Safety and Efficacy of Pf-06650833 In Subjects With Rheumatoid Arthritis, With An Inadequate Response To Methotrexate

A 12 WEEK RANDOMIZED, DOUBLE-BLIND, DOUBLE DUMMY, PARALLEL GROUP, ACTIVE AND PLACEBO-CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY PROFILE OF PF-06650833 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE

This is a Phase 2, multicenter, randomized, double blind, double dummy, placebo and active-controlled, parallel group study to assess the efficacy and safety of PF 06650833 at Week 12 in subjects with moderate-severe, active, RA who have had an inadequate response to MTX. PF-06650833 or matching placebo tablets will be administered orally QD under fasting conditions, and tofacitinib or matching tofacitinib placebo tablets will be administered orally BID for 12 weeks in a blinded fashion.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Placebo; Drug: PF-06650833; Drug: Tofacitinib

• Study Type: Interventional
• Enrollment (Actual): 269
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia, 2605
      • Canberra Hospital
  • New South Wales
    • Broadmeadow, New South Wales, Australia, 2292
      • Genesis Research Services
• Bosnia and Herzegovina
  • Kanton Sarajevo
    • Sarajevo, Kanton Sarajevo, Bosnia and Herzegovina, 71000
      • General Hospital "Prim.dr.Abdulah Nakas"
  • Republika Srpska
    • Banja Luka, Republika Srpska, Bosnia and Herzegovina, 78000
      • University Clinical center Republic of Srpska
    • Gradiska, Republika Srpska, Bosnia and Herzegovina, 78400
      • Health center Gradiska
• Bulgaria
  • Plovdiv, Bulgaria, 4001
    • UMHAT Kaspela
  • Sofia, Bulgaria, 1336
    • MHAT Liulin
  • Sofia, Bulgaria, 1612
    • UMHAT "Sv.Ivan Rilski", Clinic of rheumatology
  • Sofia, Bulgaria, 1784
    • Medical Center Synexus Sofia EOOD
  • Sofia, Bulgaria, 1784
    • Specialized Hospital for Active Treatment of Oncology Diseases EAD, Department of Imaging Diagnostic
• Croatia
  • Zagreb, Croatia, 10000
    • Medicinski centar Kuna&Peric
  • GRAD Zagreb
    • Zagreb, GRAD Zagreb, Croatia, 10000
      • Poliklinika K-Centar
• Czechia
  • Ostrava, Czechia, 702 00
    • CCBR Ostrava s.r.o.
  • Praha, Czechia, 140 00
    • Revmatologicka ambulance
  • Uherske Hradiste, Czechia, 68601
    • MEDICAL Plus s.r.o.
• Georgia
  • Tbilisi, Georgia, 0160
    • LTD "MediClubGeorgia"
  • Tbilisi, Georgia, 0159
    • LTD Unimedi Kakheti
  • Tbilisi, Georgia, 0112
    • Ltd Israeli-Georgian Medical Research Clinic Helsicore
  • Tbilisi, Georgia, 0159
    • LTD Institute of Clinical Cardiology
  • Tbilisi, Georgia, 0159
    • LTD " Diagnostic Service "
  • Tbilisi, Georgia, 0186
    • Ltd "Medicore"
  • Telavi, Georgia, 2200
    • Unimedi Kakheti LTD
• Germany
  • Puettlingen, Germany, 66346
    • Knappschaftsklinikum Saar GmbH
• Hungary
  • Budapest, Hungary, 1027
    • Revita Reumatologiai Rendelo
  • Kistarcsa, Hungary, 2143
    • Pest Megyei Flor Ferenc Korhaz
  • Miskolc, Hungary, 3529
    • CRU Hungary Ltd.
  • Szeged, Hungary, 6725
    • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
  • Szentes, Hungary, 6600
    • Csongrad Megyei Dr. Bugyi Istvan Korhaz, Mozgasszervi Rehabilitacios Osztaly
  • Veszprem, Hungary, 8200
    • VITAL MEDICAL CENTER Orvosi es Fogorvosi Kozpont
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05030
