Randomization in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 48

Primary: Double Blind Phase: Change From Randomization in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 48

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 ESR at Week 36

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 ESR at Week 36

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 (C-reactive protein [CRP]) at Weeks 36 and 48

Secondary: Double Blind Phase: Change From Randomization in DAS28-4 (C-reactive protein [CRP]) at Weeks 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Clinical Disease Activity Index (CDAI) at Weeks 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Clinical Disease Activity Index (CDAI) at Weeks 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Simplified Disease Activity Index (SDAI) at Weeks 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Simplified Disease Activity Index (SDAI) at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Low Disease Activity (LDA) Assessed by DAS28-4 (ESR) Less Than or Equal to (<=) 3.2 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Low Disease Activity (LDA) Assessed by DAS28-4 (ESR) Less Than or Equal to (<=) 3.2 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by DAS28-4 (CRP) <=3.2 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by DAS28-4 (CRP) <=3.2 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by CDAI <=10 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by CDAI <=10 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by SDAI <=11 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With LDA Assessed by SDAI <=11 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (ESR) Less Than [<] 2.6 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (ESR) Less Than [<] 2.6 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (CRP) <2.6 at Weeks 48 and 36

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by DAS28-4 (CRP) <2.6 at Weeks 48 and 36

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by CDAI <=2.8 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by CDAI <=2.8 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by SDAI <=3.3 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects With Remission Assessed by SDAI <=3.3 at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 50% (ACR50) Response at Week 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 50% (ACR50) Response at Week 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 70% (ACR70) Response at Week 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an American College of Rheumatology 70% (ACR70) Response at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Short Form 36 (SF-36) Health Survey 8 Domain Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Short Form 36 (SF-36) Health Survey 8 Domain Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the SF-36 Health Survey Component Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the SF-36 Health Survey Component Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Work Productivity and Activity Impairment (WPAI) Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Work Productivity and Activity Impairment (WPAI) Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Scale Scores at Week 36 and 48

Secondary: Double Blind Phase: Change From Randomization in the Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue Scale Scores at Week 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an Improvement of at Least 0.22 Units in HAQ-DI at Weeks 36 and 48

Secondary: Double Blind Phase: Percentage of Subjects Achieving an Improvement of at Least 0.22 Units in HAQ-DI at Weeks 36 and 48

Other pre-specified: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious AEs

Other pre-specified: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious AEs

Other pre-specified: Number of Subjects With Abnormal Laboratory Parameters

Other pre-specified: Number of Subjects With Abnormal Laboratory Parameters

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3B/4 Randomized Double Blind Placebo Controlled Study of Methotrexate (MTX) Withdrawal in Subjects With Rheumatoid Arthritis (RA) Treated With Tofacitinib 11mg Modified Release (MR) Formulation