Safety Study of Rituximab (Rituxan®) in Chronic Urticaria

Rituximab (Rituxan®) is a recombinant chimeric monoclonal antibody that binds to a molecule
(CD20) that is present on the surface of B lymphocytes. The product is approved for the
treatment of non-Hodgkin's lymphoma and has been investigated for the treatment of a number
of autoimmune diseases including rheumatoid arthritis (Edwards 2004) and lupus (Looney 2004,
Leandro 2002). As in most rheumatoid arthritis studies, the medication will be administered
in this study as a series of two intravenous infusions given 2 weeks apart.

Many cases of chronic urticaria (hives) are though to be driven by an autoimmune mechanism
(Kaplan 2002, Grattan 2002). It is our hypothesis that by interfering with the autoimmune
process, potentially by decreasing the levels of autoantibodies or by interfering with other
mechanisms that cause basophil and mast cell activation, improvments in signs and symptoms
will be seen.

Given the effectiveness demonstrated for Rituximab in other autoimmune conditions, we will
conduct a pilot open label investigation of 15 patients with chronic urticaria to determine
the safety and effectiveness of Rituximab in this disease. All patients will receive the
medication; there will be no placebo group in this study. Rituximab is not currently
indicated for the treatment of this condition however.

We will evaluate the safety of the Rituximab in 15 patients with urticaria as well as
studies of antibody levels and cellular function. We will also evaluate clinical outcomes
such as itch score, sleep disturbance, and quality of life. After receivng the Rituximab
treatment, we will begin to taper antihistamines and other medications used to control
urticaria symptoms.

Major Inclusion Criteria:

- Chronic urticaria defined as symptoms >50% of the days or 3 days per week for more
than 12 weeks

- Previous requirement for sustained or recurrent use of corticosteroids OR requirement
for immunomodulatory treatment for urticaria (eg hydroxychloroquine, sulfasalazine,
dapsone, cyclosporine, IVIg, etc) OR ongoing symptoms for at least 6 months duration
with failure to respond at least maximally approved dosages of 2 different
antihistamine therapies

- Chronic therapy with stable doses of antihistamines for at least 4 weeks. Patients
may be taking more than one antihistamine or be taking combinations of antihistamines
and leukotriene receptor antagonists

- High baseline score for pruritis (at least 2 on a 3 point scale)

- No underlying etiology clearly defined for urticaria

- Evidence of underlying autoimmunity as evidenced by clinical and laboratory criteria

- Concomitant use of hydroxychloroquine, sulfasalazine, or dapsone permitted if doses
stable for at least 12 weeks

- Negative serum pregnancy test (for women of child-bearing age)

- Men and women of reproductive potential must agree to use an acceptable method of
birth control during treatment and for twelve months (1 year) after completion of
treatment.

- No planned elective surgical procedures for at least 6 months

Major Exclusion Criteria:

- Concomitant use of corticosteroids

- Current use of immunosuppressive medication (cyclosporine, IVIg, methotrexate,
cyclophosphamide). Any such medication will be discontinued for at least 6 weeks
before screening.

- Treatment with any investigational agent within 4 weeks of screening or 5 half-lives
of the investigational drug (whichever is longer)

- Receipt of a live vaccine within 4 weeks prior to randomization

- Previous treatment with Rituximab (MabThera® / Rituxan®)

- Prior antibody therapy

- History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibodies

- Known history of HIV seropositivity (testing will be performed at screening)

- History of Hepatitis B and/or Hepatitis C (Hep BsAg and Hep C Ab will be obtained at
screening)

- History of recurrent significant infection or history of recurrent bacterial
infections

- Known active bacterial, viral, fungal, mycobacterial, or other infection (including
tuberculosis or atypical mycobacterial disease, but excluding fungal infections of
nail beds)

- Any major episode of infection requiring hospitalization or treatment with i.v.
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to
screening

- Known immunodeficiency syndrome, hypogammaglobulinemia, etc.

- Systemic lupus erythematosus

- Pregnancy (a negative serum pregnancy test will be performed for all women of
childbearing potential within 7 days of treatment) or lactation

- Malignancies within the last five years, with the exception of adequately treated
basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.

- Atopic dermatitis

- Clinically relevant medical conditions (cardiovascular including poorly controlled
hypertension or coronary artery disease, pulmonary, metabolic, renal, hepatic,
psychiatric) or clinical laboratory finding giving reasonable suspicion of a disease
or condition that contraindicates the use of an investigational drug or that may
affect the interpretation of the results or render the patient at high risk from
treatment complications

- Plans or need to receive live viral vaccination over course of the study (e.g.
Flu-Mist TM)