Phase IIb Study of Evobrutinib in Subjects With Rheumatoid Arthritis

Inclusion Criteria:

- In Japan, if a subject is less than (<) 20 years, the written informed consent from
the subject's parent or guardian will be required in addition to the subject'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 subjects 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 subjects, subjects 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.
Subjects 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.