Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study

Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study Harold Nelson, MD*; James Kemp, MD†; William Berger, MD‡; Jonathon Corren, MD§; Thomas Casale, MD储; Louise Dube, PhD¶; Karen Walton-Bowen#; Nicole LaVallee, PhD**; and Miganush Stepanians, PhD**

Background: A controlled-release (CR) formulation of zileuton was developed to simplify administration from 600 mg 4 times daily (Zyflo) to 1,200 mg twice daily. Objective: To evaluate the efficacy of zileuton CR, two 600-mg tablets twice daily, compared with placebo. Methods: Patients with moderate asthma treated with short-acting ␤-agonists only were randomized to receive zileuton CR, 1,200 mg twice daily (n ⫽ 206); placebo CR, twice daily (n ⫽ 203); zileuton immediate-release (IR), 600 mg 4 times daily (n ⫽ 101); or placebo IR, 4 times daily (n ⫽ 103), for 12 weeks. The primary efficacy variable was change from baseline in morning trough forced expiratory volume in 1 second (FEV1). Results: Improvement in trough FEV1 was observed after 2 weeks of treatment (P ⫽ .001) and was maintained throughout the study. After 12 weeks of dosing, FEV1 improved by a mean of 0.39 L (20.8%) in the zileuton CR group vs 0.27 L (12.7%) in the placebo CR group (P ⫽ .02). A significant decline in ␤-agonist use and a smaller proportion of patients reporting asthma exacerbations were observed in the zileuton CR group vs the placebo CR group. Adverse event profiles were similar across treatment groups. Elevations in alanine aminotransferase levels at least 3 times the upper limit of normal that reversed after drug withdrawal were seen in 5 zileuton CR–treated patients (2.5%) vs 1 placebo CR–treated patient (0.5%). Conclusions: Treatment with zileuton CR, 1,200 mg twice daily, resulted in a significant improvement in asthma control, and the safety and efficacy profile was similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo). Ann Allergy Asthma Immunol. 2007;99:178–184.

INTRODUCTION Leukotrienes B4, C4, D4, and E4 and other inflammatory eicosanoids (5-oxo-6,8,11,14-eicosatetraenoic acid) are potent lipid mediators formed by the action of 5-lipoxygenase on arachidonic acid and are produced by several inflammatory cells, including mast cells, eosinophils, and alveolar

* Departments of Medicine and Pediatrics, National Jewish Medical Research Center, Denver, Colorado. † Private practice, San Diego, California. ‡ Private practice, Mission Viejo, California. § Allergy Medical Clinic Inc, Los Angeles, California. 储 Allergy and Immunology, Creighton Medical Center, Omaha, Nebraska. ¶ Pleiades Consultation Inc, Scottsdale, Arizona. # Clinical Operations, Biostatistical Analysis, and Reporting, Critical Therapeutics Inc, Lexington, Massachusetts. ** PROMETRIKA LLC, Cambridge, Massachusetts. Drs Corren and Dube are consultants to Critical Therapeutics Inc. Ms Walton-Bowen is an employee of Critical Therapeutics Inc and has stock options in the company. This study was funded by a grant from Abbott Laboratories, North Chicago, Illinois. Abbott Laboratories was responsible for the design and conduct of the study and for analysis and reporting of the results. Received for publication January 31, 2007. Received in revised form February 27, 2007. Accepted for publication March 11, 2007.

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macrophages.1–3 Leukotrienes are major mediators of the underlying inflammatory process in asthma,4 and the addition of leukotriene receptor antagonists, 5-lipoxygenase inhibitors, or both to the standard inhaled corticosteroid treatment in patients with asthma has been shown to improve asthma control.5– 8 Zileuton is a specific inhibitor of 5-lipoxygenase and, thus, inhibits leukotriene B4, C4, D4, and E4 formation. Zileuton immediate-release (IR) tablets (Zyflo; Critical Therapeutics Inc, Lexington, Massachusetts) have been shown to be safe and effective for the treatment of chronic, stable asthma.9 Patients treated with zileuton IR, 600 mg 4 times daily, showed significant improvement in objective measures of pulmonary function, required fewer corticosteroid rescues, and showed decreases in ␤-agonist use and overall improvements in asthma symptoms and quality-of-life (QOL) measures.9 Although zileuton IR was generally well tolerated in phase 2/3 studies, a small number of patients experienced elevations in alanine aminotransferase (ALT) and aspartate aminotransferase levels. In placebo-controlled studies, the incidence of ALT level elevations greater than or equal to 3 times the upper limit of normal (ULN) was 1.9% in zileuton IR–treated patients vs 0.2% in placebo-treated patients. These elevations were not generally associated with elevations in

