Methotrexate Withdrawal Study of Tofacitinib Modified Release Formulation in Subjects With Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

A PHASE 3B/4 RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED STUDY OF METHOTREXATE (MTX) WITHDRAWAL IN SUBJECTS WITH RHEUMATOID ARTHRITIS (RA) TREATED WITH TOFACITINIB 11MG MODIFIED RELEASE (MR) FORMULATION

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02831855
• Other study ID #: A3921192
• Secondary ID: 2016-001825-15
• Status: Completed
• Phase: Phase 4
• Start date: September 1, 2016
• Est. completion date: December 17, 2018

Study information

• Verified date: November 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to evaluate the efficacy and safety of tofacitinib modified release formulation (11mg QD) versus tofacitinib modified release formulation plus continued methotrexate treatment in subjects with moderate to severe rheumatoid arthritis who are insufficiently responding to their stable dose of methotrexate treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 694
• Est. completion date: December 17, 2018
• Est. primary completion date: November 19, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria

• Must be 18 years of age or older.

Have a score of 6 or greater on the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis at and/or prior to Screening Visit.

• Have =4 tender/painful joints on motion and =4 swollen joints (28 joint counts) at both Screening Visit and Baseline Visit (Visit 1).

• Have moderate to severe disease activity as defined by CDAI>10 and DAS28-4(ESR) =3.2 at Baseline Visit.

• Have taken an oral MTX treatment regimen (15-25mg/week) continuously for at least 4 months prior to the screening visit and has taken a stable weekly dose of oral MTX with supplemental folic acid or folinic acid for at least 4 weeks prior to the baseline visit (conversion from parenteral MTX to oral MTX will require stabilization of the treatment regimen for at least 1 month).

• Subjects must screen negative for active tuberculosis or inadequately treated tuberculosis infection (active or latent).

Key Exclusion Criteria

• Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 3 months after the last dose of investigational product.

• Subjects with infection or infection history; subjects with any current malignancy or a history of malignancy (except adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ); subjects with history of, or current evidence for, severe gastrointestinal narrowing (pathologic or iatrogenic); and subjects with history of documented diverticulitis.

• Subjects with a history of insufficient response to =2 biologics, regardless of the class.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• CP-690,550
During the open-label run-in phase (Day 1 to Week 24), all subjects will receive one tablet open-label tofacitinib MR 11mg orally QD and open-label methotrexate capsule(s) orally every week at prior stabilized dose. During the double-blind phase, subjects who are randomized to the treatment arm will receive the same dosage of tofacitinib and methotrexate as describe above.
• Methotrexate
During the open-label run-in phase (Day 1 to Week 24), all subjects will receive one tablet open-label tofacitinib MR 11mg orally QD and open-label methotrexate capsule(s) orally every week at prior stabilized dose. During the double-blind phase, subjects who are randomized to the treatment arm will receive the same dosage of tofacitinib and methotrexate as describe above.
• Placebo
During the double-blind phase, subjects who are randomized to the comparison arm will receive 11mg QD tofacitinib and the placebo capsules matching for methotrexate.

