Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group.

Objective: To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma.

Design: Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks.

Setting: Asthma study clinics in university hospitals and private practices.

Patients Or Other Participants: Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled beta-agonists.

Interventions: Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily.)

Main Outcome Measures: Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled beta-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events.

Results: Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively.

Conclusions: Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.