Study to Investigate the Safety and Efficacy of Tregalizumab in Subjects (MTX-IR) With Active Rheumatoid Arthritis

The planned clinical study 986 (TREAT 2b) is a 24-week study in patients with Active
rheumatoid arthritis (RA) who have had an inadequate response to Methotrexate (MTX) alone.
The main phase of this study is followed by a 24-week extension phase for subjects meeting
the respective entry criteria. Patients will be randomized to one of three different Active
treatment groups or Placebo.

Inclusion Criteria:

1. Subject demonstrates active RA according to the 1987 American College of Rheumatology
(ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria
for RA with functional class I-III for ≥6 months.

2. Subject receives oral or parenteral MTX treatment for ≥12 weeks (overall), with an
unchanged mode of application and stable MTX dose of ≥15 mg per week (or ≥12.5 mg per
week in case of MTX intolerance), but no more than the highest locally approved dose
for RA, for ≥8 weeks prior to baseline. The dose of MTX is expected to remain stable
throughout the study and may be adjusted only for safety reasons. If applicable, the
dose of folic acid must be unchanged for ≥8 weeks prior to baseline.

3. Subject meets the following two criteria at both screening and baseline: − At least 6
swollen joints at 28-joint assessment. − At least 6 tender joints at 28-joint
assessment.

4. Subject has an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) above
the upper limit of normal (ULN) at screening. These tests may be repeated once during
the screening period at the discretion of the investigator.

5. Subject is ≥18 and ≤75 years of age.

6. Subject has a body mass index ≥18 and ≤35 kg/m².

7. Subject receives treatment with corticosteroids ≤10 mg prednisone equivalent, stable
for at least 4 weeks prior to baseline and during the study, if applicable.

8. Subject receives treatment with non-steroidal anti-inflammatory drugs (NSAIDs),
stable for at least 2 weeks prior to baseline and during the study, if applicable.

9. Female subjects of childbearing potential: has both a negative serum pregnancy test
at screening and a negative urine pregnancy test at baseline.

10. Subject is judged to be in good general health as determined by the investigator
based upon the results of medical history, laboratory profile, physical examination,
chest X-ray (within 3 months before screening date is acceptable), and 12−lead
electrocardiogram (ECG).

11. Subject has a cluster of differentiation 4 (CD4) cell count of > 400/µl at screening.

Exclusion Criteria:

1. Subject has previous exposure to any systemic biologic therapy (e.g., etanercept,
adalimumab, rituximab, abatacept, tocilizumab), to Janus kinase (JAK) or spleen
tyrosine kinase (SYK) inhibitors, or to Tregalizumab. Previous treatment with an
anti-TNF agent is allowed only, if all of the following criteria apply: − treatment
was stopped for reasons other than lack of efficacy or adverse events (AEs) −
treatment was stopped at least 12 weeks or five half-lives of the compound prior to
baseline (whichever is longer), and − the treatment period did not exceed 6 weeks.

2. Subject received treatment with conventional disease-modifying anti-rheumatic drugs
(DMARDs) apart from MTX in the 12 weeks prior to baseline, and for DMARD leflunomide
in the 24 weeks prior to baseline (except where specific leflunomide wash-out
procedures were completed, following applicable guidelines).

3. Subject has been treated with intra-articular or parenteral administration of
corticosteroids in the 4 weeks prior to baseline. Inhaled corticosteroids for stable
medical conditions are allowed.

4. Subject has undergone joint surgery in the 12 weeks prior to baseline (at joints to
be assessed within the study) or has undergone major surgery (e.g., abdominal
surgery) in the 8 weeks prior to baseline.

5. Subject has a history of acute inflammatory joint disease of an origin other than RA
or subject has any other rheumatic disease other than RA (e.g., mixed connective
tissue disease, seronegative spondylarthropathy, psoriatic arthritis, Reiter's
syndrome, fibromyalgia, systemic lupus erythematosus or any arthritis with onset
prior to age 17 years). However, subjects may have secondary Sjögren's syndrome.