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alkaline phosphatase or total bilirubin levels and, thus, were not indicative of hepatocellular injury. The approved package insert for zileuton IR (Zyflo) recommends that ALT levels be monitored before starting therapy, once a month for the first 3 months of zileuton therapy, every 2 to 3 months for the remainder of the first year, and periodically thereafter to minimize the risk of potential severe liver injury. The controlled-release (CR) formulation was developed to simplify zileuton administration from 4 to 2 times per day. This study was designed to compare the efficacy and safety of zileuton CR, 1,200 mg (2 ⫻ 600-mg tablets) 2 times per day, with that of placebo CR during 12 weeks of treatment in patients with moderate persistent asthma. In addition, zileuton IR, 600 mg 4 times daily, was compared with placebo IR as a benchmark comparison. METHODS Patients Patients, recruited from university hospitals and private allergy and pulmonary practices, were nonsmoking males and females 12 years or older who had not been hospitalized for asthma within 6 months and had not taken any investigational drugs within 30 days of beginning the study. Females were either postmenopausal, surgically sterile, or using an effective means of birth control. Eligible patients demonstrated a forced expiratory volume in 1 second (FEV1) of 40% to 75% of predicted when taken at least 48 hours after the last theophylline use and at least 6 hours after short-acting ␤-agonist use or 24 hours after long-acting ␤-agonist use and demonstrated a 15% or greater increase in FEV1 at least 15 minutes after 2 puffs of an albuterol metered-dose inhaler. Patients had no clinically significant abnormalities detected during screening procedures except those related to asthma and no history of elevated ALT levels 5 times the ULN or greater. Patients could not have active drug or alcohol abuse. Long-term medication use was not allowed except for oral or depot contraceptives, estrogen replacement, vitamins, diuretics for mild hypertension, and thyroid medication. Nasal corticosteroids were allowed if patients were taking a stable dose for at least 6 weeks before enrollment or if used for seasonal rhinitis, and short-term use of antibiotics and acetaminophen was permitted. Patients may not have taken any antiasthma medications except short-acting inhaled or nebulized ␤-agonists within 4 weeks of the start of the study (theophylline therapy was discontinued at least 1 week before enrollment, and long-acting ␤-agonists could not have been used within 24 hours of the start of the study). After a 2-week single-blind placebo lead-in period, patients were randomized if they used the supplied ␤-agonist inhaler on an average of at least 2 occasions per day, had an FEV1 of 40% to 75% of predicted and an improvement of 10% or less over baseline, and a mean daily score on a daily symptom evaluation scale (possible score, 0 –3) of at least 1 but not greater than 2.5. All the patients voluntarily signed an informed consent form that had been approved by the appro-

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priate institutional review board before the performance of any study-specific evaluations. Study Design This was a phase 3, randomized, multicenter study in patients with asthma of treatment with (1) zileuton CR, 1,200 mg twice daily, compared with placebo CR and (2) zileuton IR, 600 mg 4 times daily, compared with placebo IR. The study was blinded with respect to study treatment (zileuton or placebo) but not formulation (CR or IR). Seventy-six sites in the United States enrolled 786 patients who had been previously diagnosed as having asthma. Patients, initially randomized to the zileuton CR arm or to the zileuton IR arm in a 2:1 ratio, entered a 14-day, singleblind placebo lead-in period with visits on days 1, 8, and 15. Eligible patients were then randomized on day 15 (doubleblind day 1). Patients in the zileuton CR arm were randomized to receive zileuton CR, 1,200 mg twice daily, or placebo CR in a 1:1 ratio, and patients in the zileuton IR arm were randomized to receive zileuton IR, 600 mg 4 times daily, or placebo IR in a 1:1 ratio. Visits were scheduled at weeks 2, 4, 8, and 12. Patients who completed the study through week 12 then entered a 2-week run-out period during which no study drug was taken. Zileuton CR was supplied as 600-mg CR tablets. Two tablets (1,200 mg) were taken orally at 7 AM and 7 PM, approximately 1 hour after a meal. Zileuton IR was supplied as 600-mg IR tablets. One tablet was taken 4 times daily at 7 AM, 1 PM, 6 PM, and 11 PM without regard to meals. Placebo was supplied as tablets identical in appearance to zileuton supplies. Efficacy Variables The FEV1 was measured in triplicate by means of spirometry at screening and before the morning study medication dose at all study visits after withholding short-acting ␤-agonist (albuterol) for at least 6 hours. The primary efficacy analyses were change from baseline and percentage change from baseline in morning trough FEV1. Patients were required to measure peak expiratory flow rate (PEFR) in triplicate at the same time each morning and evening before any inhaler use. The first morning measurement was performed just before the first daily dose of study drug, and the evening measurement was performed at approximately 8 PM. For PEFR measurements and all assessments from the diary, means were taken for the following intervals: double-blind days 2 to 22, 23 to 43, 44 to 71, and 72 to 92. Patients were instructed to use inhaled albuterol on an as-needed basis only and to record each use (including number of puffs and number of occasions) in their diaries. The daily symptom evaluation score was recorded every evening, and the nocturnal symptom evaluation score was recorded every morning, according to the scales in Table 1. Patients were instructed to contact the investigator with any complaints of worsening of asthma symptoms. Patients were considered to have had an acute exacerbation of asthma

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Table 1. Daily and Nocturnal Symptom Assessment Scores Rating Daily symptom assessment (recorded each evening) 0 1 2 3 Nocturnal symptom assessment (recorded each morning) 0 1 2 3

if they had any of the following: a decrease of 20% or more from baseline in morning PEFR on 4 or more of 7 consecutive days, a decrease of 20% or more from baseline in the best of 3 FEV1 measurements performed at a clinic visit, 3 or more of 7 consecutive nights with awakenings requiring the use of inhaled ␤-agonist, and albuterol use of at least 12 puffs a day for 3 or more of 7 consecutive days. The self-administered asthma QOL questionnaire developed by Juniper et al10 was completed by the patients at double-blind day 1, week 4, and week 12. The asthma QOL questionnaire measured 4 domains (symptoms, activities, emotions, and environmental exposure) and overall QOL on a 7-point scale. Safety Monitoring Safety measurements included adverse events, physical examinations, vital signs, blood and urine samples for clinical laboratory measurements, electrocardiographic results, and chest radiographs. Particular attention was focused on ALT as a marker of liver cell injury. Asymptomatic patients with ALT levels at least 3 but less than 5 times the ULN were allowed to continue treatment and underwent ALT testing every 3 to 7 days until the ALT level decreased to less than 3 times the ULN or reached 5 times the ULN or greater. If the ALT level reached 5 times the ULN or greater or if the patient became symptomatic, study treatment was discontinued and the patient was followed up until the ALT elevation resolved (ie, decreased to ⬍2 times the ULN). Patients who prematurely discontinued from the study owing to an adverse event returned to the study site for a follow-up evaluation 1 month after the date of discontinuation of study drug. Statistical Analysis Statistical analyses were performed using a software program (SAS Version 8.2 for Windows; SAS Institute Inc, Cary, North Carolina). Unless otherwise specified, all analyses involving continuous data were performed using analysis of variance models adjusting for site and type III sums of squares from PROC GLM of SAS, and all categorical data

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Symptom No symptoms at all; unrestricted activity Symptoms occurred, but with little or no discomfort; unrestricted activity Symptoms occurred, were sometimes annoying or affecting routine activity (eg, dressing, walking) Symptoms severe; very little improvement after inhaler use and required the use of additional medication and/or a physician’s visit Slept well, no asthma symptoms Spent restless night, may have awakened because of asthma symptoms; may have used inhaler Awakened more than once because of symptoms; inhaler used Awake all night because of symptoms; inhaler used

analyses were performed using the Cochran-Mantel-Haenszel method, adjusting for site using PROC FREQ of SAS. The sample size determination for this study was based on comparisons of zileuton CR with placebo CR. The IR arm, which had approximately half the number of patients as the CR arm, was included to provide a comparison of trends with the CR arm and to provide a link to zileuton IR pivotal studies. The study was not powered for either the pairwise comparison between zileuton IR and placebo IR or the comparison between the zileuton IR and zileuton CR formulations. Assuming that the CR formulation was as efficacious as the IR formulation, the sample size requirements were calculated using data from 2 previous studies of zileuton IR compared with placebo in asthma. It was estimated that approximately 170 patients per treatment group would be required to provide greater than 80% power at the 2-sided ␣ level of .05 for a pairwise comparison between the zileuton CR group and the placebo group, assuming that the expected difference between these 2 treatment groups would be 8.5% for the percentage change from baseline in FEV1, as seen in previous studies of zileuton IR. Baseline values were defined as those determined at the end of the placebo lead-in phase, including predosing on double-blind day 1. The mean calculated for the last 14 days of the lead-in period was used as the baseline for daily diary data (eg, daily symptoms, PEFR, and ␤-agonist use). RESULTS Patients Of 1,370 patients screened, 591 in the full analysis set completed the single-blind lead-in period of the study and were enrolled in the double-blind treatment period. Demographic and baseline disease characteristics of these patients are given in Table 2. Overall, the demographic profiles and baseline disease characteristics were similar across treatment groups. Of 591 patients, 199 were in the zileuton CR, 1,200 mg twice daily, group; 198 were in the placebo CR group; and 97 each were in the zileuton IR, 600 mg 4 times daily, and placebo IR

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Table 2. Summary of Demographic and Baseline Disease Characteristics by Treatment Group Characteristic Age, mean (range), y Sex, No. (%) F M Race, No. (%) Black White Other History of tobacco use, No. (%) No Yes FEV1, mean ⫾ SE, % predicted PEFR, mean ⫾ SE, L/min Morning Evening Daily ␤-agonist use, mean ⫾ SE, No. Occasions Puffs

Zileuton CR, 1,200 mg twice daily (n ⴝ 199)

Placebo CR (n ⴝ 198)

Zileuton IR, 600 mg 4 times daily (n ⴝ 97)

Placebo IR (n ⴝ 97)

33.3 (12–70)

34.1 (12–78)

35.3 (12–81)

34.5 (12–74)

99 (49.7) 100 (50.3)

109 (55.1) 89 (44.9)

52 (53.6) 45 (46.4)

43 (44.3) 54 (55.7)

20 (10.1) 160 (80.4) 19 (9.5)

20 (10.1) 169 (85.4) 9 (4.5)

13 (13.4) 80 (82.5) 4 (4.1)

9 (9.3) 75 (77.3) 13 (13.4)

151 (75.9) 48 (24.1) 57.7 ⫾ 0.8

148 (74.7) 50 (25.3) 59.4 ⫾ 0.7

77 (79.4) 20 (20.6) 58.1 ⫾ 1.3

77 (79.4) 20 (20.6) 58.2 ⫾ 1.3

369.7 ⫾ 9.0 397.9 ⫾ 9.3

353.9 ⫾ 8.9 386.8 ⫾ 9.2

365.5 ⫾ 13.1 399.5 ⫾ 13.5

365.2 ⫾ 13.2 398.9 ⫾ 13.5

3.3 ⫾ 0.1 6.0 ⫾ 0.2

3.3 ⫾ 0.1 6.0 ⫾ 0.2

3.0 ⫾ 0.1 5.7 ⫾ 0.3

2.9 ⫾ 0.1 5.4 ⫾ 0.3

Abbreviations: CR, controlled-release; FEV1, forced expiratory volume in 1 second; IR, immediate-release; PEFR, peak expiratory flow rate.

groups. Of these patients, 144 (72.4%) in the zileuton CR group, 143 (72.2%) in the placebo CR group, 82 (84.5%) in the zileuton IR group, and 80 (82.5%) in the placebo IR group completed the study. Of the patients who withdrew from the study early, adverse events were the reason in at least half in each treatment group (see the “Safety” subsection for further discussion), with the remainder withdrawing from the study for “other” reasons, including noncompliance, relocation, loss to follow-up, consent withdrawal, disallowed medication use, and lack of efficacy.

Pulmonary Function The primary outcome variable was change from baseline in morning trough FEV1, measured before the morning dosing at each visit. Mean change from baseline in trough FEV1 across time is shown in Figure 1 for the CR and IR active and placebo arms. After 2 weeks of dosing (double-blind day 15), treatment with zileuton CR resulted in a significantly greater mean improvement in trough FEV1 than treatment with placebo CR (0.23 vs 0.09 L; P ⫽ .001). At week 12 (doubleblind day 85), the zileuton CR group demonstrated a 0.39-L

Figure 1. Mean change from baseline in trough forced expiratory volume in 1 second (FEV1) in each study group. CR indicates controlled-release; IR, immediate-release. *P ⱕ .001, zileuton CR vs placebo CR. †P ⱕ .01, zileuton CR vs placebo CR. ‡P ⱕ .05, zileuton CR vs placebo CR.

