Trial Information

Summary: A randomized, double-blind, parallel group, international study to evaluate the safety and efficacy of ocrelizumab compared to placebo in patients with active rheumatoid arthritis who have an inadequate response to at least one anti-TNF therapy.

Rheumatoid Arthritis treated with Methotrexate

An investigational medication is currently being tested in a medical research study to evaluate its effectiveness for rheumatoid arthritis symptoms. Patients will be considered for this study if they are taking methotrexate but not receiving as much benefit as they or their doctor feel they should. They will remain on methotrexate and add the study medication to their therapy.

Patients with active rheumatoid arthritis who have experienced an inadequate response to previous or current treatment with at least one anti-TNF agent, such as etanercept, infliximab or adalimumab because of toxicity or inadequate efficacy.

Patients must meet the following criteria to be eligible for study entry:
1. Ability and willingness to provide written informed consent and to comply with the requirements of the protocol
2. Age = 18 years
3. Have active disease defined as:

• Diagnosis of RA of at least 3 months duration using the ACR criteria for the classification of RA (see Appendix 1, ~xr1i ).
• Swollen joint count (SJC) = 4 (66 joint count) and tender joint count (TJC) = 4 (68 joint count) at screening and baseline.
• CRP = 0.6 mg/dL using a high-sensitivity assay.
• Positive rheumatoid factor or positive anti-CCP antibody or both.

4. Previous and current treatments:

• Current treatment for RA on an outpatient basis.
• Experienced an inadequate response to previous or current treatment with at least one anti-TNFagent, such as etanercept, infliximab or adalimumab because of toxicity or inadequate efficacy. An adequate trial of therapy (to define inadequate efficacy) is defined as follows:
  • Etanercept dose: 25 mg twice weekly or 50 mg once weekly for = 3 months
  • Infliximab dose: = 3mg/kg for at least 3 infusions
  • Adalimumab dose: 40 mg every other week or 20 mg weekly for = 3 months
  • Etanercept therapy should be discontinued at least 4 weeks prior to the baseline visit, while infliximab and adalimumab therapy should be discontinued at least 8 weeks prior to baseline.
• Patients must be receiving either
  • Leflunomide at a dose of 10-20 mg once daily for at least 12 weeks, with the last 4 weeks, prior to baseline at a stable dose, or
  • Methotrexate at a dose of 7.5-25 mg/week (p.o or parenteral) for at least 12 weeks, with the last 4 weeks, prior to baseline at a stable dose,
  • Patients receiving both methotrexate and leflunomide must discontinue one of the two prior to baseline. Under this circumstance methotrexate should be discontinued for at least 4 weeks prior to baseline and leflunomide should be discontinued for 12 weeks or 4 weeks after 11 days of standard cholestyramine or activated charcoal drug removal prior to baseline.
• If receiving other non-biologic DMARDs, these agents should have been administered for at least 12 weeks, with the last 4 weeks, prior to baseline at a stable dose.
• If receiving non-anti-TNFbiologic DMARDs (such as abatacept, anakinra) these agents should be washed out at least four weeks prior to baseline.
• If receiving current treatment with corticosteroids, the dose must not exceed 10 mg/day prednisolone or equivalent (see Appendix 2, ~xr2i ) and during the four weeks prior to baseline it must be at a stable dose.
• If receiving current treatment with NSAIDs, the patient must be on a stable dose for the 4 weeks prior to baseline.
• Patients receiving methotrexate must be willing to receive oral folic acid or equivalent.

5. Other:

• For patients of reproductive potential (males and females),a reliable means of contraception must be used for the duration of the study (e.g., hormonal contraceptive, intrauterine device, physical barrier) according to local guidelines.
• Female patients of childbearing age must have a negative urine pregnancy test.

Exclusion Criteria Related to Rheumatoid Arthritis
1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty’s syndrome). Patients with secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA are eligible.
2. Functional Class IV as defined by the ACR Classification of Functional Status in RA (see Appendix 3, ~xr3i ).
3. 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, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome). Exclusions Related to General Health 4. Any surgical procedure, including bone or joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to or planned within 48 weeks after baseline. 5. Sepsis in a prosthetic joint within the last 48 weeks or indefinitely if the prosthesis concerned remains in situ.
6. Lack of peripheral venous access.
7. Pregnancy or lactation.
8. Known significant cardiac disease (NYHA Class III and IV) (see Appendix 4, ~xr4i ).

• Known severe chronic obstructive pulmonary disease (COPD) (FEV1 < 50% predicted or functional dyspnoea = Grade 3 on the MRC Dyspnoea Scale) (see Appendix 5, ~xr5i ).
  10. Evidence of significant uncontrolled concomitant diseases such as nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the investigator’s opinion, would preclude patient participation.
  11. Any neurological (congenital or acquired), psychiatric, vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swelling (e.g. Parkinson’s disease, cerebral palsy, diabetic neuropathy, chronic fatigue syndrome, chronic remitting anemia of unknown origin or requiring transfusion).
  12. Uncontrolled disease states where flares are commonly treated with oral or parenteral corticosteroids.
  13. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
  14. Known active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with iv anti-infectives within 4 weeks of baseline or oral anti-infectives within 2 weeks prior to baseline.
  15. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis, septic arthritis of a native joint) within 48 weeks of baseline.
  16. Evidence of chronic active hepatitis B or C (see Sections 5.4.2.6 and 5.4.2.7, ~xr6i ).
  17. Evidence of active tuberculosis (patients receiving chemoprophylaxis for latent tuberculosis infection are eligible for the study) (see Section 5.4.2.5, ~xr7i ).
  18. History of serious recurrent or chronic infections not specified above.
  19. History of cancer within the last 10 years, including solid tumors and hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinomas of the skin or carcinoma in situ of the cervix uteri that have been excised and cured).
  20. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline.

Exclusion Criteria Related to Medications
21. History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of ocrelizumab infusion (see Section 6.3 for ocrelizumab formulation, ~xr8i ).
22. Treatment with any investigational agent 12 weeks or five half-lives of the investigational drug (whichever is longer) prior to baseline.
23. Previous treatment with any cell-depleting therapies, including investigational agents (e.g., CAMPATH, anti-CD3, anti-CD4, anti-CD5, anti-CD11a, anti-CD19, anti-CD22, anti-BLys/BAFF, and anti-CD20).
24. Treatment with iv globulin or Prosorba column within weeks prior to baseline.
25. Intra-articular or parenteral corticosteroids within 6 weeks prior to baseline.
26. Receipt of any vaccine within 6 weeks prior to baseline (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving ocrelizumab should be carefully investigated) (see Section 4.4.2, ~xr9i ).
27. Intolerance or contraindications to iv methylprednisolone.

Exclusions Related to Laboratory Values at Screening
28. Positive urine pregnancy test.
29. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limit of normal.
30. Hypogammaglobulinemia (IgG < 4 mg/mL, and/or IgM< 0.55 mg/mL).
31. Absolute neutrophil count < 1500 cells/L.

If you would like to learn more about participating in this study, please send an e-mail message using the form below.