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Safety Study Of Tofacitinib Versus Tumor Necrosis Factor (TNF) Inhibitor In Subjects With Rheumatoid Arthritis

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ClinicalTrials.gov Identifier: NCT02092467
Recruitment Status : Completed
First Posted : March 20, 2014
Results First Posted : August 17, 2021
Last Update Posted : August 17, 2021
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Arthritis, Rheumatoid
Interventions Drug: tofacitinib
Biological: adalimumab
Biological: etanercept
Enrollment 4372
Recruitment Details  
Pre-assignment Details Study started from 14 March 2014 and completed on 22 July 2020.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug. Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug. In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Period Title: Overall Study
Started 1457 1457 1458
Treated 1455 1456 1451
Completed 1053 998 1060
Not Completed 404 459 398
Reason Not Completed
Death             49             66             38
Lost to Follow-up             38             35             40
Global Deterioration of Health Status             1             0             0
Other             32             30             24
Withdrawal by Subject             282             327             289
Randomized but not treated             2             1             7
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi Total
Hide Arm/Group Description Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug. Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug. In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug. Total of all reporting groups
Overall Number of Baseline Participants 1455 1456 1451 4362
Hide Baseline Analysis Population Description
Safety Analysis Set (SAS) included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1455 participants 1456 participants 1451 participants 4362 participants
60.75  (6.80) 61.40  (7.07) 61.30  (7.47) 61.15  (7.12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1455 participants 1456 participants 1451 participants 4362 participants
Female
1169
  80.3%
1124
  77.2%
1117
  77.0%
3410
  78.2%
Male
286
  19.7%
332
  22.8%
334
  23.0%
952
  21.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1455 participants 1456 participants 1451 participants 4362 participants
Hispanic or Latino
438
  30.1%
482
  33.1%
470
  32.4%
1390
  31.9%
Not Hispanic or Latino
1017
  69.9%
974
  66.9%
981
  67.6%
2972
  68.1%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 1455 participants 1456 participants 1451 participants 4362 participants
White
1128
  77.5%
1126
  77.3%
1099
  75.7%
3353
  76.9%
Black or African American
63
   4.3%
65
   4.5%
83
   5.7%
211
   4.8%
Asian
65
   4.5%
56
   3.8%
55
   3.8%
176
   4.0%
Other
199
  13.7%
209
  14.4%
214
  14.7%
622
  14.3%
1.Primary Outcome
Title Incidence Rate of Adjudicated Malignancies Excluding Non-melanoma Skin Cancers (NMSC)
Hide Description Incidence rate (number of participants with event per 100 participant year [PY]) was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. Malignancy events, excluding NMSC were adjudicated by a steering committee. The risk period (RP) was the last contact date. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID All Tofacitinib TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
All participants who received treatment in either tofacitinib 5 mg or tofacitinib 10 mg group BID up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 2911 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
1.13
(0.87 to 1.45)
1.13
(0.86 to 1.45)
1.13
(0.94 to 1.35)
0.77
(0.55 to 1.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection All Tofacitinib, TNFi
Comments All Tofacitinib versus TNFi
Type of Statistical Test Non-Inferiority
Comments Hazard ratio (95% CI) was based on a univariate Cox proportional hazard model with treatment [All Tofacitinib (ie, tofacitinib 5 mg BID and tofacitinib 10 mg BID combined) and TNFi] as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.48
Confidence Interval (2-Sided) 95%
1.04 to 2.09
Estimation Comments Primary comparison. Non-inferiority was to be claimed between All Tofacitinib and TNFi if the upper limit of the 95% CI for HR was < 1.8 (non-inferiority criterion).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tofacitinib 5 mg BID, Tofacitinib 10 mg BID
Comments Tofacitinib 10 mg BID versus Tofacitinib 5 mg BID
Type of Statistical Test Non-Inferiority
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.70 to 1.43
Estimation Comments Secondary comparison. Non-inferiority was to be claimed between tofacitinib 10 mg BID and tofacitinib 5 mg BID if the upper limit of the 95% CI for HR was < 2.0 (non-inferiority criterion).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tofacitinib 5 mg BID, TNFi
Comments Tofacitinib 5 mg BID versus TNFi
Type of Statistical Test Other
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.47
Confidence Interval (2-Sided) 95%
1.00 to 2.18
Estimation Comments Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tofacitinib 10 mg BID, TNFi
Comments Tofacitinib 10 mg BID versus TNFi
Type of Statistical Test Other
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.48
Confidence Interval (2-Sided) 95%
1.00 to 2.19
Estimation Comments Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
2.Primary Outcome
Title Incidence Rate of Adjudicated Major Adverse Cardiovascular Events (MACE)
Hide Description MACE included the cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke of any classification, including reversible focal neurologic defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage. Incidence rate was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID All Tofacitinib TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
All participants who received treatment in either tofacitinib 5 mg or tofacitinib 10 mg group BID up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 2911 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
0.91
(0.67 to 1.21)
1.05
(0.78 to 1.38)
0.98
(0.79 to 1.19)
0.73
(0.52 to 1.01)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection All Tofacitinib, TNFi
Comments All Tofacitinib versus TNFi
Type of Statistical Test Non-Inferiority
Comments Hazard ratio (95% CI) was based on a univariate Cox proportional hazard model with treatment [All Tofacitinib (ie, tofacitinib 5 mg BID and tofacitinib 10 mg BID combined) and TNFi] as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.33
Confidence Interval (2-Sided) 95%
0.91 to 1.94
Estimation Comments Primary comparison. Non-inferiority was to be claimed between All Tofacitinib and TNFi if the upper limit of the 95% CI for HR was < 1.8 (non-inferiority criterion).
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tofacitinib 5 mg BID, Tofacitinib 10 mg BID
Comments Tofacitinib 10 mg BID versus Tofacitinib 5 mg BID
Type of Statistical Test Non-Inferiority
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.15
Confidence Interval (2-Sided) 95%
0.77 to 1.71
Estimation Comments Secondary Comparison. Non-inferiority was to be claimed between tofacitinib 10 mg BID and tofacitinib 5 mg BID if the upper limit of the 95% CI for HR was <2.0 (non-inferiority criterion).
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tofacitinib 5 mg BID, TNFi
Comments Tofacitinib 5 mg BID versus TNFi
Type of Statistical Test Other
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.24
Confidence Interval (2-Sided) 95%
0.81 to 1.91
Estimation Comments Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tofacitinib 10 mg BID, TNFi
Comments Tofacitinib 10 mg BID versus TNFi
Type of Statistical Test Other
Comments Hazard ratio (95% CI) was based on a univariate cox proportional hazard model with treatment (tofacitinib 5 mg BID, tofacitinib 10 mg BID and TNFi) as covariate.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.43
Confidence Interval (2-Sided) 95%
0.94 to 2.18
Estimation Comments Supportive analysis to the primary comparison between All Tofacitinib vs TNFi.
3.Secondary Outcome
Title Incidence Rate of Non-fatal Stroke
Hide Description Non-fatal stroke included reversible focal neurologic defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage. Incidence rate was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
0.27
(0.15 to 0.45)
0.33
(0.19 to 0.53)
0.34
(0.20 to 0.54)
4.Secondary Outcome
Title Incidence Rate of Non-fatal Myocardial Infarction
Hide Description Incidence rate was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 60 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
0.37
(0.22 to 0.57)
0.33
(0.19 to 0.53)
0.16
(0.07 to 0.31)
5.Secondary Outcome
Title Incidence Rate of Adjudicated Opportunistic Infection Events Including Tuberculosis
Hide Description Opportunistic infections (OI) were reviewed and adjudicated by the opportunistic infection review committee (OIRC). Incidence rate was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
0.76
(0.54 to 1.04)
0.91
(0.66 to 1.22)
0.42
(0.26 to 0.64)
6.Secondary Outcome
Title Incidence Rate of Adjudicated Hepatic Events
Hide Description Hepatic events (adjudicated) included drug-induced liver injury (DILI) - probable, highly likely and definite, DILI - listed separately, DILI - cases meeting classification and severity, participants with elevations of transaminase levels greater than (>) 1* upper limit of normal (ULN), greater than or equal to (>=) 3*ULN, >=5*ULN (based on laboratory values). Incidence rate was the total number of participants with admissible events divided by total (for all qualifying participants) time at risk for the cohort/treatment group of interest. The risk period (RP) was minimum of The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. Last contact date was maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). In case of death, last contact date was death date. First events counted within RP. Participant did not have an event or had an event outside risk period were censored at end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
0.90
(0.66 to 1.20)
1.51
(1.18 to 1.91)
0.70
(0.49 to 0.97)
7.Secondary Outcome
Title Incidence Rate of Adjudicated Cardiovascular Events Other Than Major Adverse Cardiovascular Events (MACE)
Hide Description Cardiovascular events (adjudicated) were death (coronary and non-coronary), MI, all coronary revascularization, unstable angina, new ischemic heart disease, stroke (fatal and non-fatal), transient ischemic attack (TIA), congestive heart failure (CHF), peripheral arterial vascular disease (PAVD), deep vein thrombosis, pulmonary embolism, arterial embolism, arterial thrombosis. Incidence rate was total number of participants with admissible events divided by total (for all qualifying participants) time at risk for cohort/treatment group of interest. Risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. Last contact date was maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). In case of death, last contact date was death date. First events counted within RP. Participant did not have an event or had an event outside risk period were censored at end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
1.21
(0.92 to 1.55)
1.45
(1.13 to 1.83)
1.05
(0.78 to 1.38)
8.Secondary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description AE was any untoward medical occurrence post treatment; event need not necessarily had causal relationship with treatment or usage. SAE: any untoward medical occurrence at any dose: resulted in death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly. TEAE: event that occurred for first time during effective duration of treatment and not seen prior to start of treatment or event seen prior to start of treatment but increase in severity during treatment. Risk period (RP) for AE: minimum of last contact date or last study treatment dose date+28 days. RP for SAEs: last contact date. Last contact date was maximum: AE start, AE stop, last study visit, withdrawal and telephone contact. In case of death, last contact was death date. First events counted within RP. Participant did not have event or had event outside risk period were censored at end of RP.