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mean improvement (20.8%) compared with a 0.27-L mean improvement (12.7%) in the placebo CR group (P ⫽ .02). Treatment with zileuton IR resulted in a greater improvement in FEV1 than treatment with placebo IR at all visits, but the differences were usually not statistically significant. At week 2 (double-blind day 15), treatment with zileuton IR resulted in a mean improvement in trough FEV1 of 0.17 L compared with 0.14 L in the placebo IR group (P ⫽ .58). At week 12 (double-blind day 85), the zileuton IR group demonstrated a 0.38-L mean improvement (19.3%) compared with a 0.28-L mean improvement (14.1%) in the placebo IR group (P ⫽ .19). The percentage of patients in each group with a clinically significant improvement in lung function, defined as a 12% or greater improvement in FEV1 at each visit, is shown in Figure 2 for the zileuton CR and IR active and placebo arms. The proportion of patients who showed 12% or greater improvement in FEV1 over baseline was significantly higher in the zileuton CR group compared with the placebo CR group at all time points. At week 12 (double-blind day 85), 63.2% of the zileuton CR–treated patients vs 50.0% of the placebo CR–treated patients showed an improvement of 12% or greater in FEV1 (P ⫽ .02). For the IR arm, the proportion of patients who showed a 12% or greater improvement in FEV1 over baseline was significantly greater in the zileuton group (45.5%) compared with the placebo group (27.8%) only at week 4 (double-blind day 29) (P ⫽ .02). The zileuton CR group also demonstrated increasing mean improvements from baseline morning PEFR from 19.42 L/min for the first interval (double-blind days 2–22) to 58.45 L/min for the final interval (double-blind days 72–92). Mean improvements were greater in the zileuton CR group than in the placebo CR group at all intervals, although the differences were not significant. Similarly, mean improvements in morning PEFR were higher in the zileuton IR group than in the placebo IR group at all intervals, but the differences were not significant. A comparable pattern was observed for evening PEFR.

␤-Agonist Use Treatment with zileuton CR resulted in significantly greater reductions in the number of daily puffs of ␤-agonist compared with treatment with placebo CR (Fig 3). During the last 3 weeks of treatment, ␤-agonist use was reduced from the baseline period by 0.96 (15.14% reduction) and 0.31 (2.29% reduction) puffs per day for the zileuton CR and placebo CR treatment groups, respectively (P ⫽ .009). There were also larger reductions in the number of puffs of ␤-agonist use per day in the zileuton IR group than in the placebo IR group at all intervals; however, the differences between the zileuton IR and placebo IR treatment groups were not statistically significant. Other Efficacy Results Treatment with zileuton CR resulted in a significantly smaller percentage of patients reporting 1 or more asthma exacerbations compared with treatment with placebo CR at all visits except week 12 (20.3% vs 29.7%), with the greatest difference occurring at week 8 (24.0% vs 37.7%; P ⫽ .02). The mean reductions from baseline in daily and nocturnal symptom evaluation scores were generally larger in the zileuton CR and zileuton IR groups than in the corresponding placebo groups, but the differences between treatment groups were not statistically significant. At week 4 (double-blind day 29), treatment with zileuton CR resulted in a significantly greater improvement in the QOL overall score (0.72 in the zileuton CR group vs 0.51 in the placebo CR group, P ⫽ .03) and in all domain scores except “symptoms” compared with the placebo CR group. Although further improvements from baseline values were seen at week 12 (double-blind day 85) across all domains of the QOL questionnaire, differences between the treatment groups were not statistically significant. Similar results were observed between the zileuton IR and placebo IR groups. The run-out analyses were performed 2 weeks after discontinuation of study drug to ascertain the extent, if any, of a residual treatment effect. Results showed that patients treated

Figure 2. Percentage of patients in each study group with a clinically significant improvement in lung function, defined as a 12% or greater improvement in forced expiratory volume in 1 second (FEV1) at each visit. CR indicates controlled-release; IR, immediate-release. *P ⱕ .05 vs placebo. †P ⱕ .01 vs placebo.

