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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02831855
Other study ID # A3921192
Secondary ID 2016-001825-15
Status Completed
Phase Phase 4
First received
Last updated
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
Health authority
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.

Study Design


Related Conditions & MeSH terms


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)

Burmester GR, Benda B, Gruben D, Bradley J, Mebus C. Tofacitinib for rheumatoid arthritis - Authors' reply. Lancet. 2013 May 25;381(9880):1812-3. doi: 10.1016/S0140-6736(13)61115-0. — View Citation

Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer. 2002 Jan 15;94(2):528-38. — View Citation

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

Hurst NP, Kind P, Ruta D, Hunter M, Stubbings A. Measuring health-related quality of life in rheumatoid arthritis: validity, responsiveness and reliability of EuroQol (EQ-5D). Br J Rheumatol. 1997 May;36(5):551-9. — View Citation

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

O'Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007 Apr;44(10):2497-506. Epub 2007 Jan 17. Review. — View Citation

Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993 Nov;4(5):353-65. — View Citation

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 allClick 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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