Time Frame AEs: Baseline up to minimum of last contact date or last study treatment dose date+28 days (maximum up to 72 months); SAEs: Baseline up to minimum of last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Count of Participants
Unit of Measure: Participants
AEs
1333
  91.6%
1344
  92.3%
1308
  90.1%
SAEs
373
  25.6%
420
  28.8%
339
  23.4%
9.Secondary Outcome
Title Number of Participants With Clinically Significant Abnormal Laboratory Parameters
Hide Description Clinically significant laboratory abnormalities: Hematology: hemoglobin, hematocrit, erythrocytes with primary criteria as less than [<] 0.8* lower limit of normal [LLN]), platelets (<0.5* LLN; >1.75* ULN), leukocytes (<0.6*LLN; >1.5*ULN), lymphocytes, lymphocytes/leukocytes, neutrophils, neutrophils/leukocytes (<0.8*LLN; >1.2*ULN), eosinophils, eosinophils/leukocytes, monocytes, monocytes/leukocytes (>1.2*ULN); urinalysis: urine glucose, urine protein, urine hemoglobin, and leukocyte esterase (>=1); chemistry: bilirubin, indirect bilirubin (>1.5*ULN) aspartate aminotransferase, alanine aminotransferase (>3.0*ULN), creatinine, triglycerides, cholesterol (>1.3*ULN) and HDL cholesterol (<0.8*LLN). Risk period (RP) was minimum of last contact date or last study treatment dose date+28 days. Last contact date was (date of death or maximum of dates: AE start, AE stop, last study visit, withdrawal, telephone contact). Participants without event or event outside RP were censored at end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population included all participants from SAS with an abnormal baseline with at least one observation of the given laboratory test while on study treatment or during lag time.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 919 911 915
Measure Type: Count of Participants
Unit of Measure: Participants
238
  25.9%
252
  27.7%
167
  18.3%
10.Secondary Outcome
Title Incidence Rate of Adjudicated All-Cause Deaths
Hide Description All-cause death was defined as the death due to any cause during the course of study. Incidence rate was defined as the total number of participants with admissible events divided by the total (for all qualifying participants) time at risk for the cohort/treatment group of interest. Incidence rate of all-cause deaths (adjudicated by Adjudication Committee) was reported in this outcome measure. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: participants with event/100 PY
Deaths-Total
0.50
(0.33 to 0.74)
0.80
(0.57 to 1.09)
0.34
(0.20 to 0.54)
Deaths - Infections
0.08
(0.02 to 0.20)
0.18
(0.08 to 0.35)
0.06
(0.01 to 0.17)
Deaths - Cardiovascular Events
0.25
(0.13 to 0.43)
0.41
(0.25 to 0.63)
0.20
(0.10 to 0.36)
Deaths - Malignancies
0.10
(0.03 to 0.23)
0.00
(0.00 to 0.08)
0.02
(0.00 to 0.11)
Deaths - Other Causes
0.08
(0.02 to 0.20)
0.21
(0.10 to 0.38)
0.06
(0.01 to 0.17)
11.Secondary Outcome
Title Number of Participants With Reasons For Permanent or Temporary Discontinuation of Study Medication
Hide Description Number of participants who permanent or temporary discontinued study medication due to any AE, treatment related AEs, Coronavirus disease 2019 (COVID 19) related AEs, and herpes zoster were reported. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). If a participant died, last contact date was the death date. First events were counted within the RP. If a participant did not have an event or had an event but outside the risk period, the participant was censored at the end of RP.
Time Frame Baseline up to last contact date (maximum up to 72 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SAS included all participants who were randomized in the study and received at least one dose of the randomized investigational drug (tofacitinib or TNFi).
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Count of Participants
Unit of Measure: Participants
Permanent discontinuation: AE
210
  14.4%
304
  20.9%
210
  14.5%
Temporary discontinuation: AEs
665
  45.7%
736
  50.5%
576
  39.7%
Permanent discontinuation: treatment related AE
111
   7.6%
179
  12.3%
114
   7.9%
Temporary discontinuation: treatment related AE
407
  28.0%
458
  31.5%
297
  20.5%
Permanent discontinuation: COVID-19 Related AEs
0
   0.0%
1
   0.1%
0
   0.0%
Temporary discontinuation: COVID-19 Related AEs
0
   0.0%
1
   0.1%
1
   0.1%
Permanent discontinuation: Herpes Zoster
6
   0.4%
13
   0.9%
2
   0.1%
Temporary discontinuation: Herpes Zoster
104
   7.1%
110
   7.6%
33
   2.3%
12.Secondary Outcome
Title Change From Baseline in Disease Activity Score 28-4 (DAS28-4) C-reactive Protein (CRP) at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Description DAS28 is a measure of disease activity in participants with rheumatoid arthritis based on a 28-joint assessment. DAS28-4 (CRP) was calculated from number of painful joints out of 28 joints (TJC28) and number of swollen joints out of 28 joints (SJC28), CRP (milligrams per liter [mg/L]) and patient's global assessment of disease activity (PtGA) on a 100 mm Visual Analog Scale (VAS) (scores ranging from 0 millimeter [mm] [very well] to 100 mm [worst], higher scores indicated worse health condition). Total DAS28-4 (CRP) score range: 0 to 9.4, higher score indicated more disease activity. DAS28-4 (CRP) <= 3.2 indicates low disease activity and > 3.2 to <=5.1 indicates moderate disease activity, >5.1 indicates high disease activity, and DAS28-4 (CRP) < 2.6 indicates remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96; ln = natural logarithm, sqrt = square root.
Time Frame Baseline, Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): all participants randomized and received at least one dose of drug. Mixed model for repeated measures used without imputation for missing values. Analyses included data while participants were receiving drug. Only visits with N > 50 participants in each treatment group included in analyses. Number of Participants Analyzed: number of participants included in mixed model for repeated measures. Number Analyzed: number of participants evaluable for each specified time point.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1409 1391 1386
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change at Month 2 Number Analyzed 1325 participants 1301 participants 1316 participants
-2.00  (0.03) -2.14  (0.03) -1.89  (0.03)
Change at Month 3 Number Analyzed 1367 participants 1328 participants 1317 participants
-2.28  (0.03) -2.42  (0.03) -2.19  (0.03)
Change at Month 6 Number Analyzed 1336 participants 1298 participants 1294 participants
-2.50  (0.03) -2.68  (0.03) -2.40  (0.03)
Change at Month 9 Number Analyzed 1286 participants 1246 participants 1245 participants
-2.64  (0.03) -2.80  (0.03) -2.54  (0.03)
Change at Month 12 Number Analyzed 1254 participants 1204 participants 1197 participants
-2.70  (0.03) -2.85  (0.03) -2.60  (0.03)
Change at Month 15 Number Analyzed 1218 participants 1171 participants 1174 participants
-2.78  (0.03) -2.93  (0.03) -2.67  (0.03)
Change at Month 18 Number Analyzed 1184 participants 1121 participants 1138 participants
-2.78  (0.03) -2.95  (0.03) -2.76  (0.03)
Change at Month 21 Number Analyzed 1169 participants 1076 participants 1115 participants
-2.82  (0.03) -2.97  (0.03) -2.76  (0.03)
Change at Month 24 Number Analyzed 1134 participants 1051 participants 1097 participants
-2.82  (0.03) -2.99  (0.03) -2.77  (0.03)
Change at Month 27 Number Analyzed 1099 participants 1015 participants 1045 participants
-2.91  (0.03) -3.03  (0.03) -2.81  (0.03)
Change at Month 30 Number Analyzed 1073 participants 999 participants 1039 participants
-2.92  (0.03) -3.03  (0.03) -2.89  (0.03)
Change at Month 33 Number Analyzed 1055 participants 974 participants 1037 participants
-2.89  (0.03) -3.03  (0.03) -2.89  (0.03)
Change at Month 36 Number Analyzed 1029 participants 951 participants 1014 participants
-2.91  (0.03) -2.98  (0.03) -2.88  (0.03)
Change at Month 39 Number Analyzed 984 participants 888 participants 960 participants
-2.96  (0.03) -2.97  (0.03) -2.91  (0.03)
Change at Month 42 Number Analyzed 851 participants 768 participants 831 participants
-2.95  (0.03) -3.05  (0.03) -2.93  (0.03)
Change at Month 45 Number Analyzed 710 participants 642 participants 673 participants
-2.94  (0.04) -2.96  (0.04) -2.97  (0.04)
Change at Month 48 Number Analyzed 567 participants 506 participants 537 participants
-2.98  (0.04) -2.99  (0.04) -2.93  (0.04)
Change at Month 51 Number Analyzed 458 participants 419 participants 414 participants
-3.00  (0.04) -2.95  (0.04) -2.96  (0.04)
Change at Month 54 Number Analyzed 363 participants 329 participants 322 participants
-2.99  (0.04) -3.01  (0.05) -2.99  (0.05)
Change at Month 57 Number Analyzed 263 participants 240 participants 247 participants
-2.97  (0.05) -2.93  (0.05) -3.02  (0.05)
Change at Month 60 Number Analyzed 182 participants 182 participants 166 participants
-3.09  (0.06) -2.94  (0.06) -3.01  (0.06)
Change at Month 63 Number Analyzed 106 participants 108 participants 96 participants
-3.07  (0.08) -2.99  (0.07) -3.05  (0.08)
13.Secondary Outcome
Title Change From Baseline in Simplified Disease Activity Index (SDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Description SDAI is the numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and physician's global assessment of health (PhyGA) both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity), and CRP (mg/L). SDAI total score ranges from 0 to 86 with higher score indicating greater disease activity. SDAI <=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. SDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10 + CRP/10.
Time Frame Baseline, Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: all participants randomized and received at least one dose of drug. Mixed model for repeated measures used without imputation for missing values. Analyses included data while participants were receiving drug. Only visits with N > 50 participants in each treatment group included in analyses. Number of Participants Analyzed: number of participants included in mixed model for repeated measures. Number Analyzed: number of participants evaluable for each specified time point.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1378 1356 1346
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change at Month 2 Number Analyzed 1272 participants 1257 participants 1258 participants
-22.95  (0.33) -23.84  (0.33) -22.24  (0.33)
Change at Month 3 Number Analyzed 1321 participants 1280 participants 1273 participants
-25.73  (0.30) -26.81  (0.30) -25.26  (0.30)
Change at Month 6 Number Analyzed 1288 participants 1245 participants 1244 participants
-27.63  (0.28) -28.93  (0.28) -27.21  (0.28)
Change at Month 9 Number Analyzed 1244 participants 1204 participants 1197 participants
-28.81  (0.28) -30.07  (0.28) -28.29  (0.28)
Change at Month 12 Number Analyzed 1215 participants 1168 participants 1143 participants
-29.56  (0.27) -30.46  (0.27) -28.71  (0.27)
Change at Month 15 Number Analyzed 1172 participants 1128 participants 1129 participants
-30.20  (0.25) -31.15  (0.26) -29.30  (0.26)
Change at Month 18 Number Analyzed 1149 participants 1085 participants 1092 participants
-30.14  (0.26) -31.29  (0.26) -30.18  (0.26)
Change at Month 21 Number Analyzed 1138 participants 1040 participants 1072 participants
-30.42  (0.26) -31.46  (0.26) -30.36  (0.26)
Change at Month 24 Number Analyzed 1092 participants 1010 participants 1051 participants
-30.51  (0.26) -31.56  (0.26) -30.33  (0.26)
Change at month 27 Number Analyzed 1056 participants 979 participants 1002 participants
-31.16  (0.25) -31.85  (0.26) -30.53  (0.26)
Change at Month 30 Number Analyzed 1046 participants 970 participants 996 participants
-31.27  (0.25) -32.02  (0.25) -31.24  (0.25)
Change at Month 33 Number Analyzed 1027 participants 947 participants 997 participants
-31.06  (0.26) -31.91  (0.26) -31.20  (0.26)
Change at Month 36 Number Analyzed 994 participants 917 participants 978 participants
-31.26  (0.26) -31.52  (0.27) -31.09  (0.26)
Change at Month 39 Number Analyzed 954 participants 857 participants 920 participants
-31.77  (0.25) -31.51  (0.26) -31.36  (0.26)
Change at Month 42 Number Analyzed 819 participants 733 participants 800 participants
-31.62  (0.27) -32.09  (0.28) -31.24  (0.27)
Change at Month 45 Number Analyzed 692 participants 617 participants 646 participants
-31.27  (0.29) -31.67  (0.30) -31.85  (0.30)
Change at Month 48 Number Analyzed 547 participants 485 participants 522 participants
-31.87  (0.31) -31.59  (0.32) -31.68  (0.32)
Change at Month 51 Number Analyzed 438 participants 406 participants 400 participants
-32.15  (0.33) -31.52  (0.34) -31.72  (0.34)
Change at Month 54 Number Analyzed 347 participants 316 participants 314 participants
-31.91  (0.33) -32.33  (0.35) -31.95  (0.35)
Change at Month 57 Number Analyzed 253 participants 235 participants 242 participants
-31.58  (0.41) -31.61  (0.42) -31.98  (0.42)
Change at Month 60 Number Analyzed 174 participants 179 participants 161 participants
-32.84  (0.46) -31.57  (0.46) -32.23  (0.48)
Change at Month 63 Number Analyzed 102 participants 107 participants 95 participants
-32.27  (0.63) -32.12  (0.62) -32.27  (0.66)
14.Secondary Outcome
Title Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Description CDAI is the numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score indicating greater disease activity. 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. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10.
Time Frame Baseline, Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: all participants randomized and received at least one dose of drug. Mixed model for repeated measures used without imputation for missing values. Analyses included data while participants were receiving drug. Only visits with N > 50 participants in each treatment group included in analyses. Number of Participants Analyzed: number of participants included in mixed model for repeated measures. Number Analyzed: number of participants evaluable for each specified time point.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1378 1356 1348
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change at Month 2 Number Analyzed 1272 participants 1258 participants 1264 participants
-21.99  (0.32) -22.84  (0.32) -21.30  (0.32)
Change at Month 3 Number Analyzed 1325 participants 1281 participants 1276 participants
-24.76  (0.29) -25.77  (0.29) -24.29  (0.30)
Change at Month 6 Number Analyzed 1292 participants 1246 participants 1249 participants
-26.59  (0.27) -27.82  (0.28) -26.21  (0.28)
Change at Month 9 Number Analyzed 1245 participants 1207 participants 1200 participants
-27.78  (0.27) -29.03  (0.27) -27.30  (0.27)
Change at Month 12 Number Analyzed 1217 participants 1169 participants 1146 participants
-28.52  (0.26) -29.38  (0.26) -27.73  (0.26)
Change at Month 15 Number Analyzed 1177 participants 1129 participants 1135 participants
-29.17  (0.25) -30.06  (0.25) -28.38  (0.25)
Change at Month 18 Number Analyzed 1152 participants 1086 participants 1096 participants
-29.12  (0.25) -30.21  (0.26) -29.15  (0.25)
Change at Month 21 Number Analyzed 1141 participants 1041 participants 1075 participants
-29.45  (0.25) -30.49  (0.26) -29.40  (0.25)
Change at Month 24 Number Analyzed 1093 participants 1013 participants 1055 participants
-29.54  (0.25) -30.49  (0.26) -29.39  (0.25)
Change at Month 27 Number Analyzed 1058 participants 979 participants 1011 participants
-30.16  (0.24) -30.82  (0.25) -29.54  (0.25)
Change at Month 30 Number Analyzed 1049 participants 970 participants 1002 participants
-30.27  (0.24) -30.99  (0.25) -30.24  (0.25)
Change at Month 33 Number Analyzed 1034 participants 951 participants 1000 participants
-30.05  (0.25) -30.85  (0.25) -30.23  (0.25)
Change at Month 36 Number Analyzed 999 participants 920 participants 982 participants
-30.29  (0.25) -30.50  (0.26) -30.14  (0.25)
Change at Month 39 Number Analyzed 958 participants 858 participants 923 participants
-30.78  (0.24) -30.49  (0.25) -30.35  (0.25)
Change at Month 42 Number Analyzed 820 participants 736 participants 801 participants
-30.66  (0.26) -31.05  (0.27) -30.25  (0.26)
Change at Month 45 Number Analyzed 694 participants 618 participants 650 participants
-30.28  (0.28) -30.68  (0.29) -30.83  (0.29)
Change at Month 48 Number Analyzed 547 participants 487 participants 522 participants
-30.85  (0.30) -30.57  (0.32) -30.69  (0.31)
Change at Month 51 Number Analyzed 440 participants 407 participants 401 participants
-31.09  (0.32) -30.50  (0.33) -30.74  (0.33)
Change at Month 54 Number Analyzed 347 participants 317 participants 314 participants
-31.03  (0.32) -31.38  (0.33) -31.02  (0.33)
Change at Month 57 Number Analyzed 254 participants 236 participants 242 participants
-30.62  (0.40) -30.75  (0.41) -30.95  (0.41)
Change at Month 60 Number Analyzed 175 participants 179 participants 161 participants
-31.74  (0.45) -30.57  (0.45) -31.31  (0.47)
Change at Month 63 Number Analyzed 102 participants 107 participants 95 participants
-31.23  (0.58) -31.08  (0.57) -31.65  (0.60)
15.Secondary Outcome
Title Percentage of Participants Who Achieved Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria
Hide Description ACR-EULAR Boolean-based definition of remission participant must satisfy all of the following: TJC28 <=1, SJC28 <=1, CRP <=10 mg/L, PtGA on a 0-100 mm scale, higher scores indicate greater affection due to disease activity.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in study and received at least one dose of randomized investigational drug. Analyses included data while participants were receiving the study drug. 'Number Analyzed' signifies number of participants evaluable for each specified time point. Last Observation Carried Forward (LOCF) applied for missing components and composite binary outcome was calculated. The percentages were calculated using numbers of participants evaluable at each visit as denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1356 participants 1342 participants 1368 participants
3.83 4.99 3.22
Month 3 Number Analyzed 1432 participants 1424 participants 1427 participants
5.73 7.72 6.10
Month 6 Number Analyzed 1417 participants 1398 participants 1411 participants
9.10 10.66 7.80
Month 9 Number Analyzed 1392 participants 1349 participants 1384 participants
10.85 12.60 8.96
Month 12 Number Analyzed 1372 participants 1332 participants 1360 participants
11.22 13.06 9.12
Month 15 Number Analyzed 1353 participants 1311 participants 1342 participants
12.56 15.18 10.28
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
12.10 16.04 11.78
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
12.90 15.22 13.45
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
13.60 15.99 13.35
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
13.24 17.59 14.82
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
13.46 16.96 14.31
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
13.88 15.97 14.82
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
14.51 16.18 14.53
