The purpose of this study is to evaluate the safety and effectiveness of HuMax-CD20 in patients with active Rheumatoid Arthritis.

Inclusion criteria:

1. Males and females ≥ 18 years
2. A diagnosis of rheumatoid arthritis according to the American College of Rheumatology (ACR) of at least six months duration

3. Active disease at the time of screening as defined by :

   • Six or more swollen joints (of 28 joints) and
   • Six or more tender joints (of 28 joints) and
   • Erythrocyte Sedimentation Rate (ESR) ≥ 22 mm/h (using Becton Dickinson Seditainer) and/or C-Reactive Protein (CRP) ≥ 10 mg/L (1 mg/dL)
4. RA functional class I, II, or III

5. Treatment failure to one or more DMARDs.

   • Treatment failure is defined as either intolerance at any time or insufficient efficacy after a minimum of 12 weeks of DMARD treatment.
   • DMARDs include, among others, methotrexate, hydroxychloroquine, chloroquine, gold preparations, azathioprine, D-penicillamine, sulfasalazine, minocycline, leflunomide, and cyclosporine A.

6. Applicable only to patients on methotrexate therapy at time of screening:

   Treatment with methotrexate for at least 12 weeks prior to planned start of trial treatment (Visit 2), with possible interruption of treatment of maximum two weeks in total, in the period 5-12 weeks from Visit 2.

7. Applicable only to patients on methotrexate therapy at time of screening:

   Treatment with a stable dose of methotrexate (7.5 - 25 mg/week, p.o., i.m., and/or s.c.) for at least four weeks prior to planned start of trial treatment (Visit 2)

8. Signed informed consent following receipt of oral and written information of the trial

Exclusion criteria:

1. Use of DMARDs (other than methotrexate, if patient is on methotrexate treatment at time of screening): ≤ 4 weeks prior to planned start of trial treatment (Visit 2). If patient is not on methotrexate treatment at time of screening: Methotrexate ≤ 4 weeks prior to planned start of trial treatment (Visit 2). Specifically for leflunomide treatment: Use of leflunomide ≤12 weeks prior to planned start of trial treatment (Visit 2) unless the patient has completed peroral cholestyramine treatment for washout, according to locally accepted clinical practices.
2. Not applicable. As per implementation of Protocol Amendment No. 5, exclusion criterion no. 2 is no longer applicable.
3. Exposure to other biological products (e.g. etanercept, infliximab, adalimumab, and kineret) within 4 weeks prior to planned start of trial treatment (Visit 2), and/or exposure to anti-CD20 antibodies within two years before screening for this trial
4. Any use of cyclophosphamide, nitrogen mustard, chlorambucil or other alkylating agents within five years before screening for this trial

5. Within four weeks prior to planned start of trial treatment (Visit 2):

   • Treatment with oral corticosteroids ( > 10 mg prednisolone per day or equivalent)
   • Start of oral corticosteroid treatment
   • Change in any ongoing oral corticosteroid dose
6. Use of intra-articular, i.m. or i.v. corticosteroids (including i.m. adrenocorticotrophe hormone) within four weeks prior to planned start of trial treatment (Visit 2)
7. Active autoimmune disease (other than RA and RA-associated secondary diseases) requiring immunosuppressive therapy
8. Diagnosis of fibromyalgia or other chronic pain syndrome requiring daily narcotic treatment

9. Past or current malignancy, except for

   • Resected cervical carcinoma Stage 1B or less
   • Resected non-invasive basal cell and squamous cell skin carcinoma
   • Malignant melanoma with a complete response of a duration of > 10 years
   • Other cancer diagnoses with a complete response of a duration of > 5 years
10. Chronic or current infectious disease such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, sinusitis, and tuberculosis
11. History of infected joint prosthesis within five years before Visit 1 and infected native joints within one year before Visit 1
12. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities
13. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease
14. History of significant cerebrovascular disease

15. Screening laboratory values:

    • Hemoglobin < 6.2 mmol/L (9.9 g/dL)
    • Neutrophils < 2 x 109/ L
    • Platelets < 100 x 109/ L
    • S-ALAT > 1.5 times the upper limit of normal
    • S-ALP > two times the upper limit of normal
    • S-creatinine > 133 µmol/L (1.5 mg/dL)
16. Known or suspected positive serology for HIV
17. Positive serology for hepatitis B or C
18. Patients previously screened for this trial, unless reason for previous screen failure was failure to fulfill inclusion criterion no. 3
19. Current or previous (within four weeks of screening) participation in any other clinical trial
20. Patients known or suspected to be unable to comply with this trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
21. Breast feeding women or women with a positive pregnancy test at screening
22. Women of childbearing potential not willing to use adequate contraception during the trial. Adequate contraception is defined as hormonal birth control or intrauterine device. For patients in the USA the use of a double barrier method is also considered adequate.