Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis

NCT ID: NCT03233230

Last Updated: 2020-09-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 390 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-18
• Study Completion Date: 2019-09-23

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.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Participants received placebo matched to M2951 orally for 12 weeks.

M2951 25 mg QD

Group Type: EXPERIMENTAL

M2591 25 mg QD

Intervention Type: DRUG

Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.

M2951 75 mg QD

Group Type: EXPERIMENTAL

M2951 75 mg QD

Intervention Type: DRUG

Participants received 75 mg of M2951 orally QD for 12 weeks.

M2951 50 mg BID

Group Type: EXPERIMENTAL

M2951 50 mg BID

Intervention Type: DRUG

Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.

Interventions

M2591 25 mg QD

Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.

Intervention Type: DRUG

M2951 75 mg QD

Participants received 75 mg of M2951 orally QD for 12 weeks.

Intervention Type: DRUG

M2951 50 mg BID

Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.

Intervention Type: DRUG

Placebo

Participants received placebo matched to M2951 orally for 12 weeks.

Intervention Type: DRUG

Other Intervention Names

Evobrutinib; Evobrutinib; Evobrutinib

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

EMD Serono Research & Development Institute, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Responsible

Role: STUDY_DIRECTOR

EMD Serono Research & Development Institute, Inc.

Locations

Arizona Arthritis & Rheumatology Associates, P.C.

Phoenix, Arizona, United States

Arizona Arthritis & Rheumatology Research, PLLC

Phoenix, Arizona, United States

East Bay Rheumatology Medical Group, Inc.

San Leandro, California, United States

Omega Research Consultants

DeBary, Florida, United States

Clinical Research of West Florida, Inc.

Tampa, Florida, United States

McIlwain Medical Group, PA

Tampa, Florida, United States

Medication Management, LLC

Greensboro, North Carolina, United States

Arthritis Clinic Of Central Texas

San Marcos, Texas, United States

Hospital Italiano de La Plata

La Plata, Buenos Aires, Argentina

Instituto de Investigaciones Clinicas

Mar del Plata, Buenos Aires, Argentina

Instituto Medico CER

Quilmes, Buenos Aires, Argentina

Instituto de Investigaciones Clinicas Quilmes

Quilmes, Buenos Aires, Argentina

Centro Medico Privado de Reumatologia

San Miguel de Tucumán, San Miguel de Tucuman, Argentina

Centro de Investigaciones Reumatológicas

San Miguel de Tucumán, Tucumán Province, Argentina

Organizacion Medica de Investigacion (OMI)

Ciudad Autonoma Buenos Aires, , Argentina

APRILLUS

Ciudad Autonoma Buenos Aires, , Argentina

Expertia S.A- Mautalen Salud e Investigación

Ciudad Autonoma Buenos Aires, , Argentina

Hospital General de Agudos Dr. J. M. Ramos Mejia

Ciudad Autonoma Buenos Aires, , Argentina

ILAIM-CEOM Inst. Latinoamericano de Inv. Medicas

Córdoba, , Argentina

Instituto Reumatológico Strusberg

Córdoba, , Argentina

Centro Polivalente de Asistencia e Inv. Clinica CER

San Juan, , Argentina

MHAT "Hadzhi Dimitar", OOD

Sliven, , Bulgaria

DCC "Alexandrovska", EOOD

Sofia, , Bulgaria

UMHAT "SofiaMed", OOD

Sofia, , Bulgaria

Centro Medico Prosalud

Santiago, , Chile

Interin

Santiago, , Chile

BioMedica Research Group

Santiago, , Chile

Centro de Estudios Reumatologicos

Santiago, , Chile

Centro de Reumatologia y Ortopedia SAS

Barranquilla, , Colombia

Riesgo de Fractura S.A.

Bogotá, , Colombia

Simedics Ips Sas

Bogotá, , Colombia

Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM

Bogotá, , Colombia

Servimed S.A.S.

Bucaramanga, , Colombia

Clinica de Artritis Temprana S.A.

Cali, , Colombia

Revmatolog, s.r.o

Jihlava, , Czechia

CCBR Ostrava s.r.o.

Ostrava, , Czechia

ARTROSCAN s.r.o.

Ostrava - Trebovice, , Czechia

CLINTRIAL s.r.o.

Prague, , Czechia

MUDR. Zuzana URBANOVA Revmatologie

Prague, , Czechia

Thomayerova nemocnice

Praha 4 - Krc, , Czechia

MUDR. Zuzana URBANOVA Revmatologie

Praha 4 Nusle, , Czechia

MEDICAL PLUS s.r.o.

Uherské Hradiště, , Czechia

PV-MEDICAL s.r.o.

Zlín, , Czechia

Centro Investigacion en Artritis y Osteoporosis S.C.

Mexicali, Baja California Norte, Mexico

Clinica de Investigacion en Reumatologia y Obesidad S.C.

Guadalajara, Jalisco, Mexico

RM Pharma Specialists SA de CV

Mexico City, Mexico City, Mexico

Investigacion y Biomedicina de Chihuahua, S.C.

Chihuahua City, , Mexico

Centro de Investigacion y Atencion Integral Durango CIAID

Durango, , Mexico

ClinicMed Daniluk, Nowak Spółka Jawna

Bialystok, , Poland

Centrum Reumatologiczne Indywidualna Specjalistyczna Praktyka Lekarska lek. Barbara Bazela

Elblag, , Poland

MCBK Iwona Czajkowska Anna Podrażka- Szczepaniak S.C.

