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Clinical Trial Results:
A Phase 3b/4 Randomized Double-Blind Study of 5 mg of Tofacitinib With and Without Methotrexate in Comparison to Adalimumab With Methotrexate in Subjects With Moderately to Severely Active Rheumatoid Arthritis

Summary
EudraCT number	2014-000358-13
Trial protocol	CZ EE LT LV GB ES PL BG RO DE HR
Global end of trial date	16 Dec 2016

Results information
Results version number	v1(current)
This version publication date	06 Dec 2017
First version publication date	06 Dec 2017
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

A3921187

ISRCTN number

US NCT number

NCT02187055

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

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

03 Feb 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to compare the efficacy of 5 mg twice daily (BID) of tofacitinib (with and without background methotrexate [MTX]) to adalimumab with MTX as measured by American College of Rheumatology (ACR) criteria 50% improvement (ACR50) response rates at Month 6 and to compare the efficacy of 5 mg BID tofacitinib monotherapy versus 5 mg BID tofacitinib with MTX as measured by ACR50 response rates at Month 6.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol and any amendments were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centres participating in the study.

Background therapy

Throughout the study subjects were to continue on their stable background arthritis therapy, which included MTX (or placebo MTX) and folic acid supplement and could have included nonsteroidal anti-inflammatory drugs, selective cyclooxygenase 2 inhibitors, opioids, cetaminophen, and/or low dose oral corticosteroids (less than or equal to 10 mg prednisone or equivalent per day).

Evidence for comparator

Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody specific for human tumor necrosis factor. It is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult subjects with moderately to severely active rheumatoid arthritis (RA). The currently approved dose is 40 mg every other week in adult subjects with RA.

Actual start date of recruitment

06 Aug 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 43

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Bosnia and Herzegovina: 36

Country: Number of subjects enrolled

Bulgaria: 56

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Chile: 16

Country: Number of subjects enrolled

Czech Republic: 13

Country: Number of subjects enrolled

Estonia: 10

Country: Number of subjects enrolled

Israel: 12

Country: Number of subjects enrolled

Korea, Republic of: 37

Country: Number of subjects enrolled

Latvia: 4

Country: Number of subjects enrolled

Lithuania: 30

Country: Number of subjects enrolled

Mexico: 200

Country: Number of subjects enrolled

Peru: 17

Country: Number of subjects enrolled

Philippines: 43

Country: Number of subjects enrolled

Poland: 115

Country: Number of subjects enrolled

Romania: 46

Country: Number of subjects enrolled

Russian Federation: 111

Country: Number of subjects enrolled

South Africa: 60

Country: Number of subjects enrolled

Spain: 29

Country: Number of subjects enrolled

Taiwan: 16

Country: Number of subjects enrolled

Thailand: 15

Country: Number of subjects enrolled

Turkey: 3

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 201

Worldwide total number of subjects

1146

EEA total number of subjects

313

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)

992

From 65 to 84 years

152

85 years and over

Subject disposition

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Recruitment details

Screening details

Confirmation of RA diagnosis and classification of RA was performed at the screening visit. Participants must have had a score of 6 or greater on the 2010 ACR/European League Against Rheumatism classification criteria for RA.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Tofacitinib 5 mg BID

Arm description

One active tofacitinib 5 mg tablet orally BID plus placebo MTX (prior dose) orally every week plus placebo adalimumab 40 mg subcutaneously (SC) every other week for up to 12 months.

Arm type

Experimental

Investigational medicinal product name

Tofacitinib

Investigational medicinal product code

CP-690550-10

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 active tofacitinib 5 mg tablet administered orally BID plus placebo MTX (prior dose) capsule(s) administered orally every week plus placebo adalimumab 40 mg injection administered subcutaneously (SC) every other week for up to 12 months.

Tofacitinib 5 mg BID + MTX

Arm description

One active tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus placebo adalimumab 40 mg SC every other week for up to 12 months.

Arm type

Experimental

Investigational medicinal product name

Tofacitinib and methotrexate

Investigational medicinal product code

CP-690550-10

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 active tofacitinib 5 mg tablet administered orally BID plus active MTX (prior dose) capsule(s) administered orally every week plus placebo adalimumab 40 mg injection administered SC every other week for up to 12 months.

Adalimumab 40 mg + MTX

Arm description

One placebo tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus active adalimumab 40 mg SC every other week for up to 12 months.

Arm type

Active comparator

Investigational medicinal product name

Adalimumab and methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 placebo tofacitinib 5 mg tablet administered orally BID plus active MTX (prior dose) capsule(s) administered orally every week plus active adalimumab 40 mg injection administered SC every other week for up to 12 months.

Number of subjects in period 1	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Started	384	376	386
Completed	315	303	312
Not completed	69	73	74
Adverse event, serious fatal	2	-	-
Consent withdrawn by subject	11	11	11
Adverse event, non-fatal	21	26	36
No longer meets eligibility criteria	-	2	-
Pregnancy	3	1	-
No longer willing to participate	6	8	10
Unspecified	5	6	3
Lost to follow-up	2	7	3
Lack of efficacy	10	3	7
Protocol deviation	9	9	4

Baseline characteristics

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Reporting group title

Tofacitinib 5 mg BID

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus placebo MTX (prior dose) orally every week plus placebo adalimumab 40 mg subcutaneously (SC) every other week for up to 12 months.

Reporting group title

Tofacitinib 5 mg BID + MTX

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus placebo adalimumab 40 mg SC every other week for up to 12 months.

Reporting group title

Adalimumab 40 mg + MTX

Reporting group description

One placebo tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus active adalimumab 40 mg SC every other week for up to 12 months.

