Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: M2591 25 mg QD; M2951 75 mg QD; M2951 50 mg BID; Placebo
Intervention description: Participants received 25 milligrams (mg) of M2951 orally once daily (QD) for 12 weeks.; Participants received 75 mg of M2951 orally QD for 12 weeks.; Participants received 50 mg of M2951 orally twice daily (BID) for 12 weeks.; Participants received placebo matched to M2951 orally for 12 weeks.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 390.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Rheumatoid Arthritis; American College of Rheumatology; High-sensitivity C-reactive protein; Bruton's tyrosine kinase

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.