Grodzisk Mazowiecki, , Poland

Care Clinic

Katowice, , Poland

Silmedic sp. z o.o

Katowice, , Poland

Indywidualna Specjalistyczna Praktyka Lekarska Maciej Zymla

Knurów, , Poland

Malopolskie Centrum Medyczne s.c.

Krakow, , Poland

Grazyna Pulka Specjalistyczny Osrodek "ALL-MED"

Krakow, , Poland

GLOBE CLINICAL RESEARCH (Globe Badania Kliniczne Sp z o.o.)

Kłodzko, , Poland

Centrum Badan Klinicznych S.C.

Poznan, , Poland

RCMed

Sochaczew, , Poland

Medycyna Kliniczna

Warsaw, , Poland

Rheuma Medicus Zaklad Opieki Zdrowotnej

Warsaw, , Poland

Centrum Medyczne AMED

Warsaw, , Poland

Wojskowy Instytut Medyczny

Warsaw, , Poland

Reum-Medica S.C Eliza Roszkowska

Wroclaw, , Poland

Research Institute of Emergency Medical Care

Saint Petersburg, Sankt-Peterburg, Russia

Limited Liability Company "Centre of Medical Common Practice"

Novosibirsk, , Russia

Ultramed

Omsk, , Russia

SPb SBIH "Clinical Rheumatological Hospital # 25"

Saint Petersburg, , Russia

LLC Medical Sanitary Unit#157

Saint Petersburg, , Russia

NIH "Departmental Hospital on Station Smolensk of OJSC "Russian Railways"

Smolensk, , Russia

SAIH of Yaroslavl region "Clinical Hospital of Emergency Medical Care n.a. N. V. Solovyev"

Yaroslavl, , Russia

SBHI of Yaroslavl Region "Clinical Hospital # 8"

Yaroslavl, , Russia

Institute of Rheumatology_Site 1

Belgrade, , Serbia

Military Medical Academy

Belgrade, , Serbia

Clinical Center Bezanijska kosa

Belgrade, , Serbia

Institute of Treatment and Rehabilitation "Niska Banja"

Niška Banja, , Serbia

General Hospital "Dr Laza K. Lazarevic" Sabac

Šabac, , Serbia

Wits Clinical Research

Johannesburg, Gauteng, South Africa

Clinresco Centres (Pty) Ltd

Kempton Park, Gauteng, South Africa

Emmed Research

Pretoria, Gauteng, South Africa

University of Pretoria Clinical Research Unit

Pretoria, Gauteng, South Africa

Naidoo, A

Durban, KwaZulu-Natal, South Africa

Arthritis Clinical Research Trial Unit

Cape Town, Western Cape, South Africa

Winelands Medical Research Centre

Stellenbosch, Western Cape, South Africa

Regional CH Dep of Rheumatology SHEI Ivano-Frankivsk NMU

Ivano-Frankivsk, , Ukraine

GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine

Kharkiv, , Ukraine

Communal Institution of Healthcare Kharkiv City Clinical Hospital #8

Kharkiv, , Ukraine

Medical Center Medical Clinic Blagomed LLC

Kyiv, , Ukraine

Med Center 'Ok!Clinic+' of International Institute of Clinical Trials LLC

Kyiv, , Ukraine

Medical Center of Revmotsentr LLC

Kyiv, , Ukraine

SI D.F.Chebotariov Institute of Gerontology of NAMSU

Kyiv, , Ukraine

CH of State Border Service of Ukraine (Military Base 2522) Dept of Therapy, D.Halytskyi Lviv NMU

Lviv, , Ukraine

M.V. Sklifosovskyi Poltava RCH Dept of Rheumatology HSEIU UMSA

Poltava, , Ukraine

A.Novak Transcarpathian Regional Clinical Hospital

Uzhhorod, , Ukraine

National Pirogov Memorial Medical University

Vinnytsia, , Ukraine

CI City Hospital #1

Zaporizhzhia, , Ukraine

CI Zaporizhzhia Regional Clinical Hospital of ZRC

Zaporizhzhia, , Ukraine

CI Zaporizhzhia Regional Clinical Hospital of ZRC

Zaporizhzhya, , Ukraine

Countries

United States; Argentina; Bulgaria; Chile; Colombia; Czechia; Mexico; Poland; Russia; Serbia; South Africa; Ukraine

References

Montalban X, Wallace D, Genovese MC, Tomic D, Parsons-Rich D, Bolay CL, Kao AH, Guehring H. A plain language summary of what clinical studies can tell us about the safety of evobrutinib - a potential treatment for multiple sclerosis. Neurodegener Dis Manag. 2023 Aug;13(4):207-213. doi: 10.2217/nmt-2023-0003. Epub 2023 Jun 22.

Reference Type: DERIVED

PMID: 37345645 (View on PubMed)

Montalban X, Wallace D, Genovese MC, Tomic D, Parsons-Rich D, Le Bolay C, Kao AH, Guehring H. Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):1-9. doi: 10.1136/jnnp-2022-328799. Epub 2022 Nov 23.

Reference Type: DERIVED

PMID: 36418156 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS200527-0060

Trial Awareness and Transparency website

https://medical.emdserono.com/en_US/home.html

US Medical Information website, Medical Resources

Other Identifiers

2017-000384-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MS200527-0060

Identifier Type: -

Identifier Source: org_study_id