Safety Study of Zileuton Injection in Patients With Asthma

Assessment of Safety, Tolerability, and Pharmacokinetics of Zileuton Injection in Patients With Asthma

The prevalence of asthma continues to increase. Despite the large number of available therapies, many patients continue to require emergency deparment (ED) visits and intensive therapy. However, ED visits continue to be a major contributor to the healthcare cost of asthma treatment. In the United States alone, asthma is the 11th most common reason for ED visits, with ED visits and hospitalizations accounting for almost 50% of the healthcare cost for asthma. Additionally, while only 20% of asthmatics have had ED visits or hospitalizations, these patients account for over 80% of the direct costs for asthma treatment. Current National Asthma Education and Prevention Program (NAEPP) guidelines regarding management of acute asthma exacerbations in the ED setting include: oxygenation for most patients, inhaled short-acting β2-agonists and systemic corticosteroids. Zileuton, a specific 5-lipoxygenase inhibitor, has been extensively studied in inflammatory diseases such as asthma, which involve leukotrienes as mediators of inflammation. Zileuton Immediate Release (IR) tablets (Zyflo®) were approved by the Food and Drug Administration (FDA) in December 1996 for the prevention and treatment of asthma in adults and children 12 years of age and older. The results of the 2 pivotal studies in asthmatics with zileuton IR tablets demonstrated that zileuton at a dose of 600 mg QID produced and maintained a lasting improvement of lung function. In addition to the lasting effect of zileuton, an acute bronchodilation (as early as 60 minutes) was observed after administration of the first 600 mg oral dose. This acute bronchodilator effect may benefit patients during an acute exacerbation of asthma when added to the usual care in the ED or clinic setting. Critical Therapeutics has developed an injectable formulation of zileuton that will be explored for use in acute asthma exacerbations. This initial study is intended to provide PK data, information on safety and tolerability and some indication of pharmacologic activity as evidenced by lung function changes. In an attempt to enhance the potential for observing effects on lung function, only those patients with a demonstrated ability to respond by an increase in FEV1 of at least 10% within 3 hours after oral zileuton dosing will be enrolled.

Inclusion Criteria: Diagnosis of asthma Morning FEV1 of 40-80% of predicted normal Evidence post-bronchodilator increase in FEV1 of at least 15% Evidence of at least 10% increase in FEV1 within 3 hours after oral 600 mg zileuton dose Signed IRB approved informed consent Patients must be willing and able to withhold: short acting β2-agonists for at least 6 hours prior to spirometry inhaled corticosteroids (ICS) for at least 24 hours prior to sprirometry long acting β2-agonists (LABA) for 7 days and be willing and able to switch from a LABA/ICS combination product to a monotherapy ICS product Exclusion Criteria: Females of childbearing potential not using effective contracception Any uncontrolled systemic disease other than asthma Patient with known hypersensitivity to zileuton IR tablets or zileuton injection or any of the components found therein An upper or lower respiratory tract infection within 2 weeks of screening An ED visit or hospitalization for asthma within 3 months of screening Oral or parenteral corticosteroid use for asthma exacerbation within 3 months of screening Current cigarette smoker and/or >10 pack-year smoking history History of hepatitis B (HBV) or hepatitis C infection or other active liver disease or chronic hepatitis Screening ALT >1.5x ULN Patient with impaired renal function or serum creatinine >1.5x ULN History of HIV infection History of drug or alcohol abuse within 1 year of screening Patient taking any of the following asthma/allergy medications: Anti-IgE meds within 3 months of screening Zileuton IR tablets within 1 month of screening Inhaled or oral steroids not stable for at least 1 month Theophylline, cromolyn, or nedocromil within 7 days of screening Leukotriene receptor agonists within 7 days of screening Warfarin, propranolol, inhaled or sytemic anticholinergics within 7 days of screening Long acting beta agonist within 7 days of screening Oral beta-2 agonists within 12 hours of screening Immunotherapy injections not in a stable dosing phase Female patient who is pregnant or breast-feeding or plans to become pregnant during the study period Participation in another research study within 30 days of screening Patient is the Investigator or other staff or relative who is directly involved in the conduct of the study

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