Reporting group values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX	Total
Number of subjects	384	376	386	1146
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	335	332	325	992
From 65-84 years	49	42	61	152
85 years and over	0	2	0	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	49.7 ± 12.2	50.0 ± 13.4	50.7 ± 13.4	-
Gender, Male/Female
Units: Subjects
Female	319	311	320	950
Male	65	65	66	196

End points

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Reporting group title

Tofacitinib 5 mg BID

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus placebo MTX (prior dose) orally every week plus placebo adalimumab 40 mg subcutaneously (SC) every other week for up to 12 months.

Reporting group title

Tofacitinib 5 mg BID + MTX

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus placebo adalimumab 40 mg SC every other week for up to 12 months.

Reporting group title

Adalimumab 40 mg + MTX

Reporting group description

One placebo tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus active adalimumab 40 mg SC every other week for up to 12 months.

Primary: Percentage of Participants Achieving American College of Rheumatology Criteria 50% Improvement (ACR50) Response at Month 6

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End point title

Percentage of Participants Achieving American College of Rheumatology Criteria 50% Improvement (ACR50) Response at Month 6

End point description

ACR50 is a greater than or equal to (≥) 50 percent (%) improvement in tender joint count (TJC) or swollen joint count (SJC) and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment (PGA) of disease activity, 2) participant's assessment (PtGA) of disease activity, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein (CRP) at each visit.

End point type

Primary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	384	376	386
Units: Percentage of participants
number (not applicable)	38.28	46.01	43.78

Analysis of ACR50 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

760

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

= 0.2101

Method

Normal approximation to proportions

Parameter type

Difference in response rate

Point estimate

-7.73

Confidence interval

level

98.34%

sides

2-sided

lower limit

-16.29

upper limit

0.83

Notes
[1] - Non-inferiority was a treatment difference larger than -13% at the population level

Analysis of ACR50 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

770

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.0512

Method

Normal approximation to proportions

Parameter type

Difference in response rate

Point estimate

-5.5

Confidence interval

level

98.34%

sides

2-sided

lower limit

-13.98

upper limit

2.98

Notes
[2] - Non-inferiority was a treatment difference larger than -13% at the population level

Analysis of ACR50 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

762

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

< 0.0001

Method

Normal approximation to proportions

Parameter type

Difference in response rate

Point estimate

2.23

Confidence interval

level

98.34%

sides

2-sided

lower limit

-6.4

upper limit

10.86

Notes
[3] - Non-inferiority was a treatment difference larger than -13% at the population level

Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) Value at Month 6

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End point title

Change from Baseline in Simplified Disease Activity Index (SDAI) Value at Month 6

End point description

SDAI is the numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PGA both assessed on a 0 to 10 centimeter (cm) visual analogue scale (VAS) (higher scores indicate greater affection due to disease activity), and CRP (mg/dL). SDAI total score ranges from 0 to 86. SDAI less than or equal to (≤) 3.3 indicates disease remission, >3.4 to 11 indicates low disease activity, >11 to 26 indicates moderate disease activity, and >26 indicates high disease activity.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	355	343	345
Units: Score on a scale
least squares mean (standard error)	-23.7 ± 0.62	-26.6 ± 0.62	-25.6 ± 0.62

Analysis of SDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.23

upper limit

4.41

Analysis of SDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

3.49

Analysis of SDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

688

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.51

upper limit

0.68

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Value at Month 6

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End point title

Change from Baseline in Clinical Disease Activity Index (CDAI) Value at Month 6

End point description

CDAI is the numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PGA both assessed on a 0 to 10 cm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76. CDAI ≤2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	345	347
Units: Score on a scale
least squares mean (standard error)	-22.9 ± 0.61	-25.5 ± 0.61	-24.8 ± 0.61

Analysis of CDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

4.18

Analysis of CDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

3.48

Analysis of CDAI at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

692

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.24

upper limit

0.86

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including CRP at Month 6

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End point title

Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including CRP at Month 6

End point description

DAS28-4 (CRP) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and CRP (mg/L) using the following: DAS28-4(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014* PtGA (millimeters [mm]) + 0.96. Total score range: 0 to 9.4, higher score indicated higher disease activity. DAS28-4 (CRP) ≤3.2 indicates low disease activity, >3.2 to 5.1 indicates moderate to high disease activity, and less than (<) 2.6 indicates remission.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	355	343	345
Units: Score on a scale
least squares mean (standard error)	-2.1 ± 0.07	-2.5 ± 0.07	-2.3 ± 0.07

Analysis of DAS28-4 (CRP) at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.5

Analysis of DAS28-4 (CRP) at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.39

Analysis of DAS28-4 (CRP) at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

688

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.06

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including Erythrocyte Sedimentation Rate (ESR) at Month 6

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End point title

Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including Erythrocyte Sedimentation Rate (ESR) at Month 6

End point description

DAS28-4 (ESR) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and ESR (mm/hour) using the following: DAS28-4(ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014* PtGA (mm). Total score range: 0 to 9.4, higher score indicated higher disease activity. DAS28-3 (ESR) ≤3.2 indicates low disease activity, >3.2 to 5.1 indicates moderate to high disease activity, and <2.6 indicates remission.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	349	342	343
Units: Score on a scale
least squares mean (standard error)	-2.1 ± 0.07	-2.4 ± 0.07	-2.4 ± 0.07

Analysis of DAS28-4 (ESR) at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

691

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

0.51

Analysis of DAS28-4 (ESR) at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

692

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.46

Analysis of DAS28-4 (ESR) at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

685

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

0.13

Secondary: Percentage of Participants Achieving Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria at Month 6

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End point title

Percentage of Participants Achieving Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria at Month 6

End point description

To meet the ACR-EULAR Boolean remission criteria, a participant must satisfy all of the following: TJC ≤1 and SJC ≤1 (both based on a 28-joint assessment), CRP ≤1 mg/dL, and PtGA ≤1 on a 0 to 10 cm VAS (higher scores indicate greater affection due to disease activity).

