Efficacy, Pharmacokinetics, and Safety of BI 695500 in Patients With Rheumatoid Arthritis
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: BI 695500; BI 695500; Rituxan®; Rituxan®; MabThera®
Intervention MeSH terms: Rituximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 294.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The primary objectives of this trial are (1) To show PK (Pharmacokinetic) similarity of BI
      695500 to rituximab. (2)To establish statistical equivalence of efficacy of BI 695500 and
      rituximab, in patients with moderately to severely active RA (Rheumatoid Arthritis), based on
      the change in Disease Activity Score 28 (DAS28) score measured at 24 weeks compared to
      Baseline and the American College of Rheumatology 20% (ACR20) response rate at Week 24.
    

Eligibility criteria:

        Inclusion criteria:

          1. Must give written informed consent and be willing to follow the protocol.

          2. Male or female participants, between 18 and 80 years of age, who have a diagnosis of
             moderately to severely active RA for at least 6 months as defined by at least six
             swollen joints (66 joint count) and at least eight tender joints (68 joint count) at
             Screening and Baseline (Day 1), and either an erythrocyte sedimentation rate (ESR) of
             > 28 mm/hour OR a C-reactive protein (CRP) level > 1.0 mg/dL (normal: < 0.4 mg/dL) at
             Screening. Patients must have had an inadequate response or intolerance to
             conventional DMARD therapy including at least one tumor necrosis factor (TNF)
             inhibitor.

          3. Positive for Radio Frequency and/or anti-CCP (Anti-cyclic citrullinated peptide)
             antibodies.

          4. Current treatment for RA on an outpatient basis:

               1. Must be currently receiving and tolerating oral or parenteral MTX therapy at a
                  dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is
                  unable to tolerate a higher dose) for at least 12 weeks immediately prior to Day
                  1. The dose should be stable for at least 4 weeks prior to Day 1 until Week 24.
                  After Week 24 the administration route can be changed at the investigator's
                  discretion.

               2. Patients must be willing to receive oral folic acid (at least 5 mg/week or as per
                  local practice) or equivalent during the entire study (mandatory co-medication
                  for MTX treatment).

               3. Biologic agents and DMARDs (other than MTX) must be withdrawn at least 2 weeks
                  prior to Day 1, except azathioprine and etanercept which must be withdrawn at
                  least 4 weeks prior to Day 1; abatacept, adalimumab, anakinra, certolizumab,
                  infliximab, and golimumab at least 8 weeks prior to Day 1; tocilizumab at least
                  10 weeks prior to Day 1.

               4. Leflunomide must be withdrawn at least 8 weeks prior to Day 1 or a minimum of 2
                  weeks prior to Day 1 if after 11 days of standard cholestyramine washout.

               5. If receiving current treatment with oral corticosteroids (other than
                  intra-articular or parenteral), the dose must not exceed 10 mg/day prednisolone
                  or equivalent. During the 4 weeks prior to Baseline (Day 1) the dose must remain
                  stable.

               6. Intra-articular and parenteral corticosteroids are not permitted within 6 weeks
                  prior to Baseline Day 1 or throughout the trial, with the exception of IV
                  administration of 100 mg methylprednisolone 30 to 60 minutes prior to each
                  infusion as this is part of the trial procedures.

               7. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable for
                  at least 2 weeks prior to Day 1.

               8. Patients may be taking oral hydroxychloroquine provided that the dose is not
                  greater than 400 mg/day or chloroquine provided that the dose is not greater than
                  250 mg/day. These doses must have been stable for a minimum of 12 weeks prior to
                  Day 1. The hydroxychloroquine or chloroquine treatment will need to be continued
                  at a stable dose with the same formulation until the end of the trial.

          5. For participants of reproductive potential (males and females), use of a reliable
             means of contraception (e.g., hormonal contraceptive, patch, intrauterine device,
             physical barrier) has to be used throughout trial participation. Females of
             child-bearing potential must also agree to use an acceptable method of contraception
             for 12 months following completion or discontinuation from the trial.

        Exclusion criteria:

          1. ACR functional Class IV or wheelchair/bed bound.

          2. Primary or secondary immunodeficiency (history of, or currently active), including
             known history of human immunodeficiency virus infection.

          3. History of positive purified protein derivative test (positive tuberculosis [TB] test)
             without treatment for TB infection or chemoprophylaxis for TB exposure.

          4. Positive HIV or TB at screening.

          5. Known coronary artery disease or significant cardiac arrhythmias or severe congestive
             heart failure (New York Heart Association classes III or IV), or interstitial lung
             disease observed on chest X-ray.

          6. History of IgE-mediated (immunoglobulin E) or non-IgE-mediated hypersensitivity or
             known anaphylaxis to mouse proteins or a history of hypersensitivity to antibody
             therapy.

          7. History of cancer including solid tumors, hematologic malignancies, and carcinoma in
             situ (except participants with previous resected and cured basal or squamous cell
             carcinoma, treated cervical dysplasia, or treated in situ Grade I cervical cancer
             within 5 years prior to the Screening Visit).

          8. History of pancreatitis or current peptic ulcer disease.

          9. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit.

         10. Any condition or treatment (including biologic therapies) that, in the opinion of the
             investigator, may place the patient at unacceptable risk during the trial.

         11. Pregnancy or breast feeding.

         12. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive
             arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or
             other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory
             bowel disease, pulmonary fibrosis, or Feltys syndrome, scleroderma, inflammatory
             myopathy, mixed connective tissue disease, or any overlap syndrome).

         13. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA
             before age 16.

         14. Any surgical procedure, including bone/joint surgery/synovectomy (including joint
             fusion or replacement) within 12 weeks prior to the Screening Visit or planned within
             24 weeks of the Screening Visit.

         15. Lack of peripheral venous access.

         16. Evidence of significant uncontrolled concomitant disease such as, but not limited to,
             nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the
             investigator's opinion, would preclude patient participation.

         17. Known concurrent viral hepatitis or known positivity to HBe-ag, HBV DNA, HBV DNA
             polymerase, HCVRNA, anti HCV antibodies.

         18. Known active infection of any kind (excluding fungal infections of nail beds), or any
             major episode of infection requiring hospitalization or treatment with IV
             anti-infectives within 4 weeks of the Screening Visit or completion of oral
             anti-infectives within 2 weeks of the Screening Visit.

         19. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis)
             within 52 weeks of the Screening Visit.

         20. History of serious infection or opportunistic infection in the last 2 years.

         21. Any neurological (congenital or acquired), vascular or systemic disorder that might
             affect any of the efficacy assessments, in particular, joint pain and swelling (e.g.,
             Parkinson's disease, cerebral palsy, diabetic neuropathy).

         22. Currently active alcohol or drug abuse or history of alcohol or drug abuse (as
             determined by the investigator) within 52 weeks of the Screening Visit.

         23. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the
             Screening Visit.

         24. Treatment with IV or intramuscular corticosteroids.

         25. Previous treatment with a B cell modulating or cell depleting therapy.

         26. Intolerance or contraindications to IV glucocorticoids.

         27. AST (aspartate aminotransferase) or ALT (alanine aminotransferase)> 3 times ULN (Upper
             Limit of Normal)

         28. Hemoglobin < 8.0 g/dL.

         29. Levels of IgG < 5.0 g/L.

         30. Absolute neutrophil count < 1500/µL.

         31. Platelet count < 75000/µL.

         32. Participation in any previous clinical trial within 12 weeks of Screening.