Clinical trial NCT04413617: TO ASSESS THE EFFICACY AND SAFETY OF PF-06650833, PF-06651600, AND TOFACITINIB ALONE AND IN COMBINATION IN PARTICIPANTS WITH ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE
Official title: A 24-WEEK RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, ACTIVE COMPARATOR, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF PF-06650833, PF-06651600 (RITLECITINIB) AND TOFACITINIB ALONE AND IN COMBINATION IN PARTICIPANTS WITH MODERATELY-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-06-04
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Dual objectives of increased efficacy compared to currently available SoC RA drugs and maintaining a favourable benefit - risk relationship.


Eligibility criteria: Inclusion Criteria:

* Male or female participants between the ages of 18 and 70 years.
* Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
* 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.
* The participant has active disease at both Screening and Randomization, as defined by both: ≥6 joints tender or painful on motion, AND ≥6 joints swollen; and fulfills 1 of the following 2 criteria: High sensitivity C reactive protein (hsCRP) \>7 mg/L at Screening (Visit 1) as performed by the central laboratory OR Erythrocyte sedimentation rate (ESR) (Westergren method) \>28 mm h.

Exclusion Criteria:

* Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
* Participants with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
* Participants with any active or latent infections.
* Participants with positive hepatitis B surface antigen (HBsAg).
* Participants with positive HCV Ab tests will be reflex tested for HCV ribonucleic acid (HCV RNA).
* Any history of either untreated or inadequately treated latent or active tuberculosis (TB) infection, current treatment for active or latent TB infection or evidence of currently active TB,
* History of a major organ transplant (eg, heart, lung, kidney and liver) or hematopoietic stem cell/marrow transplant.
* History of severe allergic or anaphylactoid reaction to kinase inhibitors, or corticosteroid preparations.
* Known history of diverticulitis or symptomatic diverticulosis, perineal abscess or fistulae.
* Participants with malignancy or history of malignancy (including lymphoma, leukemia, or lymphoproliferative disease).
* Pre-existing chronic autoimmune disease (eg, inflammatory bowel disease, systemic lupus erythematosus, moderate-severe atopic dermatitis, dermatomyositis) other than RA. Secondary Sjogren's Syndrome (due to RA) may be included.
* Participants with fibromyalgia will be excluded.
* Previous treatment with total lymphoid irradiation.
* Participants with an oral, tympanic, or temporal temperature of 38°C (100.4°F) or higher at baseline.
* Participants may not receive any live/attenuated vaccine from 30 days prior to randomization during the course of the study, or for 30 days after the last dose of study medication. Participants who have current routine household contact with children who have received varicella or oral polio vaccine within 2 months of first study dose are also excluded.
* History of any lymphoproliferative disorder.
* Have hearing loss with progression over the previous 5 years, sudden hearing loss, or middle or inner ear disease.
* History of any prior deep vein thrombosis (DVT) or pulmonary embolism \[PE\].
* Recent (within 6 months of screening) myocardial infarction, coronary revascularization, or percutaneous angioplasty with or without placement of a coronary artery stent; acute coronary syndrome; chronic uncompensated heart failure or New York Heart Association Functional Class III or IV; left ventricular assist devices; implanted defibrillators.
* Current severe chronic renal insufficiency or renal failure as defined by persistent (on repeated measurements) eGFR \<60 mL/min per 1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculation.
* Any known coagulopathy or hypercoagulant syndrome.
* Presence of any of the following laboratory abnormalities at screening or within the 3 months prior to first study dose:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥1.5 x the upper limit of normal (ULN); Participants with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is ≤ ULN and other liver function assessments are normal; Absolute neutrophil count of \<1.5 x 109/L (\<1500/mm3). Participants with cyclic (benign ethnic) neutropenia will be excluded; Absolute lymphocyte count of \<0.5 x 109/L (\<500/mm3); Absolute white blood cell (WBC) count of \<3.0 x 109/L (\<3000/mm3); Hemoglobin \<9.0 g/dL (90 g/L); Platelet count ≤100 x 109/L (100,000 cells/mm3) or ≥1000 x 109/L (1,000,000 cells/mm3); Thrombocytopenia, as defined by a platelet count \<100 x 109/L (\<100,000/mm3) at screening visit or within the 3 months prior to first study dose. \[Screening laboratory tests with abnormal results may be repeated once to confirm abnormal results. If results return to normal protocol acceptable limits within the 4-week screening period, the participant may enter the study\].

- Grade 3 or greater laboratory abnormality based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicity scale, except for the following that are allowed: Grade 3 prothrombin time (PT) secondary to warfarin treatment; Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy.

* Participants previously treated with a biologic DMARD (except for up to 25% of participants who may have been treated with 1, and only 1 prior TNF inhibitor) or any other recent DMARD treatment (eg, a JAK inhibitor), or participants currently treated with any other prohibited medications will be excluded.
* Prior use of tofacitinib or other JAK inhibitor in the context of a clinical trial is excluded. Concomitant use of tofacitinib (other than as prescribed by the randomization scheme) or other JAK inhibitor is prohibited.
* Participants who have previously been treated with other, non-TNFa inhibiting biologic DMARDs \[including, abatacept (Orencia®), tocilizumab (Actemra®), Sarilumab (Kevzara®), anakinra (Kineret®), rituximab (Rituxan®) or other selective B lymphocyte depleting agents, or other lymphocyte depleting agents/therapies (such as alemtuzab \[CamPath®\], natalizumab (Tysabri®), alkylating agents \[eg, cyclophosphamide or chlorambucil\], total lymphoid irradiation) are excluded from participation in the study.
* Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of IP used in this study (whichever is longer).
* Any 12-lead electrocardiogram (ECG) performed prior to randomization that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.

Primary outcomes:
measure: Change From Baseline (BL) in Disease Activity Score (DAS)28-C Reactive Protein (CRP) at Week 12
timeFrame: BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12
Secondary outcomes:
measure: DAS28-CRP Remission (<2.6) Rates at Week 24
timeFrame: Week 24
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs), and Withdrawals Due to TEAEs
timeFrame: From first dose of study intervention (Day 1) to Week 28
measure: Number of Participants With Clinical Laboratory Abnormalities (Hematology and Chemistry, Without Regard to Baseline Abnormality)
timeFrame: From BL to Week 28
measure: Number of Participants With Change From Baseline in Vital Signs Data Meeting the Pre-defined Categorical Summarization Criteria
timeFrame: From BL to Week 28
measure: Number of Participants With Adverse Events of Special Interest
timeFrame: From first dose of study intervention (Day 1) to Week 28
measure: Change From Baseline in DAS28-CRP at Week 24
timeFrame: BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 24
measure: American College of Rheumatology (ACR)20, ACR 50, ACR 70, and ACR 90 Responder Rates at Week 12 and Week 24
timeFrame: BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
measure: Change From Baseline in the Tender/Painful and Swollen Joint Count at Week 12 and Week 24
timeFrame: BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
measure: Change From Baseline in the Physician's Global Assessment (PhGA) of Arthritis at Week 12 and Week 24
timeFrame: BL (defined as the last non-missing measurement collected prior to the first administration of study drug on Day 1), Week 12, Week 24
Other outcomes:
Locations:
city: Pleven
country: Bulgaria
facility: ,,UMHAT - Georgi Stranski" EAD
city: Plovdiv
country: Bulgaria
facility: Medical Diagnostic Laboratory Rusev EOOD
city: Plovdiv
country: Bulgaria
facility: MHAT Plovdiv AD
city: Plovdiv
country: Bulgaria
facility: DCC Sveti Georgi EOOD
city: Plovdiv
country: Bulgaria
facility: Independent Medical Diagnostic Laboratory Mediscan EOOD
city: Ruse
country: Bulgaria
facility: "Medical Center-Teodora" EOOD
city: Ruse
country: Bulgaria
facility: UMHAT "Kanev" AD
city: Sofia
country: Bulgaria
facility: Medical Center "Spectar" OOD
city: Sofia
country: Bulgaria
facility: MHAT "Lyulin" EAD
city: Sofia
country: Bulgaria
facility: "DCC 17 - Sofia" EOOD
city: Sofia
country: Bulgaria
facility: Medical Center "N.I. Pirogov" EOOD
city: Sofia
country: Bulgaria
facility: UMHAT "Sveti Ivan Rilski" EAD
city: Winnipeg
country: Canada
facility: Manitoba Clinic
state: Manitoba
city: Rimouski
country: Canada
facility: Centre de Rhumatologie de l'Est du Quebec (CREQ)
state: Quebec
city: Santiago
country: Chile
facility: Centro Radiologico San Vicente de Paul
state: Region Metropolitana
city: Santiago
country: Chile
facility: CTR Estudios
state: Region Metropolitana
city: Santiago
country: Chile
facility: Enroll SpA
state: Region Metropolitana
city: Santiago
country: Chile
facility: Centro Radiologico Plaza Baquedano
state: Region Metropolitana
city: Santiago
country: Chile
facility: IMARED
state: Region Metropolitana
city: Santiago
country: Chile
facility: Centro de Estudios Reumatologicos (CER)
state: Region Metropolitana
city: Pardubice
country: Czechia
facility: CCR Czech a.s.
state: Vychodocesky KRAJ
city: Brno
country: Czechia
facility: REVMACLINIC s.r.o.
city: Brno
country: Czechia
facility: Revmacentrum MUDr. Mostera, s.r.o.
city: Brno
country: Czechia
facility: HV Medical s.r.o., ORL ambulance pro deti a dospele
city: Havirov
country: Czechia
facility: MRI Lekarsky servis s.r.o.
city: Ostrava - Kuncice
country: Czechia
facility: Poliklinika AMO - Audiologie
city: Ostrava
country: Czechia
facility: CCR Ostrava, s.r.o.
city: Ostrava
country: Czechia
facility: Vesalion s.r.o.
city: Ostrava
country: Czechia
facility: Mestka nemocnice Ostrava
city: Pardubice
country: Czechia
facility: ORL - sluchadla s.r.o.
city: Pardubice
country: Czechia
facility: Poliklinika Vektor
city: Praha 2
country: Czechia
facility: Revmatologicky ustav
city: Praha 4
country: Czechia
facility: Thomayerova nemocnice
city: Uherske Hradiste
country: Czechia
facility: ORL ambulance
city: Uherske Hradiste
country: Czechia
facility: Uherskohradistska nemocnice, a.s.
city: Uherske Hradiste
country: Czechia
facility: Medical Plus s.r.o.
city: Tbilisi
country: Georgia
facility: JSC "Evex Hospitals"
city: Tbilisi
country: Georgia
facility: LTD "Cardioclinic - Digomi Medical Center"
city: Tbilisi
country: Georgia
facility: LTD "Institute of Clinical Cardiology"
city: Tbilisi
country: Georgia
facility: LTD "MediClub Georgia"
city: Tbilisi
country: Georgia
facility: LTD "Multi-Profile Clinic Consilium Medulla"
city: Bekescsaba
country: Hungary
facility: Trial Pharma Kft.
city: Bekescsaba
country: Hungary
facility: Vasutegeszsegugyi Nonprofit Kozhasznu Tarsasag
city: Budapest
country: Hungary
facility: Betegapolo Irgalmasrend Budai Irgalmasrendi Korhaz
city: Budapest
country: Hungary
facility: Mammut Egeszsegkozpont, Ful-orr- gegeszet
city: Budapest
country: Hungary
facility: Betegapolo Irgalmasrend Budai Irgalmasrendi Korhaz
city: Budapest
country: Hungary
facility: Budai Irgalmasrendi Korhaz
city: Budapest
country: Hungary
facility: Revita Reumatologiai Rendelo
city: Budapest
country: Hungary
facility: Qualiclinic Kft.
city: Budapest
country: Hungary
facility: Affidea Magyarorszag Kft.
city: Budapest
country: Hungary
facility: Affidea Magyarország Kft. Bank Center Központ
city: Budapest
country: Hungary
facility: Magyar Honvédség Egészségügyi Központ
city: Budapest
country: Hungary
facility: Affidea Magyarorszag Kft. Vaci Greens Egeszsegkozpont
city: Budapest
country: Hungary
facility: Mediszintech Audiologia Kft.