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	358	346	355
Units: Percentage of participants
number (not applicable)	7.54	8.67	9.58

Analysis of Remission Criteria at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-4.99

upper limit

2.56

Analysis of Remission Criteria at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

713

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-1.78

Confidence interval

level

95%

sides

2-sided

lower limit

-5.59

upper limit

2.04

Analysis of Remission Criteria at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

701

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-4.53

upper limit

3.4

Secondary: Percentage of Participants Achieving SDAI ≤3.3 at Month 6

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End point title

Percentage of Participants Achieving SDAI ≤3.3 at Month 6

End point description

SDAI is the numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PGA both assessed on a 0 to 10 cm VAS (higher scores indicate greater affection due to disease activity), and CRP (mg/dL). SDAI total score ranges from 0 to 86. SDAI ≤3.3 indicates disease remission.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	345	348
Units: Percentage of participants
number (not applicable)	10.64	13.91	14.37

Analysis of SDAI ≤3.3 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.95

upper limit

1.15

Analysis of SDAI ≤3.3 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-3.06

Confidence interval

level

95%

sides

2-sided

lower limit

-7.55

upper limit

1.43

Analysis of SDAI ≤3.3 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-4.45

upper limit

5.14

Secondary: Percentage of Participants Achieving CDAI ≤2.8 at Month 6

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End point title

Percentage of Participants Achieving CDAI ≤2.8 at Month 6

End point description

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	358	347	350
Units: Percentage of participants
number (not applicable)	10.89	14.70	14.57

Analysis of CDAI ≤2.8 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-3.67

Confidence interval

level

95%

sides

2-sided

lower limit

-8.29

upper limit

0.94

Analysis of CDAI ≤2.8 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-3.06

Confidence interval

level

95%

sides

2-sided

lower limit

-7.59

upper limit

1.48

Analysis of CDAI ≤2.8 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-4.24

upper limit

5.47

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) <2.6 at Month 6

Top of page

End point title

Percentage of Participants Achieving DAS28-4 (ESR) <2.6 at Month 6

End point description

DAS28-4 (ESR) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and ESR (mm/hour) using the following: DAS28-4(ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014* PtGA (mm). Total score range: 0 to 9.4, higher score indicates higher disease activity. DAS28-4 (ESR) <2.6 indicates disease remission.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	353	344	346
Units: Percentage of participants
number (not applicable)	11.33	12.79	13.58

Analysis of DAS28-4 (ESR) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-1.55

Confidence interval

level

95%

sides

2-sided

lower limit

-6.03

upper limit

2.93

Analysis of DAS28-4 (ESR) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

690

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-5.11

upper limit

4.18

Analysis of DAS28-4 (ESR) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-2.02

Confidence interval

level

95%

sides

2-sided

lower limit

-6.51

upper limit

2.47

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) <2.6 at Month 6

Top of page

End point title

Percentage of Participants Achieving DAS28-4 (CRP) <2.6 at Month 6

End point description

DAS28-4 (CRP) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and CRP (mg/L) using the following: DAS28-4(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014* PtGA (mm) + 0.96. Total score range: 0 to 9.4, higher score indicates higher disease activity. DAS28-4 (CRP) <2.6 indicates remission.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	345	348
Units: Percentage of participants
number (not applicable)	22.69	32.75	30.17

Analysis of DAS28-4 (CRP) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-9.49

Confidence interval

level

95%

sides

2-sided

lower limit

-15.68

upper limit

-3.3

Analysis of DAS28-4 (CRP) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

2.61

Confidence interval

level

95%

sides

2-sided

lower limit

-3.86

upper limit

9.07

Analysis of DAS28-4 (CRP) <2.6 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in remission rate

Point estimate

-6.89

Confidence interval

level

95%

sides

2-sided

lower limit

-12.94

upper limit

-0.83

Secondary: Percentage of Participants Achieving SDAI ≤11 at Month 6

Top of page

End point title

Percentage of Participants Achieving SDAI ≤11 at Month 6

End point description

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	345	348
Units: Percentage of participants
number (not applicable)	46.78	53.33	51.15

Analysis of SDAI ≤11 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.24

Confidence interval

level

95%

sides

2-sided

lower limit

-13.32

upper limit

0.84

Analysis of SDAI ≤11 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

2.58

Confidence interval

level

95%

sides

2-sided

lower limit

-4.51

upper limit

9.68

Analysis of SDAI ≤11 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-3.66

Confidence interval

level

95%

sides

2-sided

lower limit

-10.69

upper limit

3.37

Secondary: Percentage of Participants Achieving CDAI ≤10 at Month 6

Top of page

End point title

Percentage of Participants Achieving CDAI ≤10 at Month 6

End point description

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	358	347	350
Units: Percentage of participants
number (not applicable)	45.53	52.45	50.00

Analysis of CDAI ≤10 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.22

Confidence interval

level

95%

sides

2-sided

lower limit

-13.29

upper limit

0.85

Analysis of CDAI ≤10 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.79

upper limit

9.39

Analysis of CDAI ≤10 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-3.93

Confidence interval

level

95%

sides

2-sided

lower limit

-10.94

upper limit

3.09

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) ≤3.2 at Month 6

Top of page

End point title

Percentage of Participants Achieving DAS28-4 (ESR) ≤3.2 at Month 6

End point description

DAS28-4 (ESR) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and ESR (mm/hour) using the following: DAS28-4(ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014* PtGA (mm). Total score range: 0 to 9.4, higher score indicates higher disease activity. DAS28-4 (ESR) ≤3.2 indicates low disease activity.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	353	344	346
Units: Percentage of participants
number (not applicable)	22.10	28.49	29.77

Analysis of DAS28-4 (ESR) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.02

Confidence interval

level

95%

sides

2-sided

lower limit

-12.05

upper limit

Analysis of DAS28-4 (ESR) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.89

Confidence interval

level

95%

sides

2-sided

lower limit

-12.9

upper limit

-0.87

Analysis of DAS28-4 (ESR) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

690

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-7.17

upper limit

5.44

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) ≤3.2 at Month 6

Top of page

End point title

Percentage of Participants Achieving DAS28-4 (CRP) ≤3.2 at Month 6

End point description

DAS28-4 (CRP) was calculated from the SJC and TJC (both based on a 28-joint assessment), PtGA (assessed on a 0 to 10 cm VAS; higher scores indicate greater affection due to disease activity) and CRP (mg/L) using the following: DAS28-4(CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014* PtGA + 0.96. Total score range: 0 to 9.4, higher score indicated higher disease activity. DAS28-4 (CRP) ≤3.2 indicates low disease activity.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	345	348
Units: Percentage of participants
number (not applicable)	44.54	49.57	50.86

Analysis of DAS28-4 (CRP) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

702

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-4.87

Confidence interval

level

95%

sides

2-sided

lower limit

-11.92

upper limit

2.18

Analysis of DAS28-4 (CRP) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-5.48

Confidence interval

level

95%

sides

2-sided

lower limit

-12.49

upper limit

1.52

Analysis of DAS28-4 (CRP) ≤3.2 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

693

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in rresponse rate

Point estimate

-0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7

upper limit

6.47

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 20% Improvement (ACR20) Response at Month 6

Top of page

End point title

Percentage of Participants Achieving American College of Rheumatology Criteria 20% Improvement (ACR20) Response at Month 6

End point description

ACR20 response is a ≥20% improvement in TJC or SJC and 20% improvement in 3 of the following 5 criteria: 1) PGA of disease activity, 2) PtGA of disease activity, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	354	345	349
Units: Percentage of participants
number (not applicable)	70.06	79.13	77.65

Analysis of ACR20 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-8.29

Confidence interval

level

95%

sides

2-sided

lower limit

-14.84

upper limit

-1.75

Analysis of ACR20 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

694

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

2.15

Confidence interval

level

95%

sides

2-sided

lower limit

-4.22

upper limit

8.52

Analysis of ACR20 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.14

Confidence interval

level

95%

sides

2-sided

lower limit

-12.72

upper limit

0.44

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 70% Improvement (ACR70) Response at Month 6

Top of page

End point title

Percentage of Participants Achieving American College of Rheumatology Criteria 70% Improvement (ACR70) Response at Month 6

End point description

ACR70 response is a ≥70% improvement in TJC or SJC and 70% improvement in 3 of the following 5 criteria: 1) PGA of disease activity, 2) PtGA of disease activity, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	343	349
Units: Percentage of participants
number (not applicable)	19.66	27.11	22.64

Analysis of ACR70 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-6.77

Confidence interval

level

95%

sides

2-sided

lower limit

-12.61

upper limit

-0.93

Analysis of ACR70 at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

692

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

4.27

Confidence interval

level

95%

sides

2-sided

lower limit

-1.68

upper limit

10.23

Analysis of ACR70 at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.09

upper limit

3.1

Secondary: Change From Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) at Month 6

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End point title

Change From Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) at Month 6

End point description

The HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dressing and grooming, arising, eating, walking, reach, grip, hygiene and other activities over the past week. Each activity category consists of 2 to 3 items. Each item is scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Any activity requiring assistance from another individual or the use of an assistive device adjusts to a minimum score of 2 to represent a more limited functional status. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score ranges from 0 to 3 where 0 = least difficulty and 3 = extreme difficulty.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	348	350
Units: Units on a scale
least squares mean (standard error)	-0.52 ± 0.031	-0.58 ± 0.031	-0.54 ± 0.031

Analysis of HAQ-DI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.011

upper limit

0.148

Analysis of HAQ-DI at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.054

upper limit

0.105

Analysis of HAQ-DI at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.122

upper limit

0.037

Secondary: Percentage of Participants Achieving an HAQ-DI Decrease of at Least 0.22 at Month 6

Top of page

End point title

Percentage of Participants Achieving an HAQ-DI Decrease of at Least 0.22 at Month 6

End point description

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	348	350
Units: Percentage of participants
number (not applicable)	71.07	75.57	72.86

Analysis of HAQ-DI 0.22 Decrease at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-4.07

Confidence interval

level

95%

sides

2-sided

lower limit

-10.68

upper limit

2.55

Analysis of HAQ-DI 0.22 Decrease at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

-1.21

Confidence interval

level

95%

sides

2-sided

lower limit

-7.87

upper limit

5.44

Analysis of HAQ-DI 0.22 Decrease at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Difference in response rate

Point estimate

2.86

Confidence interval

level

95%

sides

2-sided

lower limit

-3.72

upper limit

9.43

Secondary: Change From Baseline in the Short-Form-36 (SF-36) Health Survey, Physical Component Score at Month 6

Top of page

End point title

Change From Baseline in the Short-Form-36 (SF-36) Health Survey, Physical Component Score at Month 6

End point description

The SF-36 health survey is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The health domains are aggregated into two summary scores known as the physical component summary (PCS) score and the mental component summary (MCS) score. Normalized domain scores, PCS and MCS scores are used in the analyses. The component and domain scores were scored using the United States (US) 1998 general population norms. The resulting norm-based T scores for both the SF-36 version 2 (v2) and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher PCS score represents better physical health status.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	355	346	349
Units: Units on a scale
least squares mean (standard error)	6.7 ± 0.44	7.9 ± 0.43	7.8 ± 0.43

Analysis of SF-36 PCS at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

701

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.28

upper limit

-0.11

Analysis of SF-36 PCS at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.16

upper limit

0.01

Analysis of SF-36 PCS at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

695

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

1.2

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Component Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Mental Component Score at Month 6

End point description

The SF-36 health survey is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The health domains are aggregated into two summary scores known as the PCS score and the MCS score. Normalized domain scores, PCS and MCS scores are used in the analyses. The component and domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher MCS score represents better physical health status.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	355	346	349
Units: Units on a scale
least squares mean (standard error)	5.2 ± 0.52	5.7 ± 0.51	4.4 ± 0.51

Analysis of SF-36 MCS at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

701

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.74

upper limit

0.85

Analysis of SF-36 MCS at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

2.11

Analysis of SF-36 MCS at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

695

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

2.56

Secondary: Change From Baseline in the SF-36 Health Survey, Physical Functioning Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Physical Functioning Domain Score at Month 6

End point description

SF-36v2 acute is a 36-item measure evaluating 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 10 items of the physical functioning scale represent levels and kinds of limitations between extremes of physical activities, including lifting and carrying groceries; climbing stairs; bending, kneeling, or stooping; walking moderate distances; self-care limitations. The physical functioning items capture the presence and extent of physical limitations using a 3-level response continuum. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher physical functioning domain score represents better physical functioning.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	348	349
Units: Units on a scale
least squares mean (standard error)	6.4 ± 0.52	7.3 ± 0.52	7.3 ± 0.52

Analysis of SF-36 Physical Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.22

upper limit

0.39

Analysis of SF-36 Physical Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.19

upper limit

0.42

Analysis of SF-36 Physical Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.27

upper limit

1.34

Secondary: Change From Baseline in the SF-36 Health Survey, Role Physical Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Role Physical Domain Score at Month 6

End point description

SF-36v2 acute is a 36-item measure evaluating 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 4-item role physical scale covers an array of physical health-related role limitations, including: a) limitations in the kind of work or other usual activities; b) reductions in the amount of time spent on work or other usual activities; c) difficulty performing work or other usual activities; and d) accomplishing less. Items in the role physical scale are answered on a 5-point scale. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher role physical domain score represents better role physical functioning.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	347	350
Units: Units on a scale
least squares mean (standard error)	6.7 ± 0.47	7.0 ± 0.47	6.3 ± 0.47

Analysis of SF-36 Role Physical at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.52

upper limit

0.87

Analysis of SF-36 Role Physical at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

1.58

Analysis of SF-36 Role Physical at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

1.91

Secondary: Change From Baseline in the SF-36 Health Survey, Bodily Pain Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Bodily Pain Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The bodily pain scale comprises of 2 items pertaining to the intensity of bodily pain and extent of interference with normal work activities. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher bodily pain domain score represents less bodily pain.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	348	350
Units: Units on a scale
least squares mean (standard error)	8.2 ± 0.48	10.3 ± 0.48	9.9 ± 0.48

Analysis of SF-36 Bodily Pain at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.25

upper limit

-0.8

Analysis of SF-36 Bodily Pain at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.91

upper limit

-0.47

Analysis of SF-36 Bodily Pain at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

1.55

Secondary: Change From Baseline in the SF-36 Health Survey, General Health Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, General Health Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The general health scale consists of 5 items including a rating of health and 4 items addressing the respondent’s view and expectations of his or her health. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher general health domain score represents better general health perceptions.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	347	350
Units: Units on a scale
least squares mean (standard error)	5.1 ± 0.44	6.3 ± 0.44	5.4 ± 0.44

Analysis of SF-36 General Health at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.27

upper limit

-0.05

Analysis of SF-36 General Health at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

0.82

Analysis of SF-36 General Health at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.25

upper limit

1.98

Secondary: Change From Baseline in the SF-36 Health Survey, Vitality Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Vitality Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 4-item measure of vitality captures a broad range of subjective evaluations of well-being from feelings of tiredness and being worn out to feeling full of energy all or most of the time. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher vitality domain score represents better vitality.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	348	350
Units: Units on a scale
least squares mean (standard error)	5.6 ± 0.48	6.1 ± 0.47	5.7 ± 0.47

Analysis of SF-36 Vitality at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.71

upper limit

0.68

Analysis of SF-36 Vitality at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.33

upper limit

1.05

Analysis of SF-36 Vitality at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.83

upper limit

1.57

Secondary: Change From Baseline in the SF-36 Health Survey, Social Functioning Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Social Functioning Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 2-item social functioning scale assesses health-related effects on quantity and quality of social activities. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher social functioning domain score represents better social functioning.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	348	350
Units: Units on a scale
least squares mean (standard error)	6.3 ± 0.52	7.2 ± 0.52	6.2 ± 0.52

Analysis of SF-36 Social Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

0.45

Analysis of SF-36 Social Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

707

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

1.51

Analysis of SF-36 Social Functioning at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

2.39

Secondary: Change From Baseline in the SF-36 Health Survey, Role Emotional Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Role Emotional Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 3-item role emotional scale assesses mental health-related role limitations in terms of a) time spent in work or other usual activities; b) amount of work or activities accomplished; c) care with which work or other activities were performed. All 3 items are answered on a 5-point scale. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher role emotional domain score represents better role emotional functioning.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	347	350
Units: Units on a scale
least squares mean (standard error)	6.7 ± 0.58	7.7 ± 0.58	6.0 ± 0.58

Analysis of SF-36 Role Emotional at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.54

upper limit

0.39

Analysis of SF-36 Role Emotional at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

697

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

3.24

Analysis of SF-36 Role Emotional at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

2.16

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Health Domain Score at Month 6

Top of page

End point title

Change From Baseline in the SF-36 Health Survey, Mental Health Domain Score at Month 6