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 04763
    • Hanyang University Seoul Hospital
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St.Mary's Hospital
• Mexico
  • San Luis Potosí, Mexico, 78213
    • Centro de Alta Especialidad en Reumatologia e Investigacion del Potosi, S.C.
  • Morelos
    • Cuernavaca, Morelos, Mexico, 62290
      • Private Practice - Dr. Miguel Cortes Hernandez
  • Yucatan
    • Merida, Yucatan, Mexico, 97000
      • Centro Peninsular de Investigacion Clinica S.C.P
    • Merida, Yucatan, Mexico, 97070
      • Kohler & Milstein Research S.A de C.V
• Poland
  • Bytom, Poland, 41-902
    • Szpital Specjalistyczny nr 1 w Bytomiu
  • Gdansk, Poland, 80-382
    • Synexus Polska Sp. z o.o. Oddzial w Gdansku
  • Gdynia, Poland, 81-537
    • Synexus Polska Sp z o.o. Oddzial w Gdyni
  • Grodzisk Mazowiecki, Poland, 05-825
    • McBk S.C.
  • Katowice, Poland, 40-040
    • Synexus Polska Sp.zo.o.
  • Poznan, Poland, 61-397
    • Prywatna Praktyka Lekarska Prof. UM dr Hab. Med. Pawel Hrycaj
  • Warszawa, Poland, 02-691
    • Reumatika Centrum Reumatologii NZOZ
  • Warszawa, Poland, 01-192
    • Synexus Polska Sp. z o.o.
  • Wroclaw, Poland, 50-381
    • Synexus Polska Sp. z o.o. Oddział we Wroclawiu
• Romania
  • Bucuresti, Romania, 010306
    • Centrul Medical Unirea
  • Bucuresti, Romania, 010719
    • Med Life
  • Bucuresti, Romania, 011025
    • Centrul Medical Sana
  • Bucuresti, Romania, 014461
    • Euroclinic Hospital
  • Iasi, Romania, 700661
    • Spitalul Clinic de Recuperare Iasi
  • Tirgu Mures, Romania, 540136
    • Spitalul Clinic Judetean de Urgenta Tirgu Mures
• Russian Federation
  • Kazan, Russian Federation, 420064
    • FSBEI HE "Kazan State Medical University" MoH of RF
  • Kazan, Russian Federation, 420103
    • FSBEI HE "Kazan State Medical University" MoH of RF
  • Moscow, Russian Federation, 115522
    • FSBSI "Scientific Research Institute of Rheumatology n.a. V.A. Nasonova"
  • Moscow, Russian Federation, 119049
    • SBHI of Moscow City Clinical Hospital # 1 n.a. N.I. Pirogov of Moscow Healthcare Department
  • Moscow, Russian Federation, 119333
    • FSBHI Central Clinical Hospital of Russian Academy of Sciences
  • Ryazan, Russian Federation, 390026
    • State Budgetary Institution of Ryazan Region "Regional Clinical Cardiology Dispensary"
  • Saint-Petersburg, Russian Federation, 190031
    • LLC "Sanavita"
  • Saint-Petersburg, Russian Federation, 195257
    • LLC "Sanavita"
  • St. Petersburg, Russian Federation, 190068
    • Saint Petersburg State Budgetary Institution of Health Care "Clinical Rheumatology Hospital #25"
  • Vladimir, Russian Federation, 600023
    • SBHI of VR "Regional Clinical Hospital"
• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Institute of Rheumatology
  • Niska Banja, Serbia, 18205
    • Institute For Treatment and Rehabilitation "Niska Banja"
  • Novi Sad, Serbia, 21112
    • Special Hospital For Rheumatic Diseases Novi Sad
• Slovakia
  • Dunajska Streda, Slovakia, 92901
    • AAGS s.r.o., Reumatologicka ambulancia
  • Kosice-Saca, Slovakia, 040 15
    • Nemocnica Kosice-Saca, a.s.1.sukromna nemocnica
  • Považská Bystrica, Slovakia, 017 01
    • Neštátna Reumatologická Ambulancia
  • Rimavska Sobota, Slovakia, 979 01