Locations

Country	Name	City	State
Australia	Genesis Research Services Pty Ltd	Broadmeadow	New South Wales
Australia	Optimus Clinical Research Pty Ltd	Kogarah	New South Wales
Australia	Rheumatology Research Unit	Maroochydore	Queensland
Australia	Emeritus Research	Melbourne	Victoria
Belgium	ReumaClinic	Genk
Belgium	AZ Delta	Roeselare
Bulgaria	University Multiprofile Hospital for Active Treatment Dr. G. Stranski EAD	Pleven
Bulgaria	Multiprofile Hospital for Active Treatment - Plovdiv AD, Rheumatology Department	Plovdiv
Bulgaria	Multiprofile Hospital for Active Treatment Trimontium OOD	Plovdiv
Bulgaria	University Multiprofile Hospital for Active Treatment - Kaspela EOOD	Plovdiv
Bulgaria	Medical Centre Synexus Sofia EOOD	Sofia
Bulgaria	National Multiprofile Transport Hospital Tsar Boris III	Sofia
Czechia	CCBR Czech Brno, s.r.o.	Brno	Czech Republic
Czechia	LEKARNA LANCIER s.r.o.	Brno
Czechia	Lekarna Na Lidicke	Brno
Czechia	Revmacentrum MUDr. Mostera, s.r.o., Revmatologie a interna	Brno
Czechia	CCBR Ostrava, s.r.o.	Ostrava
Czechia	Lekarna Rezidence Nova Karolina	Ostrava
Czechia	Revmatologicky ustav	Praha 2
Czechia	Revmatologicky ustav, Lekrna	Praha 2
Czechia	Lekarna Hradebni s.r.o.	Uherske Hradiste
Czechia	MEDICAL PLUS, s.r.o. Revmatologicka a osteologicka ambulance	Uherske Hradiste
Czechia	PV - MEDICAL s.r.o., Revmatologicka ambulance	Zlin
Czechia	Revmavita s.r.o, Lekarna	Zlin
Germany	Hamburger Rheuma Forschungszentrum I	Hamburg
Hungary	DRC Gyogyszervizsgalo Kozpont Kft.	Balatonfured
Hungary	Qualiclinic Kft.	Budapest
Hungary	Revita Rendelo	Budapest
Hungary	CRU Hungary Kft.	Miskolc
Korea, Republic of	Clinical Trial Pharmacy, KyungHee University Hospital	Seoul
Korea, Republic of	Clinical Trial Pharmacy, The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	CTC Pharmacy, Seoul National University Hospital	Seoul
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	KyungHee University Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul, St. Mary's Hospital	Seoul
Mexico	Morales Vargas Centro de Investigacion SC (Consultorio Anexo)	Leon	Guanajuato
Mexico	Centro de Investigacion y Tratamiento Reumatologico SC Consultorio Medico de Reumatologia (CINTRE)	Mexico	Ciudad DE Mexico
Philippines	Mary Mediatrix Medical Center	Lipa City	Batangas
Philippines	Far Eastern University - Nicanor Reyes Medical Foundation, Marian Medical Arts Bldg	Quezon City	Metro Manila
Poland	ClinicMed Daniluk, Nowak. Sp. j.	Bialystok
Poland	Zdrowie OSTEO-MEDIC s.c. L i A. Racewicz, A i J. Supronik	Bialystok
Poland	Nzoz Bif - Med	Bytom
Poland	Centrum Medyczne Pratia Krakow	Krakow
Poland	Malopolskie Centrum Medyczne S.C.	Krakow
Poland	NZOZ Lecznica MAK-MED. S.C.	Nadarzyn
Poland	MTZ Clinical Research Sp. z o.o.	Warszawa
Russian Federation	Federal State Budgetary Scientific Institution "Research Institute of Rheumatology	Moscow
Russian Federation	FSBEI HE "Orenburg State Medical University" of MoH RF	Orenburg
Russian Federation	FSBEI HE "Orenburg State Medical University" of MoH RF	Orenburg
Russian Federation	SPb SBIH "Consultative-Diagnostic Centre #85"	Saint Petersburg
Russian Federation	FSBIH "Clinical Hospital #122 n.a. L.G. Sokolov" of FMBA of Russia	Saint-Petersburg
Russian Federation	SBIH "Samara Regional Clinical Hospital n.a. V.D. Seredavin"	Samara
Russian Federation	NSHI "Departmental Hospital at Smolensk station OJSC "Russian Railways"	Smolensk
Russian Federation	SAHI YR Clinical Hospital of Emergency Medical Care n.a. N.V. Soloviev	Yaroslavl
Russian Federation	State Budgetary Institution of Healthcare of Yaroslavl Region "Regional Clinical Hospital"	Yaroslavl
Slovakia	AAGS s.r.o.	Dunajska Streda
Slovakia	MEDMAN s.r.o.	Martin
Slovakia	REUMACENTRUM s.r.o.	Partizanske
Slovakia	MUDr. Zuzana Cizmarikova, s.r.o.	Poprad
Slovakia	Reumex s.r.o	Rimavska Sobota
South Africa	St. Augustine's Hospital	Durban	Kwazulu Natal
Spain	Hospital Universitario de Cruces	Baracaldo	Vizcaya
Spain	Complejo Hospitalario Universitario de Santiago	Santiago de Compostela	A Coruna
Spain	Hospital Infanta Luisa	Sevilla
United Kingdom	Hampshire Hospitals NHS Foundation Trust	Basingstoke	Hampshire
United Kingdom	Pharmacy, Hampshire Hospitals NHS Foundation Trust	Basingstoke	Hampshire
United Kingdom	Countess of Chester Hospital NHS Foundation Trust	Chester	Cheshire
United Kingdom	Pharmacy (dispensary)	Chester	Cheshire
United Kingdom	Pharmacy Department	Dudley	WEST Midlands
United Kingdom	The Dudley Group NHS Foundation Trust	Dudley	WEST Midlands
United Kingdom	Countess of Chester Hospital NHS Foundation Trust	Ellesmere Port	Cheshire
United Kingdom	Pharmacy	Manchester