End point description

The SF-36v2 acute is a 36-item measure that evaluates 8 domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The 5-item mental health scale includes 1 or more items from each of 4 major mental health dimensions: anxiety, depression, loss of behavioral/emotional control, and psychological well-being. All items are answered on a 5-point scale. The domain scores were scored using the US 1998 general population norms. The resulting norm-based T scores for both the SF-36 v2 and SF-36 health domain scales and component summary measures have means of 50 and standard deviations of 10. A higher mental health domain score represents better mental health functioning.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	356	348	350
Units: Units on a scale
least squares mean (standard error)	5.3 ± 0.52	5.5 ± 0.52	5.0 ± 0.52

Analysis of SF-36 Mental Health at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

704

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.55

upper limit

1.08

Analysis of SF-36 Mental Health at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.78

upper limit

1.86

Analysis of SF-36 Mental Health at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

706

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

1.62

Secondary: Change From Baseline in the Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6

Top of page

End point title

Change From Baseline in the Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6

End point description

The WPAI: Rheumatoid Arthritis is a 6 item questionnaire that is specific for rheumatoid arthritis and yields four types of scores: absenteeism, presenteesism (impairment at work/reduced job effectiveness), work productivity loss and activity impairment. WPAI outcomes are expressed as impairment percentages ranging from 0 to 100, with higher numbers indicating greater impairment and less productivity.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	341	343
Units: Percentage of impairment
least squares mean (standard error)
Work hours missed due to problems	-2.62 ± 0.717	-2.19 ± 0.700	-1.75 ± 0.741
Work hours missed other reason	0.14 ± 1.019	0.43 ± 0.991	-0.77 ± 1.059
Hours worked in past 7 days	4.13 ± 1.729	-0.82 ± 1.672	1.28 ± 1.788
Problems affecting productivity	-1.94 ± 0.228	-2.14 ± 0.224	-1.95 ± 0.232
Problem affecting daily activities	-2.24 ± 0.137	-2.47 ± 0.138	-2.24 ± 0.139
% work time missed due to health	-4.51 ± 1.790	-3.41 ± 1.794	-1.87 ± 1.831
% impairment while working due to health	-19.38 ± 2.276	-21.44 ± 2.235	-19.52 ± 2.320
% overall work impairment due to health	-20.16 ± 2.663	-22.27 ± 2.638	-21.87 ± 2.710
% activity impairment due to health	-22.36 ± 1.375	-24.74 ± 1.383	-22.45 ± 1.394

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed due to problems

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-2.279

upper limit

1.427

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed due to problems

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-2.783

upper limit

1.044

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed due to problems

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-2.349

upper limit

1.462

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed other reason

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-2.928

upper limit

2.346

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed other reason

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.832

upper limit

3.64

Analysis of WAPI at Month 6

Statistical analysis description

Work hours missed other reason

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.52

upper limit

3.911

Analysis of WAPI at Month 6

Statistical analysis description

Hours worked in past 7 days

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

4.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

9.37

Analysis of WAPI at Month 6

Statistical analysis description

Hours worked in past 7 days

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.85

Confidence interval

level

90%

sides

2-sided

lower limit

-1.736

upper limit

7.43

Analysis of WAPI at Month 6

Statistical analysis description

Hours worked in past 7 days

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-6.65

upper limit

2.454

Analysis of WAPI at Month 6

Statistical analysis description

Problems affecting productivity

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.373

upper limit

0.786

Analysis of WAPI at Month 6

Statistical analysis description

Problems affecting productivity

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.578

upper limit

0.607

Analysis of WAPI at Month 6

Statistical analysis description

Problems affecting productivity

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.784

upper limit

0.4

Analysis of WAPI at Month 6

Statistical analysis description

Problem affecting daily activities

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.112

upper limit

0.587

Analysis of WAPI at Month 6

Statistical analysis description

Problem affecting daily activities

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.341

upper limit

0.357

Analysis of WAPI at Month 6

Statistical analysis description

Problem affecting daily activities

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.582

upper limit

0.122

Analysis of WAPI at Month 6

Statistical analysis description

% work time missed due to health

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.748

upper limit

3.553

Analysis of WAPI at Month 6

Statistical analysis description

% work time missed due to health

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-2.64

Confidence interval

level

95%

sides

2-sided

lower limit

-7.339

upper limit

2.067

Analysis of WAPI at Month 6

Statistical analysis description

% work time missed due to health

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.54

Confidence interval

level

95%

sides

2-sided

lower limit

-6.283

upper limit

3.207

Analysis of WAPI at Month 6

Statistical analysis description

% impairment while working due to health

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.07

Confidence interval

level

95%

sides

2-sided

lower limit

-3.726

upper limit

7.858

Analysis of WAPI at Month 6

Statistical analysis description

% impairment while working due to health

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-5.777

upper limit

6.068

Analysis of WAPI at Month 6

Statistical analysis description

% impairment while working due to health

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-1.92

Confidence interval

level

95%

sides

2-sided

lower limit

-7.839

upper limit

3.998

Analysis of WAPI at Month 6

Statistical analysis description

% overall work impairment due to health

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.11

Confidence interval

level

95%

sides

2-sided

lower limit

-4.664

upper limit

8.877

Analysis of WAPI at Month 6

Statistical analysis description

% overall work impairment due to health

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.71

Confidence interval

level

95%

sides

2-sided

lower limit

-5.164

upper limit

8.58

Analysis of WAPI at Month 6

Statistical analysis description

% overall work impairment due to health

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-7.307

upper limit

6.51

Analysis of WAPI at Month 6

Statistical analysis description

% activity impairment due to health

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

698

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

2.38

Confidence interval

level

95%

sides

2-sided

lower limit

-1.118

upper limit

5.873

Analysis of WAPI at Month 6

Statistical analysis description

% activity impairment due to health

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-3.411

upper limit

3.573

Analysis of WAPI at Month 6

Statistical analysis description

% activity impairment due to health

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

684

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.818

upper limit

1.225

Secondary: Change From Baseline in the EuroQol European Quality of Life-5 Dimensions (EuroQol EQ-5D) at Month 6