    • REUMEX s.r.o. Reumatologicka ambulancia
  • Zilina, Slovakia, 010 01
    • Reumatologicka ambulancia, MUDr. Pavol Polak s.r.o.
  • Trenciansky Kraj.
    • Partizanske, Trenciansky Kraj., Slovakia, 958 01
      • Reumacentrum s.r.o.
• Spain
  • A Coruña, Spain, 15006
    • Hospital Universitario A Coruña
  • Sevilla, Spain, 41010
    • Hospital Quironsalud Infanta Luisa
  • A Coruna
    • Santiago de Compostela, A Coruna, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago de Compostela
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain, 15705
      • HM Hospital Nuestra Señora de la Esperanza
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital Universitario Cruces
• Taiwan
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taipei, Taiwan, 110
    • Taipei Medical University Hospital
  • Taipei, Taiwan, 10043
    • National Taiwan University Hospital
• Ukraine
  • Chernihiv, Ukraine, 14029
    • Komunalnyi likuvalno-profilaktychnyi zaklad "Chernihivska oblasna likarnia",
  • Kharkiv, Ukraine, 61039
    • Derzhavna ustanova "Natsionalnyi instytut terapii imeni L.T. Maloi
  • Kyiv, Ukraine, 01103
    • Komunalne nekomertsiine pidpryiemstvo "Konsultatyvno-diahnostychnyi tsentr"
  • Kyiv, Ukraine, 04070
    • Medychnyi tsentr tovarystva z obmezhenoiu vidpovidalnistiu "Revmotsentr", m. Kyiv
  • Kyiv, Ukraine, 04114
    • Derzhavna ustanova "Instytut herontolohii imeni D.F. Chebotarova
  • Poltava, Ukraine, 36011
    • Poltavska oblasna klinichna likarnia im. M.V. Sklifosovskoho,
  • Ternopil, Ukraine, 46002
    • Ternopilska universytetska likarnia, revmatolohichne viddilennia, Derzhavnyi vyshchyi navchalnyi
  • Vinnytsia, Ukraine, 21018
    • Vinnytska oblasna klinichna likarnia im. M.I.Pyrohova, revmatolohichne viddilennia
• United States
  • Alabama
    • Tuscaloosa, Alabama, United States, 35406
      • Clinical and Translational Research Center of Alabama, PC
  • Arizona
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System
    • Tucson, Arizona, United States, 85723
      • Dory Hardy, PharmD
  • Florida
    • Clearwater, Florida, United States, 33765
      • Robert W. Levin, MD,PA
    • Ormond Beach, Florida, United States, 32174
      • Millennium Research
    • South Miami, Florida, United States, 33143
      • Qps-Mra, Llc
    • South Miami, Florida, United States, 33143
      • Arthritis & Rheumatic Care Center
  • Georgia
    • Canton, Georgia, United States, 30115
      • Medical Associates of North Georgia
  • Kentucky
    • Bowling Green, Kentucky, United States, 42101
      • Graves Gilbert Clinic
  • Louisiana
    • Monroe, Louisiana, United States, 71203
      • Arthritis And Diabetes Clinic, Inc.
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Ramesh C Gupta, M.D.
  • Texas
    • Baytown, Texas, United States, 77521
      • Accurate Clinical Management, LLC
    • Houston, Texas, United States, 77084
      • Accurate Clinical Management, LLC
    • Houston, Texas, United States, 77004
      • Accurate Clinical Management, LLC
    • Tomball, Texas, United States, 77375
      • DM Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female (including WOCBP) subjects between the ages of 18 and 75 years, inclusive.
2. Diagnosis of RA and meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA with a Total Score ≥6/10.

3. The subject has active disease at both Screening and Baseline, as defined by both:

   • 6 joints tender or painful on motion, AND
   • 6 joints swollen; and fulfills 1 of the following 2 criteria at Screening:
   • High sensitivity C reactive protein (hsCRP) >7 mg/L at screening
   • Erythrocyte sedimentation rate (ESR) (Westergren method) >28 mm/hr;
4. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA.
5. Subjects must be ACPA positive between screening and randomization.
6. Subjects must have been taking oral MTX for at least 3 months at an adequate dose to determine that the subject had an inadequate response to MTX
7. Up to 50 % of subjects may have received one (and only one) approved TNF-inhibiting biologic agent administered that was inadequately effective and/or not tolerated. The anti-TNF biologic could also have been discontinued due to lack of continued access.

Exclusion Criteria:

1. Subjects with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.

2. Subjects with any of the following infections or infections history:

   1. Any infection requiring treatment within 2 weeks prior to screening (Visit 1).
   2. Any infection requiring hospitalization, parenteral antimicrobial therapy within 60 days, or as otherwise judged to be an opportunistic infection or clinically significant by the investigator, within the past 6 months.
   3. Infected joint prosthesis at any time with the prosthesis still in situ.
   4. Recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
   5. Subjects will be screened for HIV. Subjects who test positive for HIV will be excluded from the study.
   6. Subjects will be screened for hepatitis B virus infection and will be excluded if positive for hepatitis B surface antigen (HBsAg). Subjects with HBsAg negative testing but who test positive for hepatitis B core antibody (HBcAb) must have further testing for hepatitis B surface antibody (HBsAb). If HBsAb is negative, the subject will be excluded from the study.
   7. Subjects with clinically significant active hepatic disease or hepatic impairment by laboratory assessment.
   8. Subjects will be screened for hepatitis C virus (HCV Ab). Subjects with positive HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA). Only subjects with negative HCV Ab or HCV RNA will be allowed to enroll in the study.
3. Evidence of active or latent, untreated or inadequately treated infection with Mycobacterium tuberculosis (TB)
4. Pre-existing chronic autoimmune disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: 20 mg QD; PF-06650833 , 20 mg QD	Drug: PF-06650833; Investigational
Experimental: Arm 2: 60 mg QD; PF-06650833, 60 mg QD	Drug: PF-06650833; Investigational
Experimental: Arm 3: 200 mg QD; Pf-06650833, 200 mg QD	Drug: PF-06650833; Investigational
Experimental: Arm 4: 400 mg QD; PF-06650833, 400 mg QD	Drug: PF-06650833; Investigational
Placebo Comparator: Placebo; Placebo, 0 mg BID	Drug: Placebo; Placebo
Active Comparator: Arm 5: Tofacitinib; Tofacitinib 5 mg BID	Drug: Tofacitinib; Investigational; Other Names: Xeljanz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Simplified Disease Activity Index (SDAI) at Week 12	The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = Tender / Painful Joint Count(TJC) (using 28 joints) + Swollen Joint Count (SJC) (using 28 joints) + Patient Global Assessment of Arthritis (PtGA) (0-10 cm scale) + Physician's Global Assessment of Arthritis (PhGA) (0-10 cm scale) + high sensitivity C-reactive protein (hsCRP) (mg/dL). SDAI total score= 0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high disease activity. The primary analysis utilized a Bayesian ANCOVA model with an informative placebo prior distribution with borrowing from tofacitinib historical placebo data. The confidence interval was credible interval in this statistical analysis. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in SDAI at Weeks 4 and 8	The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). SDAI total score= 0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high disease activity. The descriptive summary of change from baseline in SDAI was based on a mixed effect model repeat measurement MMRM model with observed data. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4 and 8