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
13.78 14.30 15.15
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
14.79 15.41 15.01
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
14.89 15.46 15.74
Month 48 Number Analyzed 865 participants 806 participants 839 participants
15.14 13.90 17.28
Month 51 Number Analyzed 698 participants 671 participants 689 participants
14.33 15.50 16.26
Month 54 Number Analyzed 564 participants 548 participants 550 participants
14.01 16.42 16.36
Month 57 Number Analyzed 444 participants 445 participants 431 participants
15.54 14.16 15.08
Month 60 Number Analyzed 327 participants 330 participants 321 participants
11.31 12.73 15.58
Month 63 Number Analyzed 221 participants 230 participants 223 participants
11.76 16.96 15.25
Month 66 Number Analyzed 122 participants 131 participants 122 participants
9.02 16.79 13.11
Month 69 Number Analyzed 46 participants 46 participants 48 participants
13.04 19.57 14.58
Month 72 Number Analyzed 12 participants 18 participants 15 participants
8.33 22.22 13.33
16.Secondary Outcome
Title Percentage of Participants With Simplified Disease Activity Index (SDAI) Less Than or Equal to (<=) 3.3
Hide Description SDAI is the numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity), and CRP (mg/L). SDAI total score ranges from 0 to 86 with higher score indicating greater disease activity. SDAI <=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. SDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10 + CRP/10.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated. The percentages were calculated using the numbers of participants evaluable at each visit as the denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1320 participants 1308 participants 1325 participants
4.62 7.03 4.15
Month 3 Number Analyzed 1425 participants 1409 participants 1416 participants
9.19 11.14 7.84
Month 6 Number Analyzed 1414 participants 1391 participants 1404 participants
12.38 14.23 10.40
Month 9 Number Analyzed 1390 participants 1349 participants 1380 participants
15.90 17.72 12.75
Month 12 Number Analyzed 1372 participants 1332 participants 1358 participants
15.89 18.69 13.92
Month 15 Number Analyzed 1353 participants 1311 participants 1340 participants
18.26 20.29 15.90
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
18.68 21.96 16.79
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
20.89 22.07 17.93
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
20.44 22.76 18.93
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
21.91 23.62 21.12
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
21.31 23.68 21.91
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
21.43 25.06 22.19
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
22.47 24.35 21.80
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
22.99 24.21 21.48
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
24.59 24.23 23.41
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
25.27 23.20 23.26
Month 48 Number Analyzed 865 participants 806 participants 839 participants
25.32 23.20 24.20
Month 51 Number Analyzed 698 participants 671 participants 689 participants
23.35 23.85 24.24
Month 54 Number Analyzed 564 participants 548 participants 550 participants
22.34 24.09 24.55
Month 57 Number Analyzed 444 participants 445 participants 431 participants
24.10 23.82 24.83
Month 60 Number Analyzed 327 participants 330 participants 321 participants
18.65 20.30 25.23
Month 63 Number Analyzed 221 participants 230 participants 223 participants
19.00 23.48 23.32
Month 66 Number Analyzed 122 participants 131 participants 122 participants
14.75 21.37 20.49
Month 69 Number Analyzed 46 participants 46 participants 48 participants
17.39 17.39 22.92
Month 72 Number Analyzed 12 participants 18 participants 15 participants
16.67 22.22 13.33
17.Secondary Outcome
Title Percentage of Participants With Clinical Disease Activity Index (CDAI) <=2.8
Hide Description CDAI is the numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score indicating greater disease activity. 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. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated. The percentages were calculated using the numbers of participants evaluable at each visit as the denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1320 participants 1311 participants 1330 participants
4.70 7.40 4.36
Month 3 Number Analyzed 1425 participants 1410 participants 1417 participants
9.26 11.06 7.76
Month 6 Number Analyzed 1414 participants 1391 participants 1405 participants
12.87 14.31 10.32
Month 9 Number Analyzed 1390 participants 1349 participants 1381 participants
15.76 18.09 13.25
Month 12 Number Analyzed 1372 participants 1332 participants 1359 participants
16.33 18.62 14.64
Month 15 Number Analyzed 1353 participants 1311 participants 1341 participants
18.03 21.36 16.41
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
19.82 22.12 17.93
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
21.35 22.55 18.70
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
20.44 22.76 19.48
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
22.77 23.29 21.51
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
21.88 24.18 22.31
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
22.24 25.91 22.36
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
23.22 25.30 21.64
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
23.92 24.30 21.90
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
25.02 24.95 23.66
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
25.95 24.23 23.85
Month 48 Number Analyzed 865 participants 806 participants 839 participants
25.55 24.44 24.31
Month 51 Number Analyzed 698 participants 671 participants 689 participants
24.50 24.89 25.11
Month 54 Number Analyzed 564 participants 548 participants 550 participants
23.23 25.00 25.45
Month 57 Number Analyzed 444 participants 445 participants 431 participants
24.32 24.04 25.75
Month 60 Number Analyzed 327 participants 330 participants 321 participants
19.88 20.91 26.48
Month 63 Number Analyzed 221 participants 230 participants 223 participants
20.81 22.17 22.87
Month 66 Number Analyzed 122 participants 131 participants 122 participants
13.93 22.14 17.21
Month 69 Number Analyzed 46 participants 46 participants 48 participants
19.57 19.57 18.75
Month 72 Number Analyzed 12 participants 18 participants 15 participants
16.67 22.22 13.33
18.Secondary Outcome
Title Percentage of Participants With Simplified Disease Activity Index (SDAI) <=11
Hide Description SDAI is the numerical sum of five outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity), and CRP (mg/L). SDAI total score ranges from 0 to 86 with higher score indicating greater disease activity. SDAI <=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. SDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10 + CRP/10.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated. The percentages were calculated using the numbers of participants evaluable at each visit as the denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1320 participants 1308 participants 1325 participants
30.76 35.02 28.08
Month 3 Number Analyzed 1425 participants 1409 participants 1416 participants
41.47 45.00 37.99
Month 6 Number Analyzed 1414 participants 1391 participants 1404 participants
50.85 53.56 45.80
Month 9 Number Analyzed 1390 participants 1349 participants 1380 participants
56.40 59.82 52.90
Month 12 Number Analyzed 1372 participants 1332 participants 1358 participants
57.87 61.11 54.93
Month 15 Number Analyzed 1353 participants 1311 participants 1340 participants
61.12 63.92 57.39
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
62.10 65.19 60.41
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
62.75 65.26 61.21
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
63.17 66.15 61.59
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
65.17 66.97 63.67
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
67.23 68.35 65.64
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
65.75 68.82 65.36
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
67.33 66.61 65.48
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
69.74 67.11 66.03
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
68.96 70.72 66.41
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
68.36 68.97 67.55
Month 48 Number Analyzed 865 participants 806 participants 839 participants
67.28 64.76 67.94
Month 51 Number Analyzed 698 participants 671 participants 689 participants
67.91 67.51 67.78
Month 54 Number Analyzed 564 participants 548 participants 550 participants
64.89 68.61 68.00
Month 57 Number Analyzed 444 participants 445 participants 431 participants
63.51 66.29 68.21
Month 60 Number Analyzed 327 participants 330 participants 321 participants
63.30 66.67 64.17
Month 63 Number Analyzed 221 participants 230 participants 223 participants
61.54 68.26 64.57
Month 66 Number Analyzed 122 participants 131 participants 122 participants
59.02 71.76 59.02
Month 69 Number Analyzed 46 participants 46 participants 48 participants
60.87 65.22 68.75
Month 72 Number Analyzed 12 participants 18 participants 15 participants
50.00 66.67 60.00
19.Secondary Outcome
Title Percentage of Participants With Clinical Disease Activity Index (CDAI) <=10
Hide Description CDAI is the numerical sum of four outcome parameters: TJC and SJC both based on a 28-joint assessment, PtGA and PhyGA both assessed on a 0 to 100 mm VAS (higher scores indicate greater affection due to disease activity). CDAI total score ranges from 0 to 76 with higher score indicating greater disease activity. 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. CDAI = (28TJC) + (28SJC) + PhyGA/10 + PtGA/10.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated. The percentages were calculated using the numbers of participants evaluable at each visit as the denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1320 participants 1311 participants 1330 participants
29.47 34.25 26.92
Month 3 Number Analyzed 1425 participants 1410 participants 1417 participants
40.07 43.90 35.99
Month 6 Number Analyzed 1414 participants 1391 participants 1405 participants
49.36 51.83 43.63
Month 9 Number Analyzed 1390 participants 1349 participants 1381 participants
55.40 58.78 50.91
Month 12 Number Analyzed 1372 participants 1332 participants 1359 participants
56.56 59.38 53.57
Month 15 Number Analyzed 1353 participants 1311 participants 1341 participants
60.31 62.70 55.93
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
60.51 64.02 59.42
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
61.37 64.94 60.20
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
62.78 65.25 61.19
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
64.93 66.39 62.87
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
67.15 67.84 65.00
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
65.50 67.71 65.03
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
66.67 65.15 64.66
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
68.64 66.40 65.61
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
68.44 69.10 65.82
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
67.97 68.66 67.16
Month 48 Number Analyzed 865 participants 806 participants 839 participants
66.71 63.15 67.58
Month 51 Number Analyzed 698 participants 671 participants 689 participants
67.77 65.87 67.63
Month 54 Number Analyzed 564 participants 548 participants 550 participants
64.54 67.88 68.00
Month 57 Number Analyzed 444 participants 445 participants 431 participants
62.61 65.39 67.98
Month 60 Number Analyzed 327 participants 330 participants 321 participants
63.00 65.15 65.42
Month 63 Number Analyzed 221 participants 230 participants 223 participants
62.90 66.52 66.37
Month 66 Number Analyzed 122 participants 131 participants 122 participants
57.38 67.94 61.48
Month 69 Number Analyzed 46 participants 46 participants 48 participants
58.70 65.22 66.67
Month 72 Number Analyzed 12 participants 18 participants 15 participants
50.00 66.67 53.33
20.Secondary Outcome
Title Percentage of Participants With Disease Activity Score 28-4 (DAS28-4) C-reactive Protein (CRP) <=3.2
Hide Description DAS28 is a measure of disease activity in participants with rheumatoid arthritis based on a 28-joint assessment. DAS28-4 (CRP) was calculated from number of painful joints out of 28 joints (TJC28) and number of swollen joints out of 28 joints (SJC28), CRP (mg/L) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicated worse health condition). Total DAS28-4 (CRP) score range: 0 to 9.4, higher score indicated more disease activity. DAS28-4 (CRP) <= 3.2 indicates low disease activity and > 3.2 to <=5.1 indicates moderate disease activity, >5.1 indicates high disease activity, and DAS28-4 (CRP) < 2.6 indicates remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated. The percentages were calculated using the numbers of participants evaluable at each visit as the denominators.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Number
Unit of Measure: percentage of participants
Month 2 Number Analyzed 1347 participants 1327 participants 1354 participants
31.55 35.57 28.36
Month 3 Number Analyzed 1430 participants 1418 participants 1420 participants
41.68 46.05 37.54
Month 6 Number Analyzed 1416 participants 1396 participants 1406 participants
50.28 54.87 44.88
Month 9 Number Analyzed 1392 participants 1349 participants 1381 participants
56.11 59.01 50.91
Month 12 Number Analyzed 1372 participants 1332 participants 1359 participants
57.73 60.06 53.05
Month 15 Number Analyzed 1353 participants 1311 participants 1341 participants
60.38 63.54 55.03
Month 18 Number Analyzed 1322 participants 1284 participants 1316 participants
61.72 63.86 58.51
Month 21 Number Analyzed 1302 participants 1255 participants 1294 participants
62.29 63.67 59.27
Month 24 Number Analyzed 1287 participants 1226 participants 1273 participants
61.93 64.11 59.78
Month 27 Number Analyzed 1269 participants 1211 participants 1255 participants
64.22 67.63 60.56
Month 30 Number Analyzed 1248 participants 1191 participants 1237 participants
64.66 65.49 63.22
Month 33 Number Analyzed 1232 participants 1177 participants 1221 participants
63.80 66.02 62.82
Month 36 Number Analyzed 1206 participants 1162 participants 1211 participants
64.43 64.63 62.59
Month 39 Number Analyzed 1183 participants 1140 participants 1201 participants
65.85 65.18 63.53
Month 42 Number Analyzed 1163 participants 1110 participants 1179 participants
65.43 67.93 65.31
Month 45 Number Analyzed 1021 participants 970 participants 1023 participants
64.74 65.77 64.52
Month 48 Number Analyzed 865 participants 806 participants 839 participants
64.39 64.52 64.36
Month 51 Number Analyzed 698 participants 671 participants 689 participants
65.19 66.47 65.46
Month 54 Number Analyzed 564 participants 548 participants 550 participants
64.18 66.24 66.55
Month 57 Number Analyzed 444 participants 445 participants 431 participants
63.06 63.60 67.29
Month 60 Number Analyzed 327 participants 330 participants 321 participants
62.69 64.24 65.11
Month 63 Number Analyzed 221 participants 230 participants 223 participants
60.18 64.35 68.61
Month 66 Number Analyzed 122 participants 131 participants 122 participants
55.74 66.41 60.66
Month 69 Number Analyzed 46 participants 46 participants 48 participants
58.70 56.52 70.83
Month 72 Number Analyzed 12 participants 18 participants 15 participants
50.00 61.11 73.33
21.Secondary Outcome
Title Number of Participants With an American College of Rheumatology 20 Percent (%) (ACR20) Response
Hide Description ACR20 response is a >= 20% improvement in TJC (28) and SJC (28) and >=20% improvement in 3 of the 5 remaining ACR-core criteria: 1) PGA of arthritis, 2) PtGA of arthritis, 3) participant's assessment of arthritis pain, 4) participant's assessment of functional disability by HAQ-DI, and 5) CRP (mg/L) at each visit. PGA: physician's global assessment of arthritis on VAS, 0 (very well) to 100 mm (worst arthritis), higher scores=worse condition. PtGA: participant's global assessment of arthritis on VAS, 0 mm (very well) to 100 mm (worst arthritis condition), higher scores = worse condition. Participant's assessment of arthritis pain: assessed on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Count of Participants
Unit of Measure: Participants
Month 2 Number Analyzed 1335 participants 1316 participants 1337 participants
832
  62.3%
867
  65.9%
812
  60.7%
Month 3 Number Analyzed 1418 participants 1398 participants 1396 participants
979
  69.0%
992
  71.0%
923
  66.1%
Month 6 Number Analyzed 1402 participants 1375 participants 1382 participants
999
  71.3%
1012
  73.6%
981
  71.0%
Month 9 Number Analyzed 1375 participants 1328 participants 1356 participants
1019
  74.1%
1004
  75.6%
987
  72.8%
Month 12 Number Analyzed 1362 participants 1308 participants 1333 participants
1033
  75.8%
992
  75.8%
966
  72.5%
Month 15 Number Analyzed 1341 participants 1291 participants 1315 participants
1017
  75.8%
1003
  77.7%
969
  73.7%
Month 18 Number Analyzed 1309 participants 1266 participants 1289 participants
981
  74.9%
974
  76.9%
937
  72.7%
Month 21 Number Analyzed 1289 participants 1238 participants 1271 participants
955
  74.1%
953
  77.0%
949
  74.7%
Month 24 Number Analyzed 1275 participants 1209 participants 1251 participants
956
  75.0%
922
  76.3%
922
  73.7%
Month 27 Number Analyzed 1255 participants 1190 participants 1234 participants
961
  76.6%
917
  77.1%
913
  74.0%
Month 30 Number Analyzed 1237 participants 1173 participants 1213 participants
932
  75.3%
899
  76.6%
931
  76.8%
Month 33 Number Analyzed 1220 participants 1157 participants 1194 participants
935
  76.6%
888
  76.8%
922
  77.2%
Month 36 Number Analyzed 1193 participants 1145 participants 1189 participants
907
  76.0%
881
  76.9%
887
  74.6%
Month 39 Number Analyzed 1172 participants 1122 participants 1180 participants
896
  76.5%
843
  75.1%
887
  75.2%
Month 42 Number Analyzed 1153 participants 1091 participants 1154 participants
905
  78.5%
848
  77.7%
883
  76.5%
Month 45 Number Analyzed 1010 participants 955 participants 1006 participants
780
  77.2%
718
  75.2%
790
  78.5%
Month 48 Number Analyzed 854 participants 795 participants 821 participants
654
  76.6%
587
  73.8%
639
  77.8%
Month 51 Number Analyzed 691 participants 659 participants 675 participants
535
  77.4%
485
  73.6%
518
  76.7%
Month 54 Number Analyzed 559 participants 536 participants 538 participants
434
  77.6%
396
  73.9%
400
  74.3%
Month 57 Number Analyzed 441 participants 436 participants 421 participants
337
  76.4%
321
  73.6%
302
  71.7%
Month 60 Number Analyzed 323 participants 323 participants 314 participants
243
  75.2%
237
  73.4%
232
  73.9%
Month 63 Number Analyzed 217 participants 221 participants 220 participants
163
  75.1%
166
  75.1%
161
  73.2%
Month 66 Number Analyzed 119 participants 130 participants 122 participants
85
  71.4%
101
  77.7%
89
  73.0%
Month 69 Number Analyzed 46 participants 46 participants 48 participants
26
  56.5%
36
  78.3%
37
  77.1%
Month 72 Number Analyzed 11 participants 18 participants 15 participants
5
  45.5%
15
  83.3%
10
  66.7%
22.Secondary Outcome
Title Number of Participants With an American College of Rheumatology 50% (ACR50) Response
Hide Description ACR50 response is a >= 50% improvement in TJC (28) and SJC (28) and >=50% improvement in 3 of the 5 remaining ACR-core criteria: 1) PGA of arthritis, 2) PtGA of arthritis, 3) participant's assessment of arthritis pain, 4) participant's assessment of functional disability by HAQ-DI, and 5) CRP (mg/L) at each visit. PGA: physician's global assessment of arthritis on VAS, 0 (very well) to 100 mm (worst arthritis), higher scores=worse condition. PtGA: participant's global assessment of arthritis on VAS, 0 mm (very well) to 100 mm (worst arthritis condition), higher scores = worse condition. Participant's assessment of arthritis pain: assessed on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Count of Participants
Unit of Measure: Participants
Month 2 Number Analyzed 1337 participants 1321 participants 1346 participants
402
  30.1%
452
  34.2%
336
  25.0%
Month 3 Number Analyzed 1422 participants 1405 participants 1404 participants
528
  37.1%
561
  39.9%
460
  32.8%
Month 6 Number Analyzed 1408 participants 1378 participants 1387 participants
605
  43.0%
614
  44.6%
533
  38.4%
Month 9 Number Analyzed 1381 participants 1333 participants 1356 participants
620
  44.9%
651
  48.8%
577
  42.6%
Month 12 Number Analyzed 1362 participants 1312 participants 1334 participants
631
  46.3%
654
  49.8%
577
  43.3%
Month 15 Number Analyzed 1340 participants 1290 participants 1313 participants
652
  48.7%
668
  51.8%
582
  44.3%
Month 18 Number Analyzed 1312 participants 1265 participants 1290 participants
633
  48.2%
643
  50.8%
609
  47.2%
Month 21 Number Analyzed 1290 participants 1234 participants 1272 participants
607
  47.1%
623
  50.5%
608
  47.8%
Month 24 Number Analyzed 1276 participants 1209 participants 1249 participants
622
  48.7%
616
  51.0%
592
  47.4%
Month 27 Number Analyzed 1258 participants 1194 participants 1231 participants
620
  49.3%
602
  50.4%
596
  48.4%
Month 30 Number Analyzed 1236 participants 1177 participants 1213 participants
599
  48.5%
609
  51.7%
610
  50.3%
Month 33 Number Analyzed 1220 participants 1158 participants 1200 participants
585
  48.0%
611
  52.8%
594
  49.5%
Month 36 Number Analyzed 1195 participants 1143 participants 1188 participants
603
  50.5%
566
  49.5%
592
  49.8%
Month 39 Number Analyzed 1170 participants 1121 participants 1179 participants
595
  50.9%
588
  52.5%
561
  47.6%
Month 42 Number Analyzed 1151 participants 1093 participants 1161 participants
592
  51.4%
578
  52.9%
587
  50.6%
Month 45 Number Analyzed 1011 participants 955 participants 1008 participants
521
  51.5%
481
  50.4%
519
  51.5%
Month 48 Number Analyzed 854 participants 794 participants 826 participants
422
  49.4%
385
  48.5%
424
  51.3%
Month 51 Number Analyzed 693 participants 659 participants 677 participants
350
  50.5%
320
  48.6%
346
  51.1%
Month 54 Number Analyzed 560 participants 538 participants 540 participants
284
  50.7%
271
  50.4%
268
  49.6%
Month 57 Number Analyzed 440 participants 437 participants 422 participants
200
  45.5%
210
  48.1%
209
  49.5%
Month 60 Number Analyzed 325 participants 322 participants 314 participants
152
  46.8%
151
  46.9%
150
  47.8%
Month 63 Number Analyzed 220 participants 223 participants 219 participants
100
  45.5%
104
  46.6%
103
  47.0%
Month 66 Number Analyzed 122 participants 129 participants 121 participants
52
  42.6%
68
  52.7%
55
  45.5%
Month 69 Number Analyzed 45 participants 45 participants 47 participants
16
  35.6%
20
  44.4%
27
  57.4%
Month 72 Number Analyzed 11 participants 18 participants 15 participants
3
  27.3%
6
  33.3%
7
  46.7%
23.Secondary Outcome
Title Number of Participants With an American College of Rheumatology 70% (ACR70) Response
Hide Description ACR70 response is a >= 70% improvement in TJC (28) and SJC (28) and >=70% improvement in 3 of the 5 remaining ACR-core criteria: 1) PGA of arthritis, 2) PtGA of arthritis, 3) participant's assessment of arthritis pain, 4) participant's assessment of functional disability by HAQ-DI, and 5) CRP (mg/L) at each visit. PGA: physician's global assessment of arthritis on VAS, 0 (very well) to 100 mm (worst arthritis), higher scores=worse condition. PtGA: participant's global assessment of arthritis on VAS, 0 mm (very well) to 100 mm (worst arthritis condition), higher scores = worse condition. Participant's assessment of arthritis pain: assessed on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability.
Time Frame Month 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants randomized in the study and received at least one dose of investigational drug. Analyses included the data while the participants were receiving the study drug. Here, 'Number Analyzed' signifies number of participants evaluable for each specified time point. LOCF was applied for missing components, and then composite binary outcome was calculated.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1455 1456 1451
Measure Type: Count of Participants
Unit of Measure: Participants
Month 2 Number Analyzed 1343 participants 1326 participants 1354 participants
152
  11.3%
193
  14.6%
113
   8.3%
Month 3 Number Analyzed 1425 participants 1414 participants 1413 participants
253
  17.8%
268
  19.0%
199
  14.1%
Month 6 Number Analyzed 1409 participants 1388 participants 1397 participants
282
  20.0%
331
  23.8%
234
  16.8%
Month 9 Number Analyzed 1383 participants 1336 participants 1366 participants
328
  23.7%
367
  27.5%
291
  21.3%
Month 12 Number Analyzed 1364 participants 1312 participants 1338 participants
337
  24.7%
373
  28.4%
284
  21.2%
Month 15 Number Analyzed 1342 participants 1294 participants 1323 participants
359
  26.8%
390
  30.1%
304
  23.0%
Month 18 Number Analyzed 1311 participants 1269 participants 1295 participants
358
  27.3%
382
  30.1%
325
  25.1%
Month 21 Number Analyzed 1293 participants 1238 participants 1277 participants
362
  28.0%
370
  29.9%
322
  25.2%
Month 24 Number Analyzed 1279 participants 1211 participants 1255 participants
349
  27.3%
386
  31.9%
328
  26.1%
Month 27 Number Analyzed 1259 participants 1192 participants 1238 participants
374
  29.7%
390
  32.7%
342
  27.6%
Month 30 Number Analyzed 1238 participants 1177 participants 1221 participants
369
  29.8%
397
  33.7%
358
  29.3%
Month 33 Number Analyzed 1222 participants 1160 participants 1204 participants
357
  29.2%
392
  33.8%
355
  29.5%
Month 36 Number Analyzed 1195 participants 1145 participants 1193 participants
362
  30.3%
343
  30.0%
351
  29.4%
Month 39 Number Analyzed 1173 participants 1125 participants 1186 participants
371
  31.6%
361
  32.1%
338
  28.5%
Month 42 Number Analyzed 1152 participants 1098 participants 1163 participants
376
  32.6%
342
  31.1%
343
  29.5%
Month 45 Number Analyzed 1010 participants 957 participants 1006 participants
313
  31.0%
298
  31.1%
298
  29.6%
Month 48 Number Analyzed 855 participants 794 participants 826 participants
256
  29.9%
228
  28.7%
238
  28.8%
Month 51 Number Analyzed 691 participants 657 participants 677 participants
216
  31.3%
195
  29.7%
199
  29.4%
Month 54 Number Analyzed 559 participants 538 participants 538 participants
159
  28.4%
163
  30.3%
160
  29.7%
Month 57 Number Analyzed 441 participants 438 participants 421 participants
128
  29.0%
127
  29.0%
118
  28.0%
Month 60 Number Analyzed 326 participants 321 participants 315 participants
79
  24.2%
83
  25.9%
92
  29.2%
Month 63 Number Analyzed 220 participants 223 participants 219 participants
58
  26.4%
57
  25.6%
64
  29.2%
Month 66 Number Analyzed 122 participants 130 participants 122 participants
25
  20.5%
38
  29.2%
35
  28.7%
Month 69 Number Analyzed 46 participants 45 participants 48 participants
8
  17.4%
15
  33.3%
14
  29.2%
Month 72 Number Analyzed 11 participants 18 participants 15 participants
2
  18.2%
5
  27.8%
4
  26.7%
24.Secondary Outcome
Title Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Description HAQ-DI assesses the degree of difficulty a participant has experienced during the past week in 8 domains of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities. There were total of 30 items distributed in these 8 domains. Each item was scored on a 4-point scale from 0 to 3: 0= no difficulty; 1= some difficulty; 2= much difficulty; 3= unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities.
Time Frame Baseline, Months 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 and 63
Hide Outcome Measure Data
Hide Analysis Population Description
FAS: all participants randomized and received at least one dose of drug. Mixed model for repeated measures used without imputation for missing values. Analyses included data while participants were receiving drug. Only visits with N > 50 participants in each treatment group included in analyses. Number of Participants Analyzed: number of participants included in mixed model for repeated measures. Number Analyzed: number of participants evaluable for each specified time point.
