| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) Lower Lever Term (LLT) code number 10039073 |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the efficacy and safety of ocrelizumab versus placebo in reducing signs and symptoms of Rheumatoid Arthritis (RA), when used in combination with methotrexate (MTX) in patients with active RA who have an inadequate response to MTX therapy.
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| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of ocrelizumab to slow or inhibit structural damage
• To assess the effect of ocrelizumab on physical function
• To investigate the pharmacokinetics and pharmacodynamics of ocrelizumab
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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:
a) Diagnosis of Rheumatoid Arthritis (RA) of at least 3 months duration using the ACR criteria for the classification of RA
b) Swollen joint count (SJC) ≥(66 joint count) and tender joint count (TJC) ≥(68 joint count) at screening and baseline
c) CRP ≥0.6 mg/dL using a high-sensitivity assay
d) Positive rheumatoid factor or positive anti-CCP antibody or both
4. Previous and current treatments:
a) Current treatment for RA on an outpatient basis
b) Patients with an inadequate clinical response to methotrexate (MTX) taken at a dose of
7.5-25 mg/week for at least 12 weeks with the last 4 weeks prior to baseline at a
stable dose
c) If receiving current treatment with corticosteroids, the dose must not exceed
10 mg/day prednisolone or equivalent and during the four weeks prior to baseline it must be at a stable dose
d) If receiving current treatment with NSAIDs, the patient must be on a stable dose
for the 4 weeks prior to baseline
e) Patient must be willing to receive oral folic acid or equivalent
5. Other:
a) 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
b) Female patients of childbearing age must have a negative urine pregnancy test
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
Exclusion Criteria Related to Rheumatoid Arthritis (RA)
1. Rheumatic autoimmune disease other than Rheumatoid Arthritis (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 American College of Rheumatology (ACR) Classification of Functional Status in RA
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)
9. Known severe chronic obstructive pulmonary disease (COPD) (FEV1 < 50%
predicted or Functional dyspnea ≥ Grade 3 on the MRC Dyspnea Scale)
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
17. Evidence of active tuberculosis (patients receiving chemoprophylaxis for latent
tuberculosis infection are eligible for the study)
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
22. Prior receipt of any biologic therapy used for treatment of RA
23. Concurrent treatment with any Disease Modifying Anti-Rheumatic Drug
(DMARD) (except MTX). All DMARDs should be withdrawn at least 4 weeks prior to baseline (12 weeks for leflunomide or 4 weeks after 11 days of standard cholestyramine or activated charcoal drug removal)
24. Treatment with any investigational agent 12 weeks or five half-lives of the
investigational drug (whichever is longer) prior to baseline
25. 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)
26. Treatment with iv γ-globulin or Prosorba® column within 24 weeks prior to baseline
27. Intra-articular or parenteral corticosteroids within 6 weeks prior to baseline
28. 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)
29. Intolerance or contraindications to iv methylprednisolone
Exclusions Related to Laboratory Values at Screening
30. Positive urine pregnancy test
31. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limit of normal
32. Hypogammaglobulinemia (IgG < 4 mg/mL, and/or IgM< 0.55 mg/mL)
33. Absolute neutrophil count < 1500 cells/µL
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Endpoints
•Proportion of patients with ACR20 responses at 24 weeks
•Proportion of patients with ACR20 responses at 48 weeks
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Please refer to Section 3.1.4 in the Protocol |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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