Percentage of Participants With SDAI Low Disease Activity Score (LDAS) (SDAI <=11) at 4, 8, and 12 Weeks	The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). The criterion of SDAI LDAS was SDAI<=11. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With SDAI Remission (SDAI <=3.3) at 4, 8, and 12 Weeks	The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). The criterion of SDAI remission was SDAI<=3.3. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With Disease Activity Score-28 (4 Components Based on Erythrocyte Sedimentation Rate) (DAS28-4 [ESR]) LDAS (DAS28 <3.2) at 4, 8, and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 (ESR) LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-3 (ESR) LDAS (DAS28 <3.2) at 4, 8, and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With Disease Activity Score-28 (4 Components Based on High-Sensitivity C-Reactive Protein) (DAS28-4 [CRP]) LDAS (DAS28 <3.2) at 4, 8, and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-3 (CRP) LDAS (DAS28 <3.2) at 4, 8, and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+ 1.15. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-4 (ESR) Remission (DAS28 <2.6) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PtGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-3 (ESR) Remission (DAS28 <2.6) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-4 (CRP) Remission (DAS28 <2.6) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants With DAS28-3 (CRP) Remission (DAS28 <2.6) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+1.15. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Change From Baseline in DAS28-4 (ESR) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PtGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Higher score indicated more disease activity. Total score range: 0-9.4. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in DAS28-3 (ESR) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR) [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in DAS28-4 (CRP) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in DAS28-3 (CRP) at 4, 8 and 12 Weeks	The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+ 1.15. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at 4, 8 and 12 Weeks	ACR20 was calculated as a 20% improvement in TJC and SJC and 20% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at 4, 8 and 12 Weeks	ACR50 was calculated as a 50% improvement in TJC and SJC and 50% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at 4, 8 and 12 Weeks	ACR70 was calculated as a 70% improvement in TJC and SJC and 70% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Weeks 4, 8 and 12
Change From Baseline in the Tender/Painful and Swollen Joint Counts at 4, 8 and 12 Weeks	The TJC (28) included the following joints: shoulders, elbows, wrists, metatarsophalangeal (MCP) joints, PIP joints, and knees. This count was calculated from the TJC (68) assessed. The SJC (28) included the same joints as TJC (28), and was calculated from the SJC 66 assessed for swelling.Sixty eight (68) joints were assessed by a blinded joint assessor to determine the number of joints that were considered tender or painful. The 68 joints assessed were: temporomandibular, sternoclavicular, acromioclavicular; shoulder, elbow, wrist, MCPs, thumb interphalangeal, proximal interphalangeals, and distal interphalangeals; hip, knee, ankle, tarsus, metatarsophalangeals, great toe interphalangeal, proximal and distal interphalangeals combined. Sixty-six (66) joints were assessed for swelling, the same as those listed for TJC, excluding the right and left hip joints. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in High-Sensitivity C-Reactive Protein (Hs-CRP) at 4, 8 and 12 Weeks	Serum samples were analyzed to determine the level of hs-CRP, which was an acute-phase reactant. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in the Physician's Global Assessment of Arthritis (PhGA) at 4, 8, and 12 Weeks	The investigator assessed how the participant's overall arthritis appeared at the time of the visit. This was an evaluation based on the participant's disease symptoms, functional capacity and physical examination, and was independent of the participant's reported assessments of PtGA (patient's global assessment of arthritis). The investigator's response was recorded using a 100 mm visual analog scale (VAS), with the 0 mm end labeled "None" and the 100 mm end labeled "Extreme". Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Treatment-Related TEAEs	AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator.	Baseline up to 28 calendar days after the last administration of the investigational product (about 21 months)
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	Laboratory evaluation included hematology, clinical chemistry, and urinalysis. Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test [for all female participants]) and urine (urine pregnancy test [for all female participants]). Each parameter was evaluated against commonly used and widely accepted criteria. Clinical significance of laboratory parameters was determined at the investigator's discretion. The investigator judged the abnormality.	Baseline up to 28 calendar days after the last administration of the investigational product (about 21 months)
Number of Participants With Vital Signs Data Meeting Pre-sepcified Criteria	Vital Signs tests included sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) and pulse rate. Vital signs categorical summarization criteria were 1), systolic BP (SBP) <90 millimeters of mercury (mm Hg) or change from baseline (Chg) >=30mm Hg; diastolic BP (DBP) <50mm Hg or change from baseline >=20mm Hg; 2), pulse rate <40bpm or > 120bpm.	Baseline up to 28 calendar days after the last administration of the investigational product (about 21 months)