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Gyula
country: Hungary
facility: Sanitas Diagnosztikai es Rehabilitacios Kozpont
city: Kistarcsa
country: Hungary
facility: Pest Megyei Flór Ferenc Kórház Fül- Orr- Gégészet és Gyermek Fül-Orr-Gégészet
city: Kistarcsa
country: Hungary
facility: Pest Megyei Flór Ferenc Kórház Reumatológiai es Fizioterápiás Osztály
city: Miskolc
country: Hungary
facility: Huniko Kereskedelmi és Egészségügyi Szolgáltató Kft.
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Reumatologiai Klinika
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem
city: Szeged
country: Hungary
facility: Szent-Gyorgyi Albert Klinikai Kozpont
city: Veszprem
country: Hungary
facility: Csolnoky Ferenc Korhaz, Ful- Orr- Gegeszeti Osztaly
city: Veszprém
country: Hungary
facility: VITAL MEDICAL CENTER (VITÁL-MEDICINA Kft.)
city: Bialystok
country: Poland
facility: Podlaskie Centrum Sluchu i Mowy Sluchmed
city: Bialystok
country: Poland
facility: Nzoz Zdrowie Osteo-Medic
city: Bialystok
country: Poland
facility: Lar-Med
city: Bialystok
country: Poland
facility: NZOZ Kendron
city: Bialystok
country: Poland
facility: Tomma Diagnostyka obrazowa
city: Bialystok
country: Poland
facility: ClinicMed Daniluk, Nowak Sp. J.
city: Bydgoszcz
country: Poland
facility: Nzoz McD Voxel
city: Bydgoszcz
country: Poland
facility: Klinika Foniatrii i Audiologii, Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
city: Bydgoszcz
country: Poland
facility: Klinika Reumatologii i Ukladowych Chorob Tkanki Lacznej
city: Gdynia
country: Poland
facility: Centrum Medyczne Pratia Gdynia
city: Gdynia
country: Poland
facility: Portowy Zaklad Opieki Zdrowotnej Sp. z o.o.
city: Gdynia
country: Poland
facility: Centrum Medyczne Enel-Med., Oddzial Alfa Plaza - Gdynia
city: Grodzisk Mazowiecki
country: Poland
facility: MCBK
city: Grodzisk Mazowiecki
country: Poland
facility: Samodzielny Publiczny Specjalistyczny Szpital Zachodni im. sw. Jana Pawla II
city: Krakow
country: Poland
facility: Malopolskie Badania Kliniczne
city: Krakow
country: Poland
facility: LUX MED.
city: Krakow
country: Poland
facility: Centrum Badan Klinicznych JCI
city: Krakow
country: Poland
facility: Centrum medyczne PLEJADY
city: Krakow
country: Poland
facility: LUXMED
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Krakow
country: Poland
facility: Centrum Medycyny Profilaktycznej Sp. z o. o.
city: Krakow
country: Poland
facility: Centrum Medyczne iMed24
city: Nowa Sol
country: Poland
facility: FONMED
city: Nowa Sol
country: Poland
facility: Twoja Przychodnia - Centrum Medyczne Nowa Sol
city: Nowy Tomysl
country: Poland
facility: LIVMED Sp. z.o.o.
city: Poznan
country: Poland
facility: Ai Centrum Medyczne
city: Poznan
country: Poland
facility: Tomma Diagnostyka Obrazowa S.A.
city: Poznan
country: Poland
facility: GEERS Dobry Sluch
city: Poznan
country: Poland
facility: Prywatna Praktyka Lekarska Prof. dr hab. med. Pawel Hrycaj
city: Poznan
country: Poland
facility: Pracownia Rezonansu Magnetycznego i RTG
city: Warszawa
country: Poland
facility: Centrum Mowy i Sluchu Medincus
city: Warszawa
country: Poland
facility: Rex Medica Sport
city: Warszawa
country: Poland
facility: Medycyna Kliniczna
city: Warszawa
country: Poland
facility: Tomma Diagnostyka Obrazowa
city: Warszawa
country: Poland
facility: "MTZ CLINICAL RESEARCH" Spolka z ograniczona odpowiedzialnoscia
city: Warszawa
country: Poland
facility: "Reumatika - Centrum Reumatologii" NZOZ
city: Warszawa
country: Poland
facility: ArtAna Anna Piotrowska
city: Warszawa
country: Poland
facility: Spoldzielnia Pracy Specjalistow Rentgenologow im. prof. W. Zawadowskiego
city: Warszawa
country: Poland
facility: Szpital LUX MED
city: Bratislava
country: Slovakia
facility: Dermatovenerologicka ambulancia
city: Bratislava
country: Slovakia
facility: ROMJAN, s.r.o.
