Subcutaneous Omalizumab for Treatment of Chronic Rhinosinusitis With Nasal Polyposis

Title of study: Subcutaneous Xolair (omalizumab) for treatment of chronic rhinosinusitis with nasal polyposis (CRS/NP)

Objectives: To compare the efficacy of subcutaneous Xolair (omalizumab) to placebo in treatment of CRS/NP in terms of: (a) the effect on polypoid mucosal thickening in the anterior ethmoid and maxillary sinuses as measured on sinus CT scan, (b) the effect on volume of polypoid mucosal tissue in the nose and sinuses on rhinoscopic examination, and (c) the effect on CRS symptoms as measured by total symptom score.

Study Rationale: Chronic rhinosinusitis (CRS) is a persistent inflammatory condition with periodic flares, affecting 14% of the United States population with an estimated annual health care expenditure of $3.4 billion. CRS patients with nasal polyposis (NP) are the most difficult to treat and the most likely to undergo sinus surgery. Tissue eosinophilia is the hallmark feature and is associated with specific IgE to inhalants, elevated total serum immunoglobulin E (IgE), and peripheral eosinophilia. Omalizumab is a humanized monoclonal antibody that binds to the Fc portion of IgE. Omalizumab treatment reduces peripheral eosinophilia and prevents nasal tissue eosinophilia. Endoscopic NP severity directly correlates with total serum IgE levels, and anti-IgE therapy in the postpolypectomy management of atopic asthmatic patients may reduce the severity of NP recurrence. In a patient with CRS/NP with asthma treated with omalizumab, symptoms were relieved, and MRI showed resolution of nasal mucosa swelling and reduction of polypoid swelling and inflammation of the paranasal sinuses. We hypothesize that subcutaneous Xolair (omalizumab) treatment will reduce the size of nasal polyps and/or sinus polypoid thickening and relieve CRS symptoms in patients with CRS/NP.

Methodology:

Xolair (omalizumab) or placebo injections every 2-4 weeks for 5 months. Procedures will include:

• Quantification of polypoid mucosal thickening in the anterior ethmoid and maxillary sinuses on sinus CT scan (primary outcome variable) on Day 0 and on Day 140.
• Total symptom score (TSS) recorded daily. CRS Facial Pain/Headache questionnaire at each visit.
• Rhinoscopic evaluation during screening and on Days 28, 84 and 140. Number of centers & patients: Single center. 30 patients (15 per treatment group).

Population: Outpatient male or female, 18 years of age or older, with CRS/NP, without uncontrolled moderate to severe asthma.

Investigational drug: Xolair (omalizumab), dosage and frequency to be determined based on patient's weight and total IgE level, administered by subcutaneous injection.

Reference therapy: Placebo of similar volume and frequency, administered by subcutaneous injection

Inclusion criteria

• Subjects will be male or female and 18 years of age or older.
• Females of childbearing potential will use approved contraception, defined as the use of hormonal (oral, injectable, or implantable) or barrier-method contraceptives, intrauterine device, or history of bilateral tubal ligation. Women who have undergone a total hysterectomy or are two years post-menopausal will also be eligible.
• Subjects must meet the criteria for CRS, namely they must have (1) at least two major criteria (facial pain/pressure or headache, nasal congestion, anterior or posterior nasal drainage, hyposmia/anosmia) for at least 3 consecutive months; (2) an abnormal sinus CT scan in at least two sinus areas documented within 3 months of entry or endoscopic evidence of disease.
• Subjects must have bilateral polypoid disease demonstrated either by CT or endoscopy with evidence of nasal polyps or polypoid mucosa on examination in at least two of the following areas: right maxillary sinus, left maxillary sinus, right anterior ethmoid sinus, left anterior ethmoid sinus plus a minimal polyp/polypoid score of 4 on the baseline rhinoscopic examination. (Nasal polyps are defined as discreet polyps visible in the middle meatus area.)
• Evidence or history of positive skin test or in vitro reactivity to a perennial aeroallergen.
• Subjects must meet the study drug-dosing table eligibility criteria (serum IgE level ≥ 30 to ≤ 1500 IU/mL and body weight ≥ 30 to ≤ 150 kg).
• Subjects must have a minimum total symptom score of 5 (range of scores 0-15) at baseline.

Exclusion criteria

• Females who are pregnant or nursing, or females of childbearing potential not using approved contraception, defined as the use of hormonal (oral, injectable, or implantable) or barrier-method contraceptives, intrauterine device, or history of bilateral tubal ligation.
• Subjects who do not meet the clinical criteria for Xolair (omalizumab)
• Subjects who are taking a beta blocker.
• Known sensitivity to Xolair (omalizumab).
• Subjects who have evidence of acute bacterial exacerbation of rhinosinusitis requiring antibiotic therapy manifesting as gross purulent drainage on physical examination or untreated air/fluid level on sinus CT scan.
• Subjects who have received antibiotics within 3 weeks of the screening visit.
• Subjects with uncontrolled moderate to severe asthma who have experienced a recent exacerbation requiring use of systemic steroids burst within 6 weeks of study enrollment. Subjects who are receiving a maintenance dose of Prednisone of 5 mg/day or less will be allowed provided the dose of Prednisone is not changed during the study.
• Subjects with a history of uncontrolled recurrent epistaxis within the past 6 weeks.
• Subjects with a history of hypogammaglobulinemia, cystic fibrosis, bronchiectasis, immotile cilia syndrome, systemic granulomatous disease, malignancy (or strong family history of malignancy), or history of recent cocaine use.
• Cigarette smoking in the past 3 years.
• Subjects with other serious medical problems, such as Grade III/IV cardiac problems as defined by the New York Heart Association Criteria within 6 months of study, severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal or liver disease, infection with HIV or other active uncontrolled infection). Subjects who have had a major surgery within 3 months of the screening visit.
• Subjects with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
• Subjects with alcohol or drug abuse/dependence within the past 3 months.
• Subjects with persistent abnormalities of hepatic, renal or hematologic function, defined as the following: total bilirubin, SGOT and SGPT > 1.5 x upper limit of normal, creatinine > 2.0 x upper limit of normal, absolute neutrophil count < 1.5 x 109/L, platelets < 100 x 109/L.
• Subjects who have used oral or systemic steroid burst within 6 weeks of study enrollment.
• Use of any other investigational agent in the 30 days prior to enrollment.