Safety and Efficacy of Abatacept in Subjects With Chronic Urticaria Who Have Had an Inadequate Response to Anti-histamine Therapy

Inclusion criteria

• Chronic active urticaria defined as symptoms > 50% of days or 3 days/week for more than 12 weeks
• 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) AND failure to respond to at least maximally approved dosages of 2 different antihistamine therapies
• One of the following 3 conditions:

• Previous or ongoing requirement for corticosteroids for symptom control OR
• Prior steroid treatment with steroid discontinuation due to unacceptable morbidity
• Previous or current use (without symptom control or with unacceptable morbidity: e.g., hypertension from cyclosporine, hemolysis from dapsone) of immunomodulatory treatment for urticaria (e.g., hydroxychloroquine, methotrexate, sulfasalazine, dapsone, cyclosporine, intravenous immunoglobulin (IVIg), mycophenolate, azathioprine, etc)
• High baseline score for pruritis (at least 2 on a 3 point scale)
• No underlying etiology clearly defined for urticaria
• Patients should exhibit evidence of underlying autoimmunity of at least one of the following:

• elevated erythrocyte sedimentation rate (ESR), C-Reactive Protein (CRP), anti-nuclear antibody (ANA)
• extractable nuclear antigens
• Thyroid antibodies
• other autoantibodies (e.g., intrinsic factor, parietal cell, ovarian), *elevated complement levels
• clinical characteristics suggestive of systemic autoimmune disease but without satisfying criteria for another diagnosis (e.g., arthralgias, myalgias, arthritis, low grade fever, significant fatigue associated with outbreaks)
• family history of autoimmune disease including thyroid autoimmunity
• a biopsy showing perivascular lymphocytic or mixed cellular infiltrate without vasculitis
• Concomitant use of hydroxychloroquine, methotrexate, or sulfasalazine will be permitted if dose stable for at least 8 weeks
• Concomitant use of steroids (≤ 15 mg/d Prednisone or equivalent) will be permitted if stable for 4 weeks and patient agrees to continue dose for the first 90 days
• Negative pregnancy test (for women of child-bearing age)
• Men and women of reproductive potential must agree to use an acceptable birth control during treatment and for 3 months after treatment
• No planned elective surgical procedures for at least 6 months from day#1

Exclusion criteria

• Current use of other immunosuppressive medications (cyclosporine, tacrolimus, sirolimus, IVIg, cyclophosphamide, mycophenolate mofetil, azathioprine). Any such medication will be discontinued for at least 4 weeks before study drug start.
• Concomitant treatment with corticosteroids (≤ 15 mg/d), hydroxychloroquine, methotrexate, and sulfasalazine will be permitted if doses are stable at least 8 weeks
• Treatment with an 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 of randomization
• Prior treatment with Abatacept (Orencia®)
• Previous treatment with Rituximab (MabThera®/Rituxan®), unless 6 months after administration AND B cell reconstitution has occurred into normal range
• History of severe allergic or anaphylactic reactions to monoclonal antibodies or Fc fusion proteins
• History of significant laryngeal edema, tongue swelling, or airway compromise in the setting of urticarial/angioedema episode (isolated perioral, lip, and periorbital edema will not be exclusionary)
• Known history of Human Immunodeficiency Virus (HIV), Hepatitis B and/or Hepatitis C
• purified protein derivative (PPD) testing as part of screening that is positive*
• HIV, Hepatitis B surface antigen or Core Antibody positive, or anti Hepatitis C Antibody positive detected with screening
• History of recurrent significant infection, active bacterial, viral, fungal, mycobacterial, or other infection excluding fungal infections of nail beds, or major infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 wks of screening
• Known immunodeficiency, hypogammaglobulinemia, etc.
• Systemic lupus erythematosus (meeting American College of Rheumatology (ACR)) criteria; patients with autoantibodies such as ANA will NOT be excluded)
• Lack of peripheral venous access
• Drug, alcohol, or chemical abuse within 6 months
• Pregnancy or lactation and all women must be willing to practice contraception through the study duration and for 3 months after discontinuing abatacept treatment.

• Sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized.
• Prior to study enrollment, women of childbearing potential (WOCBP) will be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.
• In addition, men enrolled on this study will be informed of the risks to any sexual partner of childbearing potential and counseled to practice an effective method of birth control.
• All WOCBP must have a negative urine pregnancy test within 7 days prior to first receiving the investigational product.
• If the pregnancy test is positive, the subject will be excluded from the study.
• In addition, all WOCBP will be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation and the Investigator will notify Bristol Myers Squibb (BMS) within 24 hours of becoming aware of a confirmed pregnancy in a subject participating in the study.
• Women must agree to practice adequate birth control for a minimum of 3 months post-treatment.
• Concomitant malignancies or previous malignancies within five years, with exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of cervix
• Atopic dermatitis, psoriasis, or autoimmune bullous skin disease (pemphigus, pemphigoid, etc)
• Significant cardiovascular disease (angina, arrhythmia, known coronary artery disease, cerebrovascular accident (CVA), transient ischemic attack (TIA), uncontrolled hypertension > 150/90)
• Significant pulmonary disease (asthma or chronic obstructive pulmonary disease (COPD) requiring current use of corticosteroids, history ever of severe asthma or status asthmatics)
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates an investigational drug or that may affect interpretation of the results or render patient at high risk from treatment complications
• Plans or need to receive live viral vaccination over course of the study (e.g., Flu-Mist)
• Inability to comply with study and follow-up procedures