city: Bratislava
country: Slovakia
facility: ORL ambulancia RHINO s.r.o.
city: Kosice
country: Slovakia
facility: Klinika dermatovenerologie UNLP
city: Kosice
country: Slovakia
facility: ARTROMAC n. o.
city: Kosice
country: Slovakia
facility: Oddelenie radiodiagnostiky a zobrazovacich metod, UNLP
city: Kosice
country: Slovakia
facility: Poliklinika Terasa s.r.o.
city: Martin
country: Slovakia
facility: Dermabene, s.r.o
city: Martin
country: Slovakia
facility: MEDMAN, s. r. o.,
city: Martin
country: Slovakia
facility: ORL ML, s.r.o
city: Nitra
country: Slovakia
facility: Jessenius - Diagnosticke centrum
city: Partizanske
country: Slovakia
facility: Otorinolaryngologicka ambulancia MUDr. Olga Salgova
city: Partizanske
country: Slovakia
facility: PARDERM, s. r. o., Dermatovenerologicka ambulancia
city: Partizanske
country: Slovakia
facility: REUMACENTRUM s.r.o.
city: Piestany
country: Slovakia
facility: MEDICENTRUM Piestany, s.r.o.
city: Piestany
country: Slovakia
facility: Narodny ustav reumatickych chorob
city: Piestany
country: Slovakia
facility: Nemocnica Alexandra Wintera n.o.
city: Rimavska Sobota
country: Slovakia
facility: Vseobecna nemocnica Rimavska Sobota
city: Rimavska Sobota
country: Slovakia
facility: AZIMED-ORL s.r.o.
city: Rimavska Sobota
country: Slovakia
facility: Dg.s.r.o. - Diagnosticke- centrum
city: Rimavska Sobota
country: Slovakia
facility: REUMEX s.r.o.
city: Ruzomberok
country: Slovakia
facility: Spinn, s.r.o.
city: Topolcany
country: Slovakia
facility: Zdravomak s.r.o. Topoľčany
city: Santiago de Compostela
country: Spain
facility: Clinica Gaias - Santiago
state: A Coruna
city: Santiago de Compostela
country: Spain
facility: Grupo Hospitalario La Rosaleda - Hospital Nuestra Senora de la Esperanza
state: A Coruna
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Barcelona
country: Spain
facility: Clinica Sagrada Familia
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario Santiago de Compostela
city: Sevilla
country: Spain
facility: Hospital Quironsalud Infanta Luisa
city: Chernihiv
country: Ukraine
facility: Communal non-profit enterprise "Chernihiv Regional Hospital" of Chernihiv Regional Council
city: Kharkiv
country: Ukraine
facility: Communal Non-commercial Enterprise of Kharkiv Regional Council
city: Kyiv
country: Ukraine
facility: Medical сепtег of "Medical Clinic "Blagomed" LLC
city: Kyiv
country: Ukraine
facility: Medical Center 'Ok!Clinic+' of International Institute of Clinical Research LLC
city: Kyiv
country: Ukraine
facility: Communal non-profit enterprise "Kyiv City Clinical Hospital #3" of executive body of Kyiv
city: Kyiv
country: Ukraine
facility: Limited Liability Company "Medical Centre "Consilium Medical"
city: Kyiv
country: Ukraine
facility: "Revmocenter" LLC
city: Kyiv
country: Ukraine
facility: Clinic of the State Institution "DF Chebotaryov Institute of Gerontology of the NAMS of Ukraine"
city: Odesa
country: Ukraine
facility: Communal Non-Commercial Enterprise "Odesa Regional Clinical Hospital" of Odesa Regional Council
city: Poltava
country: Ukraine
facility: Comunal Enterprise "Poltava Regional Clinical Hospital n. a. M.S. Sklifosovskogo of Poltava
city: Zaporizhzhya
country: Ukraine
facility: LLC "Modern Clinic"
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: