Tocilizumab for the Treatment of Behcet's Syndrome

This is a double-blind placebo controlled study targeting individuals with active Behcet's Syndrome who have oral ulcers and are resistant (have not responded after 4 weeks) to conventional treatments. Maximum allowable dose of colchicine (0.6mg twice a day) and stable dose for 4 weeks before enrollment. Prednisone or equivalent (\< 10mg/day) permitted if dose stable for 6 weeks prior to enrollment.

The study will investigate the safety of tocilizumab for this vasculitic condition in addition to its efficacy.

The planned sample size is 30 participants per arm for a total of 60 participants. The study would be for 3 months, with a safety follow up at 2 months after study termination.

Study participants will stay on their current treatments and either tocilizumab or placebo infusions will be given every 4 weeks in addition. Patients will be randomized to Actemra IV 8mg/kg Q 4 weeks X 3 doses or placebo.

Behcet's syndrome is a vasculitis that causes oral and genital ulcerations, skin lesions, eye disease and arthritis, in addition to vascular complications with thrombophlebitis, thrombosis and rarely central nervous system involvement. IL-6 activity has been suggested in the pathogenesis in some studies. Tocilizumab with its unique mode of action among biologic agents may be a good candidate in this orphan disease.

Eligibility Criteria:
Inclusion Criteria:

1. Any patient with BS with at least 1 active oral ulcer resistant (have not responded after 4 weeks to colchicine or local measures.
2. dose (maximum allowable 0.6mg twice a day ) stable for 4 weeks and prednisone or equivalent (maximum dose \< 10mg/day) stable for 6 weeks prior to enrollment.
3. Patients must have Behcet's syndrome based on International Study Group criteria.

Patients will be included in the trial based on the following criteria:

* Normal organ function, except if abnormal due to the disease under investigation such as mucocutaneous involvement or joint involvement.
* Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
* Subject has provided written informed consent.

Exclusion Criteria:

1. Patients with eye, CNS, vascular involvement such as DVT, thrombosis, or aneurysms.
2. Patients who are currently being treated or have been exposed in the last 3 months to other immunosuppressive medications (azathioprine, TNF inhibitors, methotrexate, mycophenolate mofetil). Patients who are currently being treated or have been exposed to Cyclosporine or cyclophosphamide in the past 6 months will be excluded).
3. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
4. Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening.
5. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti¬CD3, anti-CD19 and anti-CD20 (please note exceptions above).
6. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
7. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
8. Previous treatment with TCZ (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on a case-by-case basis).
9. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
10. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
11. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.)
12. Current liver disease as determined by principal investigator unless related to primary disease under investigation
13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
14. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
15. Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for tuberculosis with no recurrence in 3 years are permitted. (Appendix 8)
16. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
17. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years unless related to primary disease under investigation.
18. Pregnant women or nursing (breast feeding) mothers.
19. Patients with reproductive potential not willing to use an effective method of contraception.
20. History of alcohol, drug or chemical abuse within 1 year prior to screening.
21. Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation.
22. Patients with lack of peripheral venous access.

    Laboratory Exclusion criteria (at screening):
23. Serum creatinine \> 1.6 mg/dL (141 µmol/L) in female patients and \> 1.9 mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are \>30.
24. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 1.5 times upper limit of normal (ULN)
25. Total Bilirubin \> ULN
26. Platelet count \< 100 x 109/L (100,000/mm3)
27. Hemoglobin \< 85 g/L (8.5 g/dL; 5.3 mmol/L)
28. White Blood Cells \< 3.0 x 109/L (3000/mm3)
29. Absolute Neutrophil Count \< 2.0 x 109/L (2000/mm3)
30. Absolute Lymphocyte Count \< 0.5 x 109/L (500/mm3)
31. Positive Hepatitis BsAg, or Hepatitis C antibody