Tocilizumab for the Treatment of Behcet's Syndrome
Condition: Behcet Syndrome
MeSH terms: Behcet Syndrome; Syndrome
Intervention: Tocilizumab
Intervention description: Intravenous infusions every 4 weeks for 3 doses.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Behcet's syndrome; oral ulcers

Summary:

      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.
    

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