Top of page

End point title

Change From Baseline in the EuroQol European Quality of Life-5 Dimensions (EuroQol EQ-5D) at Month 6

End point description

The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state ("confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	348	351
Units: Units on a scale
least squares mean (standard error)
Utility score	0.20 ± 0.013	0.22 ± 0.013	0.22 ± 0.013
Mobility score	-0.29 ± 0.027	-0.26 ± 0.027	-0.28 ± 0.027
Self-care score	-0.27 ± 0.028	-0.33 ± 0.028	-0.32 ± 0.028
Usual activities score	-0.24 ± 0.029	-0.26 ± 0.029	-0.30 ± 0.029
Pain/discomfort score	-0.32 ± 0.026	-0.34 ± 0.026	-0.37 ± 0.026
Anxiety/depression score	-0.21 ± 0.029	-0.24 ± 0.029	-0.22 ± 0.029
VAS score	20.84 ± 1.100	20.98 ± 1.100	19.61 ± 1.100

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Utility score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

0.011

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Utility score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.054

upper limit

0.013

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Utility score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.031

upper limit

0.036

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Mobility score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.098

upper limit

0.042

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Mobility score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.079

upper limit

0.06

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Mobility score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.051

upper limit

0.089

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Self-care score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.014

upper limit

0.127

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Self-care score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.027

upper limit

0.114

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Self-care score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.083

upper limit

0.058

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Usual activities score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.062

upper limit

0.084

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Usual activities score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.129

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Usual activities score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.029

upper limit

0.118

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Pain/discomfort score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.041

upper limit

0.091

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Pain/discomfort score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.116

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Pain/discomfort score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.041

upper limit

0.091

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Anxiety/depression score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.046

upper limit

0.103

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Anxiety/depression score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.066

upper limit

0.083

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

Anxiety/depression score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.094

upper limit

0.055

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

VAS score

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-2.934

upper limit

2.648

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

VAS score

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

708

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

-1.556

upper limit

4.016

Analysis of EuroQol EQ-5D at Month 6

Statistical analysis description

VAS score

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

699

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.425

upper limit

4.171

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Total Score at Month 6

Top of page

End point title

Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Total Score at Month 6

End point description

FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). The larger the participant’s response (with the exception of 2 negatively stated), the greater the participant’s fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant’s response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score).

End point type

Secondary

End point timeframe

Month 6

End point values	Tofacitinib 5 mg BID	Tofacitinib 5 mg BID + MTX	Adalimumab 40 mg + MTX
Number of subjects analysed	357	348	352
Units: Units on a scale
least squares mean (standard error)	7.14 ± 0.500	7.59 ± 0.498	6.07 ± 0.499

Analysis of FACIT-F at Month 6

Comparison groups

Tofacitinib 5 mg BID v Tofacitinib 5 mg BID + MTX

Number of subjects included in analysis

705

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-1.706

upper limit

0.808

Analysis of FACIT-F at Month 6

Comparison groups

Tofacitinib 5 mg BID v Adalimumab 40 mg + MTX

Number of subjects included in analysis

709

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.178

upper limit

2.325

Analysis of FACIT-F at Month 6

Comparison groups

Tofacitinib 5 mg BID + MTX v Adalimumab 40 mg + MTX

Number of subjects included in analysis

700

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS mean difference

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.266

upper limit

2.779

Adverse events

Top of page

Timeframe for reporting adverse events

SAEs were assessed from informed consent up to at least 28 calendar days after last dose of investigational product. AEs were recorded from the time the subject has taken at least one dose of study treatment through last subject visit.

Adverse event reporting additional description

An event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Tofacitinib 5 mg BID

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus placebo MTX (prior dose) orally every week plus placebo adalimumab 40 mg subcutaneously (SC) every other week for up to 12 months.

Reporting group title

Adalimumab 40 mg + MTX

Reporting group description

One placebo tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus active adalimumab 40 mg SC every other week for up to 12 months.

Reporting group title

Tofacitinib 5 mg BID + MTX

Reporting group description

One active tofacitinib 5 mg tablet orally BID plus active MTX (prior dose) orally every week plus placebo adalimumab 40 mg SC every other week for up to 12 months.

Serious adverse events	Tofacitinib 5 mg BID	Adalimumab 40 mg + MTX	Tofacitinib 5 mg BID + MTX
Total subjects affected by serious adverse events
subjects affected / exposed	35 / 384 (9.11%)	24 / 386 (6.22%)	27 / 376 (7.18%)
number of deaths (all causes)	2	1	0
number of deaths resulting from adverse events	2	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Enteropathy-associated T-cell lymphoma
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Lobular breast carcinoma in situ
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Meningioma
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Vascular disorders
Hypertensive emergency
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Unintended pregnancy
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 384 (0.52%)	1 / 386 (0.26%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 384 (0.00%)	2 / 386 (0.52%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Uterine prolapse
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Acute respiratory distress syndrome
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 384 (0.26%)	1 / 386 (0.26%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Pulmonary embolism
subjects affected / exposed	1 / 384 (0.26%)	1 / 386 (0.26%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatoid lung
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Exposure via father
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Fibula fracture
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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	0 / 384 (0.00%)	0 / 386 (0.00%)	3 / 376 (0.80%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Meniscus injury
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Rib fracture
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Tendon rupture
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Thermal burn
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Thoracic vertebral fracture
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Atrial fibrillation
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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 failure congestive
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Cor pulmonale
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Coronary artery disease
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Myocardial ischaemia
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Wolff-Parkinson-White syndrome
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Cerebellar infarction
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Cerebrovascular accident
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertonia
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Hypoaesthesia
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Migraine
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Paraesthesia
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Radicular syndrome
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Syncope
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Transient ischaemic attack
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Eye disorders
Corneal thinning
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrotising retinitis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
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
Diarrhoea
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Diverticulum intestinal
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Intestinal obstruction
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Vomiting
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Cholecystitis acute
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Cholecystitis chronic
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Cholelithiasis
subjects affected / exposed	2 / 384 (0.52%)	1 / 386 (0.26%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Hepatitis
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Renal and urinary disorders
Diabetic nephropathy
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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 colic
subjects affected / exposed	0 / 384 (0.00%)	2 / 386 (0.52%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone disorder
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Intervertebral disc degeneration
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Osteoarthritis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Osteochondrosis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Osteonecrosis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Rheumatoid arthritis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Rotator cuff syndrome
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Atypical pneumonia
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Cellulitis
subjects affected / exposed	3 / 384 (0.78%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridial sepsis
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
H1N1 influenza
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis tuberculous
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Pneumonia
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	2 / 376 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salpingo-oophoritis
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 384 (0.00%)	1 / 386 (0.26%)	0 / 376 (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
Urosepsis
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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
Cellulitis with abscess
subjects affected / exposed	0 / 384 (0.00%)	0 / 386 (0.00%)	1 / 376 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	1 / 384 (0.26%)	0 / 386 (0.00%)	0 / 376 (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: 5%