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-sepcified Criteria	ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), QT interval corrected for heart rate using Fridericia's formula (QTcF interval), and QTc calculated using Bazett's correction factor (QTcB interval).	Baseline up to 28 calendar days after the last administration of the investigational product (about 21 months)
Number of Participants With Urinalysis Data Meeting Pre-specified Criteria	The urine sample was collected for central laboratory urinalysis and urine microscopy. The urinalysis included pH, protein, glucose, erythrocytes, leukocytes, ketones, nitrite, urobilinogen, urine bilirubin, urine hemoglobin, leukocyte esterase, granular casts, hyaline casts, bacteria, atypical, needle-like crystals urine, specific gravity, microscopy and urine albumin test.	Baseline up to 28 calendar days after the last administration of the investigational product (about 21 months)
Change From Baseline in the Patient's Assessment of Arthritis Pain (PAAP) Visual Analogue Scale (VAS) at Weeks 4, 8, 12	Patients assess the severity of their arthritis pain using a 100 mm VAS by placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponds to the magnitude of their pain. This assessment was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in the Patient Global Assessment of Arthritis (PtGA) VAS at Weeks 4, 8, 12	Patients answer the following question: "Considering all the ways your arthritis affects you, how are you feeling today?" The patient's response is recorded using a 100 mm VAS. This assessment was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. The higher score indicated more severe disease. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Weeks 4, 8, and 12	The HAQ-DI was defined as participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 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 0-3 where 0 = least difficulty and 3 = extreme difficulty. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline, Weeks 4, 8 and 12
Change From Baseline in the 36 Item Short Form Health Survey (SF-36) Version 2 (Acute) 8 Domain Scores at Week 12	The SF-36 version 2 (acute) is a 36 item generic health status measure. It measures 8 general health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The SF-36 summary scores range from 0-100, with higher scores representing better self-reported health. This was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline and Week 12
Change From Baseline in the Physical Component Score (PCS) and Mental Component Score (MCS) at Week 12	The SF 36 version 2 (acute) is a 36 item generic health status measure. It measures 8 general health domains. These domains can also be summarized as physical component score (PCS) and mental component score (MCS). The PCS and MCS summary scores range from 0-100, with higher scores representing better self-reported health. The lower the score the more disability. This was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline and Week 12
Change From Baseline in the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) Score at Week 12	The EQ-5D-3L health state profile is a patient completed questionnaire designed to assess impact on health related quality of life in 5 domains: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Additionally, scores from the 5 domains might have been used to calculate a single index value, also known as a utility score. The validity and reliability of the EQ-5D-3L have been established in a number of disease states, including RA. EQ-5D-3L scores marked health status from 0 and 100. There were notes at the both ends of the scale that the bottom rate (0) corresponded to " the worst health you could imagine", and the highest rate (100) corresponded to "the best health you could imagine". Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline and Week 12
Change From Baseline in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score at Week 12	The FACIT-F is a patient completed questionnaire consisting of 13 items that assess fatigue. Instrument scoring yields a range from 0 to 52, with higher scores representing better patient status (less fatigue). This questionnaire was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.	Baseline and Week 12

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2016
• Primary Completion (Actual): August 15, 2018
• Study Completion (Actual): August 15, 2018

Study Registration Dates

• First Submitted: October 13, 2016
• First Submitted That Met QC Criteria: December 16, 2016
• First Posted (Estimate): December 19, 2016

Study Record Updates

• Last Update Posted (Actual): February 27, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: B7921005; 2016-002337-30 (EudraCT Number); IRAK 4 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No