Clinical trial NCT03233230: Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis
Official title: A Phase IIb, Randomized, Double-blind Study in Subjects With Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared With Placebo in Subjects With an Inadequate Response to Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis
American College of Rheumatology
High-sensitivity C-reactive protein
Bruton's tyrosine kinase
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2017-07-28
Enrollment: 390
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to determine the efficacy, dose response, and safety of M52951 in participants with Rheumatoid Arthritis (RA), and to consider a dose to took forward into Phase III development.


Eligibility criteria: Inclusion Criteria:

* In Japan, if a participant is less than (\<) 20 years, the written informed consent from the participant's parent or guardian will be required in addition to the participant's written consent.
* Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at least 6 months duration prior to Screening
* Persistently active moderate to severe RA at both Screening and Randomization (if significant surgical treatment of a joint has been performed, that joint cannot be counted for entry or enrollment purposes), as defined by: \>= 6 swollen joints (of 66 assessed) and \>= 6 tender joints (of 68 assessed).
* An hsCRP \>= 5.0 milligram/liter (mg/L) at Screening
* Treatment for \>= 16 weeks with 7.5 to 25 mg/week Methotrexate (MTX) at a stable dose and route of administration (oral or parenteral) for at least 8 weeks prior to dosing with the Investigational Medicinal Product (IMP) and maintained throughout the trial
* For participants entering the trial on MTX doses \< 15 mg/week (\< 10 mg/week in Japan), there must be clear documentation in the medical record that higher doses of MTX were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines.
* For MRI Sub-study participants, participants must have palpable synovitis of the wrist and/or \>= 1 of metacarpophalangeal joints 1 to 5, defined as loss of bony contours with palpable joint effusion and/or swelling, in the MRI-designated hand (that is., the hand being used in MRI assessments).

Exclusion Criteria:

* ACR functional class IV as defined by the ACR classification of functional status or wheelchair/bedbound
* Use of oral corticosteroids greater than (\>) 10 mg daily prednisone equivalent, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening
* Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular hyaluronic acid within 4 weeks prior to Screening or during Screening
* Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) (including low-dose aspirin and cyclooxygenase-2 inhibitors) within 2 weeks prior to dosing with the IMP
* High potency opioid analgesics are prohibited within 2 weeks prior to Screening and during the trial; other analgesics are allowed (that is, acetaminophen, codeine, hydrocodone\*, propoxyphene\*, or tramadol), although not within 24 hours of study visits with clinical assessments (\*not approved in Japan)
* Current or prior treatment with any of the following:
* Biologic Disease-modifying anti-rheumatic drugs (DMARDs) (approved or investigational), including but not limited to:
* Tumor necrosis factor (TNF) antagonists or biosimilars of these agents (approved or investigational), or any investigational TNF antagonist
* Interleukin-6 antagonists
* Abatacept (CTLA4-Fc)
* Anakinra\* (IL-1 receptor antagonist) (\*not approved in Japan)
* B cell-depleting antibodies (example, rituximab, ocrelizumab\*, ofatumumab, obinutuzumab\*, ocaratuzumab\*, veltuzumab\*, or any biosimilars of these agents \[approved or investigational\]) (\*not approved in Japan)
* Anti-BLyS (B lymphocyte stimulator) agents (example, belimumab, tabalumab\*) (\*not approved in Japan)
* Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (that is, atacicept\*, RCT-18\*) (\*not approved in Japan)
* Targeted synthetic DMARDs, specifically:
* Janus kinase inhibitors
* Other Bruton's tyrosine kinase (BTK) inhibitors
* Alkylating agents (example, chlorambucil\*, cyclophosphamide) (\*not approved in Japan).
* The following restrictions on nonbiologic DMARD must be followed:
* Auranofin (Ridaura), minocycline, penicillamine, sulfasalazine, cyclosporine, mycophenolate (mycophenolate sodium not approved in Japan), tacrolimus, azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP
* Leflunomide (Arava) must have been discontinued 12 weeks prior to dosing with the IMP if no elimination procedure is followed. Alternately, it should have been discontinued with the following elimination procedure at least 4 weeks prior to dosing with the IMP:
* Cholestyramine at a dosage of 8 gram 3 times a day for at least 24 hours, or activated charcoal at a dosage of 50 gram 4 times a day for at least 24 hours.
* Injectable Gold (aurothioglucose\* or aurothiomalate): must have been discontinued for 8 weeks prior to dosing with the IMP (\*not approved in Japan)
* Anti-malarials (hydroxychloroquine, chloroquine\*) will be allowed in this trial. Participants may be taking oral hydroxychloroquine (=\< 400 mg/day) or chloroquine (=\< 250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with the IMP, and will need to be continued at that stable dose for the duration of the trial. If discontinued prior to this trial, they must have been discontinued for 4 weeks prior to dosing with the IMP (\*not approved in Japan).
* For MRI Substudy:
* Inability to comply with MRI scanning, including contraindications to MRI such as known allergy to gadolinium contrast media, claustrophobia (if the site does not have ability to scan extremities only), presence of a pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, and nerve stimulators.
* More than 25% of applicable joints of the target hand and wrist having had prior surgery or showing maximum Genant-modified Sharp erosion (3.0) or joint-space narrowing (4.0) scores, based on single posteroanterior radiographs of target hand and wrist read centrally.

Primary outcomes:
measure: Percentage of Participants Who Achieved American College of Rheumatology 20 Percent (%) Response Criteria (ACR20) Assessed Using High-Sensitivity C-reactive Protein (hsCRP) at Week 12
timeFrame: Week 12
Secondary outcomes:
measure: Percentage of Participants With Low Disease Activity Score (DAS28 Less Than [<] 3.2) Based on 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Remission Disease Activity Score (DAS28 Less Than [<] 2.6) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving American College of Rheumatology 50% Response Criteria (ACR50)
timeFrame: Week 12
measure: Percentage of Participants Achieving American College of Rheumatology 70% Response Criteria (ACR70)
timeFrame: Week 12
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
timeFrame: up to Week 16
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
timeFrame: up to Week 16
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: up to Week 16
measure: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
timeFrame: up to Week 16
measure: Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
timeFrame: up to Week 16
measure: Change From Baseline in Serum Immunoglobulin (Ig) Levels (IgG, IgA, IgM) at Week 2, 4, 8, 12 and 16
timeFrame: Baseline, Week 2, 4, 8, 12 and 16
measure: Change From Baseline in B Cell Count at Week 2, 4, 8, 12 and 16
timeFrame: Baseline, Week 2, 4, 8, 12 and 16
measure: Percentage of Participants With Remission Assessed by American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) Boolean at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Clinical Disease Activity Index (CDAI) Score Less Than or Equal to [=<] 2.8 at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Simplified Disease Activity Index (SDAI) Score Less Than or Equal to [=<] 3.3 at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Responses at Week 12
timeFrame: Week 12
measure: American College of Rheumatology (ACR) Hybrid Scores Computed Using High-Sensitivity C-reactive Protein (hsCRP)
timeFrame: Baseline, Week 12
measure: Change From Baseline in Disease Activity Score (DAS) Based on a 28 Joint Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Participant's Global Assessment of Disease Activity Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Participant's Assessment of Pain Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in Physician's Global Assessment of Disease Activity Scale Based on Visual Analog Scale (VAS) Score at Week 12
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Synovitis Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Bone Marrow Edema (Osteitis) Score According to the Outcomes Measures in Rheumatology Clinical Trials Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (OMERACT RAMRIS) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Physical Function Using Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Short-Form (SF-36) Health Survey Physical Component Score and Mental Component Score at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 12
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Arthritis & Rheumatology Associates, P.C.
state: Arizona
city: Phoenix
country: United States
facility: Arizona Arthritis & Rheumatology Research, PLLC
state: Arizona
city: San Leandro
country: United States
facility: East Bay Rheumatology Medical Group, Inc.
state: California
city: DeBary
country: United States
facility: Omega Research Consultants
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Tampa
country: United States
facility: McIlwain Medical Group, PA
state: Florida
city: Greensboro
country: United States
facility: Medication Management, LLC
state: North Carolina
city: San Marcos
country: United States
facility: Arthritis Clinic Of Central Texas
state: Texas
city: La Plata
country: Argentina
facility: Hospital Italiano de La Plata
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Instituto de Investigaciones Clinicas
state: Buenos Aires
city: Quilmes
country: Argentina
facility: Instituto Medico CER
state: Buenos Aires
city: Quilmes
country: Argentina
facility: Instituto de Investigaciones Clinicas Quilmes
state: Buenos Aires
city: Tucuman
country: Argentina
facility: Centro Medico Privado de Reumatologia
state: San Miguel De Tucuman
city: San Miguel de Tucuman
country: Argentina
facility: Centro de Investigaciones Reumatológicas
state: Tucuman
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Organizacion Medica de Investigacion (OMI)
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: APRILLUS
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Expertia S.A- Mautalen Salud e Investigación
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital General de Agudos Dr. J. M. Ramos Mejia
city: Cordoba
country: Argentina
facility: ILAIM-CEOM Inst. Latinoamericano de Inv. Medicas
city: Cordoba
country: Argentina
facility: Instituto Reumatológico Strusberg
city: San Juan
country: Argentina
facility: Centro Polivalente de Asistencia e Inv. Clinica CER
city: Sliven
country: Bulgaria
facility: MHAT "Hadzhi Dimitar", OOD
city: Sofia
country: Bulgaria
facility: DCC "Alexandrovska", EOOD
city: Sofia
country: Bulgaria
facility: UMHAT "SofiaMed", OOD
city: Santiago
country: Chile
facility: Centro Medico Prosalud
city: Santiago
country: Chile
facility: Interin
city: Santiago
country: Chile
facility: BioMedica Research Group
city: Santiago
country: Chile
facility: Centro de Estudios Reumatologicos
city: Barranquilla
country: Colombia
facility: Centro de Reumatologia y Ortopedia SAS
city: Bogota
country: Colombia
facility: Riesgo de Fractura S.A.
city: Bogotá
country: Colombia
facility: Simedics Ips Sas
city: Bogotá
country: Colombia
facility: Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM
city: Bucaramanga
country: Colombia
facility: Servimed S.A.S.
city: Cali
country: Colombia
facility: Clinica de Artritis Temprana S.A.
city: Jihlava
country: Czechia
facility: Revmatolog, s.r.o
city: Ostrava - Trebovice
country: Czechia
facility: ARTROSCAN s.r.o.
city: Ostrava
country: Czechia
facility: CCBR Ostrava s.r.o.
city: Praha 10
country: Czechia
facility: CLINTRIAL s.r.o.
city: Praha 4 - Krc
country: Czechia
facility: Thomayerova nemocnice
city: Praha 4 Nusle
country: Czechia
facility: MUDR. Zuzana URBANOVA Revmatologie
city: Praha 4
country: Czechia
facility: MUDR. Zuzana URBANOVA Revmatologie
city: Uherske Hradiste
country: Czechia
facility: MEDICAL PLUS s.r.o.
city: Zlin
country: Czechia
facility: PV-MEDICAL s.r.o.
city: Mexicali
country: Mexico
facility: Centro Investigacion en Artritis y Osteoporosis S.C.
state: Baja California Norte
city: Mexico
country: Mexico
facility: RM Pharma Specialists SA de CV
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Clinica de Investigacion en Reumatologia y Obesidad S.C.
state: Jalisco
city: Chihuahua
country: Mexico
facility: Investigacion y Biomedicina de Chihuahua, S.C.
city: Durango
country: Mexico
facility: Centro de Investigacion y Atencion Integral Durango CIAID
city: Bialystok
country: Poland
facility: ClinicMed Daniluk, Nowak Spółka Jawna
city: Elblag
country: Poland
facility: Centrum Reumatologiczne Indywidualna Specjalistyczna Praktyka Lekarska lek. Barbara Bazela
city: Grodzisk Mazowiecki
country: Poland
facility: MCBK Iwona Czajkowska Anna Podrażka- Szczepaniak S.C.
city: Katowice
country: Poland
facility: Care Clinic
city: Katowice
country: Poland
facility: Silmedic sp. z o.o
city: Klodzko
country: Poland
facility: GLOBE CLINICAL RESEARCH (Globe Badania Kliniczne Sp z o.o.)
city: Knurow
country: Poland
facility: Indywidualna Specjalistyczna Praktyka Lekarska Maciej Zymla
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne s.c.
city: Krakow
country: Poland
facility: Grazyna Pulka Specjalistyczny Osrodek "ALL-MED"
city: Poznan
country: Poland
facility: Centrum Badan Klinicznych S.C.
city: Sochaczew
country: Poland
facility: RCMed
city: Warsaw
country: Poland
facility: Centrum Medyczne AMED
city: Warszawa
country: Poland
facility: Medycyna Kliniczna
city: Warszawa
country: Poland
facility: Rheuma Medicus Zaklad Opieki Zdrowotnej
city: Warszawa
country: Poland
facility: Wojskowy Instytut Medyczny
city: Wroclaw
country: Poland
facility: Reum-Medica S.C Eliza Roszkowska
city: St. Petersburg
country: Russian Federation
facility: Research Institute of Emergency Medical Care
state: Saint Petersburg
city: Novosibirsk
country: Russian Federation
facility: Limited Liability Company "Centre of Medical Common Practice"
city: Omsk
country: Russian Federation
facility: Ultramed
city: Saint-Petersburg
country: Russian Federation
facility: SPb SBIH "Clinical Rheumatological Hospital # 25"
city: Saint-Petersburg
country: Russian Federation
facility: LLC Medical Sanitary Unit#157
city: Smolensk
country: Russian Federation
facility: NIH "Departmental Hospital on Station Smolensk of OJSC "Russian Railways"
city: Yaroslavl
country: Russian Federation
facility: SAIH of Yaroslavl region "Clinical Hospital of Emergency Medical Care n.a. N. V. Solovyev"
city: Yaroslavl
country: Russian Federation
facility: SBHI of Yaroslavl Region "Clinical Hospital # 8"
city: Belgrade
country: Serbia
facility: Institute of Rheumatology_Site 1
city: Belgrade
country: Serbia
facility: Military Medical Academy
city: Belgrade
country: Serbia
facility: Clinical Center Bezanijska kosa
city: Niska Banja
country: Serbia
facility: Institute of Treatment and Rehabilitation "Niska Banja"
city: Sabac
country: Serbia
facility: General Hospital "Dr Laza K. Lazarevic" Sabac
city: Johannesburg
country: South Africa
facility: Wits Clinical Research
state: Gauteng
city: Kempton Park
country: South Africa
facility: Clinresco Centres (Pty) Ltd
state: Gauteng
city: Pretoria
country: South Africa
facility: Emmed Research
state: Gauteng
city: Pretoria
country: South Africa
facility: University of Pretoria Clinical Research Unit
state: Gauteng
city: Durban
country: South Africa
facility: Naidoo, A
state: KwaZulu-Natal
city: Cape Town
country: South Africa
facility: Arthritis Clinical Research Trial Unit
state: Western Cape
city: Stellenbosch
country: South Africa
facility: Winelands Medical Research Centre
state: Western Cape
city: Ivano-Frankivsk
country: Ukraine
facility: Regional CH Dep of Rheumatology SHEI Ivano-Frankivsk NMU
city: Kharkiv
country: Ukraine
facility: GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine
city: Kharkiv
country: Ukraine
facility: Communal Institution of Healthcare Kharkiv City Clinical Hospital #8
city: Kyiv
country: Ukraine
facility: Medical Center Medical Clinic Blagomed LLC
city: Kyiv
country: Ukraine
facility: Med Center 'Ok!Clinic+' of International Institute of Clinical Trials LLC
city: Kyiv
country: Ukraine
facility: Medical Center of Revmotsentr LLC
city: Kyiv
country: Ukraine
facility: SI D.F.Chebotariov Institute of Gerontology of NAMSU
city: Lviv
country: Ukraine
facility: CH of State Border Service of Ukraine (Military Base 2522) Dept of Therapy, D.Halytskyi Lviv NMU
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH Dept of Rheumatology HSEIU UMSA
city: Uzhgorod
country: Ukraine
facility: A.Novak Transcarpathian Regional Clinical Hospital
city: Vinnytsia
country: Ukraine
facility: National Pirogov Memorial Medical University
city: Zaporizhzhia
country: Ukraine
facility: CI City Hospital #1
city: Zaporizhzhia
country: Ukraine
facility: CI Zaporizhzhia Regional Clinical Hospital of ZRC
city: Zaporizhzhya
country: Ukraine
facility: CI Zaporizhzhia Regional Clinical Hospital of ZRC
Study officials:
affiliation: EMD Serono Research & Development Institute, Inc.
name: Medical Responsible
role: STUDY_DIRECTOR
References: