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

• 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: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: March 3, 2014
• First Posted Date: March 20, 2014
• Results First Submitted Date: July 21, 2021
• Results First Posted Date: August 17, 2021
• Last Update Posted Date: August 17, 2021
• Actual Study Start Date: March 14, 2014
• Actual Primary Completion Date: July 22, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 21, 2021)

• Incidence Rate of Adjudicated Malignancies Excluding Non-melanoma Skin Cancers (NMSC) [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Adjudicated Major Adverse Cardiovascular Events (MACE) [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.

Original Primary Outcome Measures (submitted: March 18, 2014)

• Malignancies, excluding non-menlanoma skin cancer (NMSC) [ Time Frame: 5 years ]
  Events meeting pre-defined adjudication criteria
• Incidence of major adverse cardiovascular events (MACE) [ Time Frame: 5 years ]
  Events meeting pre-defined adjudication criteria

Current Secondary Outcome Measures (submitted: July 21, 2021)

• Incidence Rate of Non-fatal Stroke [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Non-fatal Myocardial Infarction [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Adjudicated Opportunistic Infection Events Including Tuberculosis [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Adjudicated Hepatic Events [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Adjudicated Cardiovascular Events Other Than Major Adverse Cardiovascular Events (MACE) [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ 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) ]
  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.
• Number of Participants With Clinically Significant Abnormal Laboratory Parameters [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Incidence Rate of Adjudicated All-Cause Deaths [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• Number of Participants With Reasons For Permanent or Temporary Discontinuation of Study Medication [ Time Frame: Baseline up to last contact date (maximum up to 72 months) ]
  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.
• 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 [ 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 ]
  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.
• 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 [ 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 ]
  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.
• 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 [ 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 ]
  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.
• Percentage of Participants Who Achieved Observed American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean Remission Criteria [ 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 ]
  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.
• Percentage of Participants With Simplified Disease Activity Index (SDAI) Less Than or Equal to (<=) 3.3 [ 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 ]
  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.
• Percentage of Participants With Clinical Disease Activity Index (CDAI) <=2.8 [ 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 ]
  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.
• Percentage of Participants With Simplified Disease Activity Index (SDAI) <=11 [ 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 ]
  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.
• Percentage of Participants With Clinical Disease Activity Index (CDAI) <=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 ]
  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.
• Percentage of Participants With Disease Activity Score 28-4 (DAS28-4) C-reactive Protein (CRP) <=3.2 [ 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 ]
  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.
• Number of Participants With an American College of Rheumatology 20 Percent (%) (ACR20) Response [ 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 ]
  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.
• Number of Participants With an American College of Rheumatology 50% (ACR50) Response [ 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 ]
  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.
• Number of Participants With an American College of Rheumatology 70% (ACR70) Response [ 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 ]
  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.
• 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 [ 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 ]
  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.

Original Secondary Outcome Measures (submitted: March 18, 2014)

• Opportunistic infections [ Time Frame: 5 years ]
  Adjudicated, including tuberculosis
• Hepatic events [ Time Frame: 5 years ]
  Adjudicated
• Cardiovascular events other than MACE [ Time Frame: 5 years ]
  Adjudicated
• All cause mortality [ Time Frame: 5 years ]
  Adjudicated
• Disease Activity Score Based on 28-joints Count (DAS28) [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
  DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity.
• Number of Participants With an American College of Rheumatology 20% (ACR20) Response [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
  ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP).
• Clinical Disease Activity Index (CDAI) [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
• Simplified Disease Activity Index (SDAI) [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
• ACR-EULAR Boolean remission [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
  Must have all of the following: < or = 1 tender joint count, < or = 1 swollen joint count, CRP < or = 1 mg/dL, patient global assessment < or = 1 on 0-10 scale
• Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
  ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
• Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]
  ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
• Health Assessment Questionnaire-Disability Index (HAQ-DI) [ Time Frame: Month 3, 6, 9, 12, 24, 36, 48, 60 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study Of Tofacitinib Versus Tumor Necrosis Factor (TNF) Inhibitor In Subjects With Rheumatoid Arthritis
• Official Title: PHASE 3B/4 RANDOMIZED SAFETY ENDPOINT STUDY OF 2 DOSES OF TOFACITINIB IN COMPARISON TO A TUMOR NECROSIS FACTOR (TNF) INHIBITOR IN SUBJECTS WITH RHEUMATOID ARTHRITIS
• Brief Summary: This post-marketing study is designed to compare the safety of tofacitinib versus TNF inhibitor with respect to major cardiovascular adverse events and malignancies, excluding non-melanoma skin cancers when given to subjects with rheumatoid arthritis. Other safety events, including non-melanoma skin cancers, hepatic events, infections, and efficacy parameters will be collected and evaluated in the study.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Arthritis, Rheumatoid

Intervention

• Drug: tofacitinib
  Oral tablet, 5 mg BID
• Drug: tofacitinib
  Oral tablet, 10 mg BID
• Biological: adalimumab
  Pre-filled syringe, 40 mg subcutaneous injection, every other week
  Other Name: Humira
• Biological: etanercept
  Pre-filled syringe, 50 mg subcutaneous injection, every week
  Other Name: Enbrel

Study Arms

• Experimental: Treatment Arm 1
  Intervention: Drug: tofacitinib
• Experimental: Treatment Arm 2
  Intervention: Drug: tofacitinib
• Active Comparator: Treatment Arm 3
  TNF inhibitor Arm - adalimumab will be used in US, Canada and Puerto Rico; etanercept will be used in all other countries.
  Interventions:

  • Biological: adalimumab
  • Biological: etanercept

Publications *

• Weitz JI, Szekanecz Z, Charles-Schoeman C, Vranic I, Sahin B, Paciga SA, Wang Z, Hyde C, Martin DA. Biomarkers to predict risk of venous thromboembolism in patients with rheumatoid arthritis receiving tofacitinib or tumour necrosis factor inhibitors. RMD Open. 2022 Nov;8(2):e002571. doi: 10.1136/rmdopen-2022-002571.
• Charles-Schoeman C, Buch MH, Dougados M, Bhatt DL, Giles JT, Ytterberg SR, Koch GG, Vranic I, Wu J, Wang C, Kwok K, Menon S, Rivas JL, Yndestad A, Connell CA, Szekanecz Z. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis. 2023 Jan;82(1):119-129. doi: 10.1136/ard-2022-222259. Epub 2022 Sep 22.
• Balanescu AR, Citera G, Pascual-Ramos V, Bhatt DL, Connell CA, Gold D, Chen AS, Sawyerr G, Shapiro AB, Pope JE, Schulze-Koops H. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022 Nov;81(11):1491-1503. doi: 10.1136/ard-2022-222405. Epub 2022 Aug 3.
• Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, Germino R, Menon S, Sun Y, Wang C, Shapiro AB, Kanik KS, Connell CA; ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022 Jan 27;386(4):316-326. doi: 10.1056/NEJMoa2109927.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 7, 2021): 4372
• Original Estimated Enrollment (submitted: March 18, 2014): 4000
• Actual Study Completion Date: July 22, 2020
• Actual Primary Completion Date: July 22, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Moderate to severe rheumatoid arthritis
• Taking methotrexate without adequate control of symptoms
• Have at least one cardiovascular risk factor (eg, current smoker, high blood pressure, high cholesterol levels, diabetes mellitus, history of heart attack, family history of coronary heart disease, extra-articular RA disease)

Exclusion Criteria:

• Current or recent infection
• Clinically significant laboratory abnormalities
• Pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Finland, Hong Kong, Israel, Jordan, Lebanon, Malaysia, Mexico, Netherlands, New Zealand, Peru, Poland, Puerto Rico, Russian Federation, Slovakia, South Africa, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States
• Removed Location Countries: Austria, Czech Republic, Sweden

Administrative Information

• NCT Number: NCT02092467
• Other Study ID Numbers: A3921133; 2013-003177-99 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: July 2021