A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Combination Therapy of T-614 and Methotrexate in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate

• T-614 (Drug): T-614 is administered twice daily in combination with methotrexate. The daily dose of T-614 is 25 mg for the first 4 weeks and 50 mg for subsequent weeks.
• Placebo (Drug): Placebo is administered twice daily in combination with methotrexate. In placebo group, patients will receive T-614 after completing 28 weeks of treatment.

Primary outcomes

• Percentage of American College of Rheumatology [ACR] 20 Criteria Responders [Week 24 Last Observation Carried Forward (LOCF) (for T-614 arm and placebo arm) and Week 52 LOCF (for T-614 arm and placebo/T614 arm)]: ACR20 response is defined as at least a 20% improvement in tender joint count and swollen joint count, and in three of five of the following measures: patient pain intensity assessment, patient global assessment, physician global assessment, Health assessment questionnaire disability index (HAQ-DI), and an acute phase reactant \[erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)\].

Secondary outcomes

• Change From Baseline in Tender Joint Counts and Swollen Joint Counts [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: Assessment of individual ACR core components like Tender Joint Counts (TJC) and Swollen Joint Counts (SJC)
• Change From Baseline in PAP, PtGADA and PyGADA [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: Patient's assessment of pain (PAP), patient's global assessment of disease activity (PtGADA) and physician's global assessment of disease activity (PyGADA) each was assessed on a visual analog scale ranging from 0-100 mm, with higher scores indicating severe disease.
• Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: HAQ-DI was a participant assessed measure of health assessment, measured on a single scale ranging from 0 (no difficulty) to 3 (unable to do), with higher scores indicating severe disease.
• Change From Baseline in C-reactive Protein (CRP) [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: Assessment of individual ACR core components i.e. CRP
• Change From Baseline in Erythrocyte Sedimentation Rate (ESR) [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: Assessment of individual ACR core components i.e. ESR
• Disease Activity Score in 28 Joints (DAS28): The Rates of Remission (DAS28-CRP Less Than 2.6), and Low Disease Activity (DAS28-CRP Less Than 3.2) [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: The DAS28 is a composite score derived from 4 of these measures i.e count of 28 swollen joints, 28 tender joints, measure erythrocyte sedimentation rate (ESR) or C reactive protein (CRP) and to make a 'global assessment of health' (indicated by marking a 10 cm line between very good and very bad). DAS28 is assessed as score on scale from 0 to 10 indicating current rheumatoid arthritis (RA) disease activity (0= low disease activity and 10 = high disease activity).
• Percentage of ACR 50 Criteria Responders [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: ACR50 response is defined as at least a 50% improvement in tender joint count and swollen joint count, and in three of five of the following measures: patient pain intensity assessment, patient global assessment, physician global assessment, Health assessment questionnaire disability index (HAQ-DI), and an acute phase reactant \[erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)\].
• Percentage of ACR 70 Criteria Responders [Week 24 LOCF (for T-614 arm and placebo arm) and Week 52 LOCF (for T614 arm and placebo/T614 arm)]: ACR70 response is defined as at least a 70% improvement in tender joint count and swollen joint count, and in three of five of the following measures: patient pain intensity assessment, patient global assessment, physician global assessment, Health assessment questionnaire disability index (HAQ-DI), and an acute phase reactant \[erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)\].

Sex: All, ages: 20 Years to 69 Years

Inclusion criteria:

* Subjects who have a diagnosis of Rheumatoid Arthritis by the ACR criteria
* Age greater or 20 years and less than 70 years old

Exclusion criteria:

* Subject who is considered by the investigator, for any reason, to be an unsuitable candidate for the study
* Women of childbearing potential who are not practicing a successful method of contraception, or wish to become pregnant

Participant flow

Outcome results

• Change From Baseline in Tender Joint Counts and Swollen Joint Counts (Secondary), Mean, joint counts: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 12.5 +/- 6.5; Placebo (Double-blind, 1-28 Weeks) 13.3 +/- 8.1; Placebo/T-614 (Extension, 29-52 Weeks) 13.8 +/- 8.5
• Change From Baseline in PAP, PtGADA and PyGADA (Secondary), Mean, mm: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 47.5 +/- 22.2; Placebo (Double-blind, 1-28 Weeks) 46.4 +/- 23.1; Placebo/T-614 (Extension, 29-52 Weeks) 44.8 +/- 22.4
• Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) (Secondary), Mean, score on scale: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 0.8178 +/- 0.5525; Placebo (Double-blind, 1-28 Weeks) 0.7344 +/- 0.5117; Placebo/T-614 (Extension, 29-52 Weeks) 0.7188 +/- 0.5274
• Change From Baseline in C-reactive Protein (CRP) (Secondary), Mean, mg/dl: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 1.843 +/- 1.943; Placebo (Double-blind, 1-28 Weeks) 1.705 +/- 1.583; Placebo/T-614 (Extension, 29-52 Weeks) 1.714 +/- 1.611
• Change From Baseline in Erythrocyte Sedimentation Rate (ESR) (Secondary), Mean, mm/hr: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 45.6 +/- 21; Placebo (Double-blind, 1-28 Weeks) 41.8 +/- 22.5; Placebo/T-614 (Extension, 29-52 Weeks) 40.1 +/- 23.2
• Disease Activity Score in 28 Joints (DAS28): The Rates of Remission (DAS28-CRP Less Than 2.6), and Low Disease Activity (DAS28-CRP Less Than 3.2) (Secondary), Number, participants: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 45; Placebo (Double-blind, 1-28 Weeks) 8; Placebo/T-614 (Extension, 29-52 Weeks) NA
• Percentage of ACR 50 Criteria Responders (Secondary), Number, Percentage of Participants: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 38.4 (30.9 to 46.3); Placebo (Double-blind, 1-28 Weeks) 15.9 (9 to 25.2); Placebo/T-614 (Extension, 29-52 Weeks) NA (NA to NA)
• Percentage of ACR 70 Criteria Responders (Secondary), Number, Percentage of Participants: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 17.1 (11.7 to 23.7); Placebo (Double-blind, 1-28 Weeks) 5.7 (1.9 to 12.8); Placebo/T-614 (Extension, 29-52 Weeks) NA (NA to NA)
• Percentage of American College of Rheumatology [ACR] 20 Criteria Responders (Primary), Number, Percentage of Participants: T-614 (Double-blind, 1-28 Weeks) and (Extension, 29-52 Weeks) 69.5 (61.9 to 76.5); Placebo (Double-blind, 1-28 Weeks) 30.7 (21.3 to 41.4); Placebo/T-614 (Extension, 29-52 Weeks) NA (NA to NA)

Adverse events

Time frame: Up to 1 - 52 weeks for T614 (double-blind and extension) arm, up to 1 - 24 weeks for placebo (double-blind) arm and Up to 29 - 52 Weeks for placebo/T614 (extension) arm.

Serious adverse events by term

Other adverse events by term

• Kota Nagai, Study director, JAC PCU. EPCS, Eisai Co., Ltd.