United Kingdom	University Hospital of South Manchester NHS Foundation Trust	Manchester
United Kingdom	Department of Rheumatology, Wirral University Teaching Hospital NHS Foundation Trust	Wirral	Merseyside
United Kingdom	Pharmacy Department, Wirral University Teaching Hospital NHS Foundation Trust	Wirral	Merseyside
United Kingdom	Wirral University Teaching Hospital NHS Foundation Trust	Wirral	Merseyside
United States	AARDS Research Inc	Aventura	Florida
United States	Ochsner Clinic Baton Rouge	Baton Rouge	Louisiana
United States	Bronson Internal Medicine and Rheumatology	Battle Creek	Michigan
United States	East Penn Rheumatology Associates, P.C.	Bethlehem	Pennsylvania
United States	RASF-Clinical Research Inc	Boca Raton	Florida
United States	Center for Arthritis and Rheumatic Diseases	Chesapeake	Virginia
United States	Cincinnati Rheumatic Disease Study Group, Inc.	Cincinnati	Ohio
United States	Group Health Associates	Cincinnati	Ohio
United States	Pioneer Research Solutions, Inc.	Cypress	Texas
United States	Metroplex Clinical Research Center	Dallas	Texas
United States	STAT Research, Inc.	Dayton	Ohio
United States	Omega Research Consultants	DeBary	Florida
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Med Investigations, Inc	Fair Oaks	California
United States	Phase III Clinical Research	Fall River	Massachusetts
United States	Arthritis & Osteoporosis Associates	Freehold	New Jersey
United States	Arthrocare, Arthritiscare & Research, PC	Gilbert	Arizona
United States	Beacon Medical Group Rheumatology Main Street	Granger	Indiana
United States	Physicians East, PA	Greenville	North Carolina
United States	Piedmont Arthritis Clinic	Greenville	South Carolina
United States	CHI St. Vincent Medical Group Hot Springs	Hot Springs	Arkansas
United States	HCP Clinical Research, LLC	Huntington Beach	California
United States	Rheumatology Associates of North Alabama, PC	Huntsville	Alabama
United States	Institute of Arthritis Research	Idaho Falls	Idaho
United States	Diagnostic Rheumatology and Research, PC	Indianapolis	Indiana
United States	University of Florida College of Medicine - Jacksonville - Rheumatology Research	Jacksonville	Florida
United States	University of Florida, Rheumatology at ACC	Jacksonville	Florida
United States	Western Michigan University Homer Stryker MD	Kalamazoo	Michigan
United States	Radnet	Marlton	New Jersey
United States	Center for Arthritis and Rheumatic Diseases	Miami	Florida
United States	Trinity Health Center-Medical Arts	Minot	North Dakota
United States	Jeffrey Alper, MD	Naples	Florida
United States	Medallion Clinical Research Institute, LLC	Naples	Florida
United States	Suncoast Clinical Research, Inc.	New Port Richey	Florida
United States	Health Research of Oklahoma	Oklahoma City	Oklahoma
United States	Lynn Health Science Institute	Oklahoma City	Oklahoma
United States	Oklahoma Medical Research Foundation (OMRF)	Oklahoma City	Oklahoma
United States	Articularis Healthcare Group dba ACME Research	Orangeburg	South Carolina
United States	SunValley Arthritis Center, Ltd.	Peoria	Arizona
United States	Florida Arthritis & Osteoporosis Center	Port Richey	Florida
United States	Gulf Coast Medical Center	Port Richey	Florida
United States	Quincy Medical Group	Quincy	Illinois
United States	AAIR Research Center	Rochester	New York
United States	Sierra Rheumatology	Roseville	California
United States	PMG Research of Salisbury	Salisbury	North Carolina
United States	Pacific Arthritis Center Medical Group	Santa Maria	California
United States	Center for Arthritis and Rheumatic Diseases	Suffolk	Virginia
United States	Articularis Healthcare Group d/b/a Low Country Rheumatology	Summerville	South Carolina
United States	West Broward Rheumatology Associates, Inc.	Tamarac	Florida
United States	BayCare Medical Group, Inc	Tampa	Florida
United States	USF Health Morsani Center for Advanced Healthcare	Tampa	Florida
United States	North Mississippi Medical Clinics, Inc. - Clinical Research	Tupelo	Mississippi
United States	Robin K. Dore, MD, Inc.	Tustin	California
United States	Inland Rheumatology and Osteoporosis Medical Group	Upland	California
United States	Inland Rheumatology Clinical Trials, Inc.	Upland	California
United States	Desert Valley Medical Group	Victorville	California
United States	Arthritis, Rheumatic & Back Disease Associates, P.A.	Voorhees	New Jersey
United States	Open MRI & Diagnostic Imaging of Wall	Wall	New Jersey
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Czechia,  Germany,  Hungary,  Korea, Republic of,  Mexico,  Philippines,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  United Kingdom, 

References & Publications (16)

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Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, Aletaha D, Allaart CF, Bathon J, Bombardieri S, Brooks P, Brown A, Matucci-Cerinic M, Choi H, Combe B, de Wit M, Dougados M, Emery P, Furst D, Gomez-Reino J, Hawker G, Keystone E, Khanna D, Kirwan J, Kvien TK, Landewé R, Listing J, Michaud K, Martin-Mola E, Montie P, Pincus T, Richards P, Siegel JN, Simon LS, Sokka T, Strand V, Tugwell P, Tyndall A, van der Heijde D, Verstappen S, White B, Wolfe F, Zink A, Boers M; American College of Rheumatology; European League Against Rheumatism. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011 Mar;63(3):573-86. doi: 10.1002/art.30129. — View Citation

Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012 Mar;64(3):617-29. doi: 10.1002/art.33383. — View Citation

Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS; ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):495-507. doi: 10.1056/NEJMoa1109071. — View Citation

Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol. 1982 Sep-Oct;9(5):789-93. — View Citation

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Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358. — View Citation

Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, Isaacs JD, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Riese R, Bradley J. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013 Aug 20;159(4):253-61. doi: 10.7326/0003-4819-159-4-201308200-00006. — View Citation

Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, Gruben D, Kanik KS, Krishnaswami S, Pascual-Ramos V, Wallenstein G, Zwillich SH. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012 Apr;64(4):970-81. doi: 10.1002/art.33419. Epub 2011 Oct 17. — View Citation

Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, Gross CJ, Dowty ME, Ramaiah SK, Hirsch JL, Saabye MJ, Barks JL, Kishore N, Morris DL. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010 Aug 11;7:41. doi: 10.1186/1476-9255-7-41. — View Citation

Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007 Mar 1;178(5):2623-9. Review. — View Citation

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van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, Forejtova S, Zwillich SH, Gruben D, Koncz T, Wallenstein GV, Krishnaswami S, Bradley JD, Wilkinson B; ORAL Standard Investigators. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508-19. doi: 10.1056/NEJMoa1112072. Erratum in: N Engl J Med. 2013 Jul 18;369(3):293. — View Citation

Ware JE KM, Dewey JE. . How to score Version 2 of the SF 36 Health Survey (Standard & Acute forms). In: How to score Version 2 of the SF 36 Health Survey (Standard & Acute forms). Lincoln, Rhode Island: QualityMetric, Incorporated. 2000.

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to Week 52 (up to 28 days after last dose) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs.	For OL Phase: Baseline up to Week 24; For DB Phase: Week 24 up to Week 52 (up to 28 days after last dose)
Other	Number of Participants With Abnormal Laboratory Parameters	Abnormality criteria: Hemoglobin (Hb),Hematocrit,Erythrocytes(Ery): <0.8*LLN;Ery. Mean corpuscular volume <0.9*lower limit of normal (LLN), >1.1*upper limit of normal (ULN); Platelets:<0.5*LLN,>1.75*ULN;WBCs:<0.6*LLN,>1.5*ULN; Lymphocytes/WBCs, Neutrophils/WBCs:<0.8*LLN,>1.2* ULN;Basophils,Basophils/WBCs,Eosinophils,Eosinophils/WBCs,Monocytes, Monocytes/WBCs: >1.2*ULN;Prothrombin Time, Prothrombin Intl. Normalized Ratio:>1.1*ULN; ESR:>1.5*ULN; Bilirubin,Direct Bilirubin,Indirect Bilirubin: >1.5*ULN; Aspartate Aminotransferase (AT),Alanine AT,Gamma Glutamyl Transferase,Alkaline Phosphatase:>3.0*ULN; Protein, Albumin: <0.8*LLN, >1.2x ULN; Blood Urea Nitrogen, Creatinine, Triglycerides: >1.3*ULN;HDL Cholesterol:<0.8*LLN;Sodium <0.95*LLN, >1.05*ULN;Potassium, Chloride, Calcium, Bicarbonate: <0.9*LLN, >1.1*ULN; Glucose: <0.6*LLN, >1.5*ULN; Creatine Kinase: >2.0*ULN; Cholesterol:>1.3*ULN;Specific Gravity:<1.003;pH:<4.5; urine glucose,Ketones,urine protein,urine Hb,WBCs Esterase: >=1.	For OL Phase: Baseline up to Week 24; For DB Phase: Week 24 up to Week 48
Primary	Double Blind Phase: Change From Randomization in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from swollen joint count (SJC) and tender/painful joint count (TJC) using 28 joints count, ESR (millimeters per hour [mm/hr]) and participant global assessment of arthritis (PtGA) on a 100 millimeter (mm) visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) less than or equal to (<=) 3.2 implied low disease activity and greater than (>) 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) less than (<) 2.6 implied remission. DAS28-4 (ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/hour) + 0.014*PtGA in mm; ln = natural logarithm, sqrt = square root of.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 48
Secondary	Double Blind Phase: Change From Randomization in DAS28-4 ESR at Week 36	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 millimeter (mm) VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) less than or equal to (<=) 3.2 implied low disease activity and greater than (>) 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) less than (<) 2.6 implied remission. DAS28-4 (ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/hour) + 0.014*PtGA in mm; ln = natural logarithm, sqrt = square root of.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36
Secondary	Double Blind Phase: Change From Randomization in DAS28-4 (C-reactive Protein [CRP]) at Weeks 36 and 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (milligrams per liter [mg/L]) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <= 3.2 implied low disease activity and > 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) < 2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96; ln = natural logarithm, sqrt = square root of.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in Clinical Disease Activity Index (CDAI) at Weeks 36 and 48	CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and physician global assessment of arthritis (PhyGA). PtGA and PhyGA both were assessed on 0-10 centimeter (cm) VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm).	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in Simplified Disease Activity Index (SDAI) at Weeks 36 and 48	SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity. SDAI score of <=11 indicates low disease activity and a score of <=3.3 indicates remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL).	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Low Disease Activity (LDA) Assessed by DAS28-4 (ESR) Less Than or Equal to (<=) 3.2 at Weeks 36 and 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicated worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. DAS28-4 (ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/hour) + 0.014*PtGA in mm; ln = natural logarithm, sqrt = square root of.	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With LDA Assessed by DAS28-4 (CRP) <=3.2 at Weeks 36 and 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/L) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/L +1) + 0.014*PtGA in mm+ 0.96; ln = natural logarithm, sqrt = square root of.	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With LDA Assessed by CDAI <=10 at Weeks 36 and 48	CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and PhyGA. PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. Percentage of participants with CDAI <=10 were reported. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm).	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With LDA Assessed by SDAI <=11 at Weeks 36 and 48	SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity. SDAI score of <=11 indicated low disease activity and a score of <=3.3 indicated remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL).	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Weeks 36 and 48	ACR-EULAR Boolean remission was when a participant satisfied all of the following: tender joint count, swollen joint count (both based on a 28-joint assessment), CRP (in mg/dL), and PtGA (VAS: 0 cm [very well] to 10 cm [worst], higher scores indicated worse health condition) and all scores were <=1.	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Remission Assessed by DAS28-4 (ESR) Less Than [<] 2.6 at Weeks 36 and 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. DAS28-4 (ESR) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*In(ESR in mm/hour) + 0.014*PtGA in mm. Percentage of participants with DAS remission (DAS28-4-ESR<2.6) were reported in this outcome measure.	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Remission Assessed by DAS28-4 (CRP) <2.6 at Weeks 36 and 48	DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/L) and PtGA on a 100 mm VAS (VAS: scores ranging from 0 mm [very well] to 100 mm [worst], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. DAS28-4 (CRP) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP in mg/l +1) + 0.014*PtGA in mm+ 0.96. Percentage of participants with DAS remission (DAS28-4-CRP<2.6) were reported in this outcome measure.	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Remission Assessed by CDAI <=2.8 at Weeks 36 and 48	CDAI was calculated from tender and swollen joints using 28 joint count, PtGA and PhyGA. PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). CDAI total score ranged from 0 to 76, where higher scores indicated higher disease activity. CDAI score of <=10 indicated low disease activity and a score of <= 2.8 indicated remission. CDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm).	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants With Remission Assessed by SDAI <=3.3 at Weeks 36 and 48	SDAI was calculated from tender and swollen joints using 28 joint count, PtGA, PhyGA and CRP (in mg/dL). PtGA and PhyGA both were assessed on 0-10 cm VAS scale (VAS: scores ranging from 0 cm [very well] to 10 cm [worst]), where higher scores indicated greater affliction due to disease activity). SDAI total score ranged from 0 to 86, where higher scores indicated higher disease activity. SDAI score of <=11 indicates low disease activity and a score of <=3.3 indicates remission. SDAI = (28TJC) + (28SJC) + (PhyGA in cm) + (PtGA in cm) + (CRP in mg/dL).	Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants Achieving an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 36 and 48	Participants with 20% improvement in tender and swollen joint counts and 20% improvement in at least 3 of the 5 measures: PtGA, PhyGA, participant's assessment of arthritis pain, Health Assessment Questionnaire-Disability Index (HAQ-DI) and CRP. PtGA: participant assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged participants' pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Participant's assessment of arthritis pain: participant assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1).	Baseline (Day 1), Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants Achieving an American College of Rheumatology 50% (ACR50) Response at Weeks 36 and 48	Participants with 50% improvement in tender and swollen joint counts and 50% improvement in at least 3 of the 5 measures: PtGA, PhyGA, participant's assessment of arthritis pain, HAQ-DI and CRP. PtGA: participant assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged participants' pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Participant's assessment of arthritis pain: participant assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1).	Baseline (Day 1), Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants Achieving an American College of Rheumatology 70% (ACR70) Response at Weeks 36 and 48	Participants with 70% improvement in tender and swollen joint counts and 70% improvement in at least 3 of the 5 measures: PtGA, PhyGA, participant's assessment of arthritis pain, HAQ-DI and CRP. PtGA: participant assessed health on VAS, 0 mm (very well) to 100 mm (worst health condition), higher scores = worse condition. PhyGA: physician judged participants' pain on VAS, 0 (no pain) to 100 mm (extreme pain), higher scores = more pain. Participant's assessment of arthritis pain: participant assessed pain on VAS, 0 mm (no pain) to 100 mm (most severe pain), higher score = more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability. The improvement was relative to baseline (Day 1).	Baseline (Day 1), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 36 and 48	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.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in the Short Form 36 (SF-36) Health Survey 8 Domain Scores at Weeks 36 and 48	SF-36 is a participant reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health perception. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were summarized to derive the 2 component scores (physical component scores [PCS], mental component scores [MCS]) ranging from 0 (worst) to 100 (best), where higher PCS/MCS indicated good health condition.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in the SF-36 Health Survey Component Scores at Weeks 36 and 48	SF-36 is a participant reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health perception. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were summarized aggregated to derive the two 2 component scores PCS and MCS ranging from 0 (worst) to 100 (best), where higher PCS/MCS indicated good health condition.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in the Work Productivity and Activity Impairment (WPAI) Scores at Week 36 and 48	WPAI is 6-question participant rated questionnaire to determine the impact of rheumatoid arthritis and yields 4 types of outcomes: absenteeism (work time missed), presenteeism (impairment while working), work productivity loss (overall work impairment), and daily activity impairment (activity impairment) for a period of 7 days prior to a visit. These 4 outcomes are expressed as an impairment percentage (range from 0 to 100), with higher numbers indicating greater impairment and less productivity.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Week 36 and 48
Secondary	Double Blind Phase: Change From Randomization in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Weeks 36 and 48	EQ-5D was a participant completed instrument designed to assess impact on quality of life in terms of a single utility score in 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. 3 possible answers for mobility: 1=no problem in walking, 2=moderate problems in walking, 3= confined to bed; self-care: 1=no problem, 2=moderate problems, 3= unable to wash/dress; usual activities: 1=no problem, 2=moderate problems, 3= unable to do usual activities; pain and discomfort: 1=no pain or discomfort, 2=moderate pain or discomfort, 3= extreme pain or discomfort; anxiety and depression: 1=not anxious or depressed, 2=moderately anxious or depressed, 3= extremely anxious or depressed. The 5-dimensional systems are converted into a single index utility score between 0 and 1, where higher score indicated a better health state.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Change From Randomization in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Scores at Weeks 36 and 48	The FACIT-Fatigue scale was a participant completed questionnaire consisted of 13 items that assessed fatigue. Each item was scored on a scale of 0 (maximum fatigue) to 4 (no fatigue), higher scores indicate less fatigue. Total FACIT-fatigue score was obtained by addition of scores from 13 items, giving a possible overall range from 0 (maximum fatigue) to 52 (no fatigue). Higher FACIT-fatigue scores indicated lower level of fatigue, better participant status.	Randomization (last non-missing measurement on or prior to the first dosing date in DB phase at Week 24), Weeks 36 and 48
Secondary	Double Blind Phase: Percentage of Participants Achieving an Improvement of at Least 0.22 Units in HAQ-DI at Weeks 36 and 48	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. Percentage of participants with an improvement of at least 0.22 units in HAQ scores from baseline (Day 1) to Weeks 36 and 48 were reported in this outcome measure.	Baseline (Day 1), Weeks 36 and 48

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