Non-serious adverse events	Tofacitinib 5 mg BID	Adalimumab 40 mg + MTX	Tofacitinib 5 mg BID + MTX
Total subjects affected by non serious adverse events
subjects affected / exposed	51 / 384 (13.28%)	69 / 386 (17.88%)	72 / 376 (19.15%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	8 / 384 (2.08%)	26 / 386 (6.74%)	23 / 376 (6.12%)
occurrences all number	8	38	28
Infections and infestations
Nasopharyngitis
subjects affected / exposed	22 / 384 (5.73%)	18 / 386 (4.66%)	16 / 376 (4.26%)
occurrences all number	28	23	19
Upper respiratory tract infection
subjects affected / exposed	25 / 384 (6.51%)	29 / 386 (7.51%)	37 / 376 (9.84%)
occurrences all number	35	37	48

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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 Study of 5 mg of Tofacitinib With and Without Methotrexate in Comparison to Adalimumab With Methotrexate in Subjects With Moderately to Severely Active Rheumatoid Arthritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving American College of Rheumatology Criteria 50% Improvement (ACR50) Response at Month 6

Primary: Percentage of Participants Achieving American College of Rheumatology Criteria 50% Improvement (ACR50) Response at Month 6

Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) Value at Month 6

Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI) Value at Month 6

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Value at Month 6

Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Value at Month 6

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including CRP at Month 6

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including CRP at Month 6

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including Erythrocyte Sedimentation Rate (ESR) at Month 6

Secondary: Change from Baseline in Disease Activity Score 28-4 (DAS28-4) Including Erythrocyte Sedimentation Rate (ESR) at Month 6

Secondary: Percentage of Participants Achieving Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria at Month 6

Secondary: Percentage of Participants Achieving Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria at Month 6

Secondary: Percentage of Participants Achieving SDAI ≤3.3 at Month 6

Secondary: Percentage of Participants Achieving SDAI ≤3.3 at Month 6

Secondary: Percentage of Participants Achieving CDAI ≤2.8 at Month 6

Secondary: Percentage of Participants Achieving CDAI ≤2.8 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) <2.6 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) <2.6 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) <2.6 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) <2.6 at Month 6

Secondary: Percentage of Participants Achieving SDAI ≤11 at Month 6

Secondary: Percentage of Participants Achieving SDAI ≤11 at Month 6

Secondary: Percentage of Participants Achieving CDAI ≤10 at Month 6

Secondary: Percentage of Participants Achieving CDAI ≤10 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) ≤3.2 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (ESR) ≤3.2 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) ≤3.2 at Month 6

Secondary: Percentage of Participants Achieving DAS28-4 (CRP) ≤3.2 at Month 6

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 20% Improvement (ACR20) Response at Month 6

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 20% Improvement (ACR20) Response at Month 6

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 70% Improvement (ACR70) Response at Month 6

Secondary: Percentage of Participants Achieving American College of Rheumatology Criteria 70% Improvement (ACR70) Response at Month 6

Secondary: Change From Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) at Month 6

Secondary: Change From Baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) at Month 6

Secondary: Percentage of Participants Achieving an HAQ-DI Decrease of at Least 0.22 at Month 6

Secondary: Percentage of Participants Achieving an HAQ-DI Decrease of at Least 0.22 at Month 6

Secondary: Change From Baseline in the Short-Form-36 (SF-36) Health Survey, Physical Component Score at Month 6

Secondary: Change From Baseline in the Short-Form-36 (SF-36) Health Survey, Physical Component Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Component Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Component Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Physical Functioning Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Physical Functioning Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Role Physical Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Role Physical Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Bodily Pain Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Bodily Pain Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, General Health Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, General Health Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Vitality Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Vitality Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Social Functioning Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Social Functioning Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Role Emotional Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Role Emotional Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Health Domain Score at Month 6

Secondary: Change From Baseline in the SF-36 Health Survey, Mental Health Domain Score at Month 6

Secondary: Change From Baseline in the Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6

Secondary: Change From Baseline in the Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6

Secondary: Change From Baseline in the EuroQol European Quality of Life-5 Dimensions (EuroQol EQ-5D) at Month 6

Secondary: Change From Baseline in the EuroQol European Quality of Life-5 Dimensions (EuroQol EQ-5D) at Month 6

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Total Score at Month 6

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Total Score at Month 6

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3b/4 Randomized Double-Blind Study of 5 mg of Tofacitinib With and Without Methotrexate in Comparison to Adalimumab With Methotrexate in Subjects With Moderately to Severely Active Rheumatoid Arthritis