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description:
Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug.
In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
Overall Number of Participants Analyzed 1409 1390 1388
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Change at Month 2 Number Analyzed 1325 participants 1301 participants 1323 participants
-0.42  (0.02) -0.45  (0.02) -0.38  (0.02)
Change at Month 3 Number Analyzed 1371 participants 1329 participants 1320 participants
-0.45  (0.02) -0.48  (0.02) -0.42  (0.02)
Change at Month 6 Number Analyzed 1341 participants 1297 participants 1299 participants
-0.50  (0.02) -0.51  (0.02) -0.46  (0.02)
Change at Month 9 Number Analyzed 1287 participants 1247 participants 1248 participants
-0.51  (0.02) -0.55  (0.02) -0.47  (0.02)
Change at Month 12 Number Analyzed 1256 participants 1205 participants 1200 participants
-0.52  (0.02) -0.53  (0.02) -0.49  (0.02)
Change at Month 15 Number Analyzed 1223 participants 1171 participants 1179 participants
-0.53  (0.02) -0.56  (0.02) -0.51  (0.02)
Change at Month 18 Number Analyzed 1189 participants 1122 participants 1143 participants
-0.52  (0.02) -0.56  (0.02) -0.49  (0.02)
Change at Month 21 Number Analyzed 1172 participants 1076 participants 1118 participants
-0.53  (0.02) -0.55  (0.02) -0.50  (0.02)
Change at Month 24 Number Analyzed 1135 participants 1052 participants 1101 participants
-0.52  (0.02) -0.57  (0.02) -0.49  (0.02)
Change at Month 27 Number Analyzed 1102 participants 1015 participants 1054 participants
-0.52  (0.02) -0.56  (0.02) -0.51  (0.02)
Change at Month 30 Number Analyzed 1078 participants 998 participants 1045 participants
-0.53  (0.02) -0.55  (0.02) -0.50  (0.02)
Change at Month 33 Number Analyzed 1063 participants 977 participants 1041 participants
-0.51  (0.02) -0.56  (0.02) -0.52  (0.02)
Change at Month 36 Number Analyzed 1034 participants 953 participants 1020 participants
-0.50  (0.02) -0.54  (0.02) -0.48  (0.02)
Change at Month 39 Number Analyzed 989 participants 892 participants 964 participants
-0.51  (0.02) -0.54  (0.02) -0.49  (0.02)
Change at Month 42 Number Analyzed 854 participants 770 participants 833 participants
-0.51  (0.02) -0.52  (0.02) -0.50  (0.02)
Change at Month 45 Number Analyzed 713 participants 642 participants 678 participants
-0.50  (0.02) -0.51  (0.02) -0.51  (0.02)
Change at Month 48 Number Analyzed 569 participants 509 participants 539 participants
-0.50  (0.02) -0.50  (0.02) -0.48  (0.02)
Change at Month 51 Number Analyzed 461 participants 420 participants 416 participants
-0.53  (0.02) -0.49  (0.02) -0.50  (0.02)
Change at Month 54 Number Analyzed 364 participants 330 participants 324 participants
-0.53  (0.02) -0.51  (0.02) -0.48  (0.02)
Change at Month 57 Number Analyzed 266 participants 240 participants 247 participants
-0.49  (0.02) -0.48  (0.02) -0.48  (0.02)
Change at Month 60 Number Analyzed 185 participants 181 participants 167 participants
-0.52  (0.03) -0.49  (0.03) -0.48  (0.03)
Change at Month 63 Number Analyzed 107 participants 108 participants 96 participants
-0.54  (0.03) -0.48  (0.03) -0.48  (0.04)
Time Frame Baseline up to last contact date (maximum up to 72 months)
Adverse Event Reporting Description Same 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 as non-serious in another, or a participant may have experienced both a serious and non-serious event. SAS included all participants randomized in the study and received at least one dose of the randomized investigational drug. Total 153 deaths of which 152 were adjudicated and 1 occurred after the participant discontinued from the study.
 
Arm/Group Title Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Hide Arm/Group Description Participants received tofacitinib 5 milligram (mg) oral tablet twice daily (BID) up to 72 months. Participants were followed up for at least 28 days after last dose of study drug. Participants received tofacitinib 10 mg oral tablets (two tablets of 5 mg each) BID up to 72 months. Dose was reduced to tofacitinib 5 mg BID on or after 19 February 2019 as per Study Protocol Amendment 8. Participants were followed up for at least 28 days after last dose of study drug. In the United States (US), Puerto Rico and Canada, participants randomized to tumor necrosis factor inhibitor (TNFi) arm received adalimumab 40 mg every other week (QOW) by subcutaneous (SC) injection and in all other countries, participants randomized to TNFi arm received etanercept 50 mg once weekly by SC injection up to 72 months. Participants were followed up for at least 28 days after last dose of study drug.
All-Cause Mortality
Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   49/1455 (3.37%)   66/1456 (4.53%)   38/1451 (2.62%) 
Hide Serious Adverse Events
Tofacitinib 5 mg BID Tofacitinib 10 mg BID TNFi
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   373/1455 (25.64%)   420/1456 (28.85%)   339/1451 (23.36%) 
Blood and lymphatic system disorders       
Agranulocytosis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Anaemia * 1  9/1455 (0.62%)  4/1456 (0.27%)  1/1451 (0.07%) 
Blood loss anaemia * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Cytopenia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Disseminated intravascular coagulation * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Haemolytic anaemia * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Iron deficiency anaemia * 1  2/1455 (0.14%)  0/1456 (0.00%)  1/1451 (0.07%) 
Leukocytosis * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Leukopenia * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Lymphadenopathy * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Neutropenia * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Pancytopenia * 1  2/1455 (0.14%)  1/1456 (0.07%)  4/1451 (0.28%) 
Cardiac disorders       
Acute coronary syndrome * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Acute left ventricular failure * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Angina pectoris * 1  4/1455 (0.27%)  2/1456 (0.14%)  3/1451 (0.21%) 
Angina unstable * 1  3/1455 (0.21%)  3/1456 (0.21%)  3/1451 (0.21%) 
Aortic valve disease * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Arrhythmia * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Arrhythmia supraventricular * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Atrial fibrillation * 1  7/1455 (0.48%)  8/1456 (0.55%)  6/1451 (0.41%) 
Atrial flutter * 1  2/1455 (0.14%)  1/1456 (0.07%)  1/1451 (0.07%) 
Atrioventricular block * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Cardiac arrest * 1  0/1455 (0.00%)  4/1456 (0.27%)  0/1451 (0.00%) 
Cardiac failure * 1  2/1455 (0.14%)  3/1456 (0.21%)  3/1451 (0.21%) 
Cardiac failure acute * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Cardiac failure chronic * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Cardiac failure congestive * 1  1/1455 (0.07%)  6/1456 (0.41%)  0/1451 (0.00%) 
Cardiac pseudoaneurysm * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Cardio-respiratory arrest * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Cardiomyopathy * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Cardiovascular insufficiency * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Chronic left ventricular failure * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Congestive cardiomyopathy * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Coronary artery disease * 1  8/1455 (0.55%)  3/1456 (0.21%)  1/1451 (0.07%) 
Coronary artery insufficiency * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Coronary artery occlusion * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Coronary artery stenosis * 1  2/1455 (0.14%)  0/1456 (0.00%)  1/1451 (0.07%) 
Diastolic dysfunction * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Ischaemic cardiomyopathy * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Mitral valve disease * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Myocardial infarction * 1  0/1455 (0.00%)  1/1456 (0.07%)  4/1451 (0.28%) 
Myocardial ischaemia * 1  4/1455 (0.27%)  3/1456 (0.21%)  0/1451 (0.00%) 
Pericarditis * 1  1/1455 (0.07%)  0/1456 (0.00%)  3/1451 (0.21%) 
Right ventricular dysfunction * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Sinus node dysfunction * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Supraventricular tachycardia * 1  0/1455 (0.00%)  3/1456 (0.21%)  0/1451 (0.00%) 
Ventricular fibrillation * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Ventricular tachycardia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Congenital, familial and genetic disorders       
Corneal dystrophy * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Developmental hip dysplasia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Exomphalos * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Hydrocele * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Ear and labyrinth disorders       
Acute vestibular syndrome * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Meniere's disease * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Vertigo * 1  1/1455 (0.07%)  2/1456 (0.14%)  1/1451 (0.07%) 
Vestibular disorder * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Endocrine disorders       
Adrenal disorder * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Adrenal haematoma * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Hyperthyroidism * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Thyroid mass * 1  0/1455 (0.00%)  0/1456 (0.00%)  2/1451 (0.14%) 
Eye disorders       
Cataract * 1  3/1455 (0.21%)  6/1456 (0.41%)  3/1451 (0.21%) 
Diabetic retinopathy * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Episcleritis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Keratoconus * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Macular hole * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Necrotising retinitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Retinal detachment * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Retinal vasculitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Ulcerative keratitis * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Uveitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Gastrointestinal disorders       
Abdominal compartment syndrome * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Abdominal discomfort * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Abdominal distension * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Abdominal hernia * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Abdominal incarcerated hernia * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Abdominal pain * 1  5/1455 (0.34%)  1/1456 (0.07%)  2/1451 (0.14%) 
Abdominal pain upper * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Ascites * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Chronic gastritis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Colitis * 1  4/1455 (0.27%)  0/1456 (0.00%)  0/1451 (0.00%) 
Colitis ischaemic * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Constipation * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Diarrhoea * 1  4/1455 (0.27%)  2/1456 (0.14%)  1/1451 (0.07%) 
Diverticular perforation * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Duodenal stenosis * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Duodenal ulcer haemorrhage * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Dysphagia * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Enteritis * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Enterocolitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Faecaloma * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Gastric polyps * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Gastric ulcer * 1  2/1455 (0.14%)  0/1456 (0.00%)  1/1451 (0.07%) 
Gastric ulcer haemorrhage * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Gastritis * 1  3/1455 (0.21%)  1/1456 (0.07%)  2/1451 (0.14%) 
Gastritis erosive * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Gastritis haemorrhagic * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Gastrointestinal erosion * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Gastrointestinal haemorrhage * 1  1/1455 (0.07%)  1/1456 (0.07%)  4/1451 (0.28%) 
Gastrointestinal inflammation * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Gastrooesophageal reflux disease * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Haematochezia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Hiatus hernia * 1  1/1455 (0.07%)  0/1456 (0.00%)  2/1451 (0.14%) 
Ileus * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Impaired gastric emptying * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Inguinal hernia * 1  2/1455 (0.14%)  3/1456 (0.21%)  3/1451 (0.21%) 
Intestinal ischaemia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Intestinal obstruction * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Irritable bowel syndrome * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Ischaemic enteritis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Jejunal ulcer * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Jejunal ulcer perforation * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Large intestinal ulcer * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Large intestine perforation * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Mallory-Weiss syndrome * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Melaena * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Mesenteric vein thrombosis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Nausea * 1  3/1455 (0.21%)  0/1456 (0.00%)  1/1451 (0.07%) 
Obstruction gastric * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Obstructive pancreatitis * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Obturator hernia * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Oesophageal food impaction * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Oesophagitis * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Pancreatitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Pancreatitis acute * 1  1/1455 (0.07%)  2/1456 (0.14%)  2/1451 (0.14%) 
Pancreatitis chronic * 1  0/1455 (0.00%)  2/1456 (0.14%)  0/1451 (0.00%) 
Pancreatitis haemorrhagic * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Peptic ulcer * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Peptic ulcer haemorrhage * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Peptic ulcer perforation * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Rectal haemorrhage * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Small intestinal obstruction * 1  3/1455 (0.21%)  1/1456 (0.07%)  0/1451 (0.00%) 
Small intestinal perforation * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Thrombosis mesenteric vessel * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Umbilical hernia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Upper gastrointestinal haemorrhage * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Vomiting * 1  2/1455 (0.14%)  1/1456 (0.07%)  3/1451 (0.21%) 
General disorders       
Accidental death * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Adverse drug reaction * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Asthenia * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Chest discomfort * 1  3/1455 (0.21%)  0/1456 (0.00%)  1/1451 (0.07%) 
Chest pain * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Complication associated with device * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Death * 1  1/1455 (0.07%)  2/1456 (0.14%)  4/1451 (0.28%) 
Device intolerance * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Drug intolerance * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Impaired healing * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Inflammation * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Mucosal inflammation * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Multiple organ dysfunction syndrome * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Non-cardiac chest pain * 1  4/1455 (0.27%)  5/1456 (0.34%)  5/1451 (0.34%) 
Oedema peripheral * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Pyrexia * 1  1/1455 (0.07%)  3/1456 (0.21%)  2/1451 (0.14%) 
Sudden death * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Systemic inflammatory response syndrome * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Hepatobiliary disorders       
Bile duct stone * 1  2/1455 (0.14%)  1/1456 (0.07%)  0/1451 (0.00%) 
Biliary colic * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Cholangitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Cholecystitis * 1  1/1455 (0.07%)  3/1456 (0.21%)  3/1451 (0.21%) 
Cholecystitis acute * 1  3/1455 (0.21%)  2/1456 (0.14%)  1/1451 (0.07%) 
Cholecystitis chronic * 1  0/1455 (0.00%)  2/1456 (0.14%)  2/1451 (0.14%) 
Cholelithiasis * 1  4/1455 (0.27%)  5/1456 (0.34%)  4/1451 (0.28%) 
Cirrhosis alcoholic * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Drug-induced liver injury * 1  0/1455 (0.00%)  0/1456 (0.00%)  2/1451 (0.14%) 
Gallbladder obstruction * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Gallbladder rupture * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Hepatic cirrhosis * 1  0/1455 (0.00%)  1/1456 (0.07%)  2/1451 (0.14%) 
Hepatorenal failure * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Hepatotoxicity * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Hypertransaminasaemia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Immune system disorders       
Anaphylactic reaction * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Anaphylactic shock * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Drug hypersensitivity * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Hypersensitivity * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Infections and infestations       
Abscess * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Abscess limb * 1  3/1455 (0.21%)  1/1456 (0.07%)  1/1451 (0.07%) 
Acute pulmonary histoplasmosis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Acute sinusitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Adenovirus infection * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Anal abscess * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Appendiceal abscess * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Appendicitis * 1  4/1455 (0.27%)  4/1456 (0.27%)  0/1451 (0.00%) 
Appendicitis perforated * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Arthritis bacterial * 1  2/1455 (0.14%)  4/1456 (0.27%)  4/1451 (0.28%) 
Arthritis infective * 1  0/1455 (0.00%)  2/1456 (0.14%)  0/1451 (0.00%) 
Atypical pneumonia * 1  0/1455 (0.00%)  0/1456 (0.00%)  2/1451 (0.14%) 
Bacteraemia * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Bacterial infection * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Bacterial sepsis * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Bone tuberculosis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Brain abscess * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Breast abscess * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Bronchiolitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Bronchitis * 1  10/1455 (0.69%)  9/1456 (0.62%)  7/1451 (0.48%) 
Bronchitis bacterial * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Bronchitis viral * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Bronchopulmonary aspergillosis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Bursitis infective * 1  0/1455 (0.00%)  0/1456 (0.00%)  2/1451 (0.14%) 
COVID-19 * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
COVID-19 pneumonia * 1  1/1455 (0.07%)  5/1456 (0.34%)  1/1451 (0.07%) 
Carbuncle * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Cellulitis * 1  12/1455 (0.82%)  13/1456 (0.89%)  15/1451 (1.03%) 
Cellulitis staphylococcal * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Cholecystitis infective * 1  1/1455 (0.07%)  1/1456 (0.07%)  1/1451 (0.07%) 
Chorioretinitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Chronic sinusitis * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Clostridium difficile colitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Colonic abscess * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Complicated appendicitis * 1  2/1455 (0.14%)  0/1456 (0.00%)  1/1451 (0.07%) 
Cytomegalovirus chorioretinitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Cytomegalovirus infection * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Dengue fever * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Device related infection * 1  2/1455 (0.14%)  2/1456 (0.14%)  1/1451 (0.07%) 
Diarrhoea infectious * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Disseminated tuberculosis * 1  0/1455 (0.00%)  2/1456 (0.14%)  1/1451 (0.07%) 
Disseminated varicella zoster virus infection * 1  0/1455 (0.00%)  4/1456 (0.27%)  0/1451 (0.00%) 
Diverticulitis * 1  7/1455 (0.48%)  6/1456 (0.41%)  2/1451 (0.14%) 
Encephalitis meningococcal * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Epididymitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Erysipelas * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Escherichia bacteraemia * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Escherichia infection * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Escherichia pyelonephritis * 1  2/1455 (0.14%)  0/1456 (0.00%)  0/1451 (0.00%) 
Escherichia sepsis * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Escherichia urinary tract infection * 1  1/1455 (0.07%)  0/1456 (0.00%)  2/1451 (0.14%) 
External ear cellulitis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Extradural abscess * 1  1/1455 (0.07%)  1/1456 (0.07%)  0/1451 (0.00%) 
Eye infection * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Gangrene * 1  0/1455 (0.00%)  1/1456 (0.07%)  1/1451 (0.07%) 
Gastroenteritis * 1  4/1455 (0.27%)  7/1456 (0.48%)  3/1451 (0.21%) 
Gastroenteritis bacterial * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Gastroenteritis viral * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Gastrointestinal infection * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
H1N1 influenza * 1  0/1455 (0.00%)  2/1456 (0.14%)  0/1451 (0.00%) 
Herpes oesophagitis * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Herpes ophthalmic * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Herpes virus infection * 1  1/1455 (0.07%)  0/1456 (0.00%)  0/1451 (0.00%) 
Herpes zoster * 1  9/1455 (0.62%)  11/1456 (0.76%)  2/1451 (0.14%) 
Histoplasmosis * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Infected bite * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Infection * 1  0/1455 (0.00%)  1/1456 (0.07%)  0/1451 (0.00%) 
Infectious pleural effusion * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Influenza * 1  4/1455 (0.27%)  3/1456 (0.21%)  2/1451 (0.14%) 
Intervertebral discitis * 1  1/1455 (0.07%)  0/1456 (0.00%)  1/1451 (0.07%) 
Joint abscess * 1  0/1455 (0.00%)  0/1456 (0.00%)  1/1451 (0.07%) 
Liver abscess * 1  0/1455 (0.00%)  0/1456 (0.00%)