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Figure 3. Mean percentage change from baseline in ␤-agonist use (puffs per day) in each study group. CR indicates controlled-release; IR, immediate-release. *P ⱕ .001 vs placebo. †P ⱕ .05 vs placebo. ‡P ⱕ .01 vs placebo.

with zileuton CR continued to demonstrate the beneficial effects of zileuton CR treatment for 2 weeks after its withdrawal, as evidenced by FEV1 and PEFR. The primary variable, FEV1, decreased by only 2.42% from the time of study drug discontinuation, and morning and evening PEFRs decreased by only 0.89% and 1.96%, respectively, indicating a strong residual effect of the drug. Safety The overall incidence of adverse events in this study was similar in all treatment groups (78.4% for zileuton CR, 76.8% for placebo CR, 75.3% for zileuton IR, and 77.3% for placebo IR). The most commonly reported adverse events in the zileuton CR and placebo CR groups (ⱖ5% in either group) are summarized in Table 3. The most commonly reported adverse events in the zileuton CR group were exacerbation of asthma, headache, sinusitis, nausea, nasopharyngitis, and pharyngolaryngeal pain. Approximately 8% more placebo CR–treated patients experienced exacerbation of asthma

compared with zileuton CR–treated patients, whereas 3.5% more zileuton CR–treated patients experienced nausea compared with placebo CR–treated patients. Otherwise, there were no clinically relevant differences between treatment groups in the incidence rates of any adverse effects. Five of the 199 patients (2.5%) in the zileuton CR group and 1 of the 198 patients (0.5%) in the placebo CR group developed ALT level elevations of 3 times the ULN or greater. For 2 of the 5 patients in the zileuton CR group, an elevation in the ALT level was not detected until the run-out visit (14 days after completion of treatment with study drug); ALT values were 3.3 and 3 times the ULN. The investigators did not attribute the elevations to treatment with study drug. The other 3 zileuton CR–treated patients had an ALT level elevation 5 times the ULN or greater detected at the week 4 visit (double-blind day 29) and discontinued zileuton CR treatment per protocol. These ALT level elevations decreased to less than 2 times the ULN 15 to 31 days after treatment

Table 3. Number (Percentage) of Patients With Adverse Events Occurring in 5% or More of Patients in the Zileuton CR or Placebo CR Group Patients, No. (%)

Adverse event (Medical Dictionary of Regulatory Activities preferred term)

Zileuton CR (n ⴝ 199)

Placebo CR (n ⴝ 198)

Any adverse event Asthma Headache Sinusitis Nausea Nasopharyngitis Pharyngolaryngeal pain Upper respiratory tract infection

156 (78.4) 95 (47.7) 19 (9.5) 13 (6.5) 10 (5.0) 10 (5.0) 10 (5.0) 9 (4.5)

152 (76.8) 110 (55.6) 21 (10.6) 8 (4.0) 3 (1.5) 12 (6.1) 8 (4.0) 12 (6.1)

Abbreviation: CR, controlled-release.

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discontinuation. Two of the 97 patients in the zileuton IR group (2.1%) and 1 of the 97 placebo IR–treated patients (1.0%) developed ALT level elevations of 3 times the ULN or greater. Elevations in the zileuton IR group resolved to less than 2 times the ULN 19 to 42 days after discontinuation. Other safety variables were unremarkable. The safety profiles of zileuton CR and zileuton IR observed in this study generally mirrored that reported for the pivotal zileuton IR studies.11 DISCUSSION The results of this study show clinically and statistically significant improvements in pulmonary function after treatment with zileuton CR, 1,200 mg twice daily, as demonstrated by significant increases in trough FEV1. This improvement was evident after 2 weeks of treatment, was maintained throughout 12 weeks of treatment, and continued for 2 weeks after the end of treatment. A significantly greater proportion of patients in the zileuton CR group also demonstrated a clinically significant response (defined as ⱖ12% improvement from baseline in FEV1) than in the placebo CR group at all study visits. The results of the FEV1 analyses for the zileuton IR arm of this study, although not statistically significant compared with the placebo IR arm at most time points, were similar in magnitude to those reported in earlier zileuton IR pivotal studies.9,12 The long-term improvement in pulmonary function was associated with a significant decline in ␤-agonist use and significantly smaller proportions of patients reporting 1 or more asthma exacerbations. Similar improvements in efficacy measures were observed after treatment with zileuton IR compared with placebo IR. The study was not powered for either the pairwise comparison between zileuton IR and placebo IR or the comparison between the zileuton IR and zileuton CR formulations. The overall incidence of adverse events reported in this study and the most commonly observed adverse events were similar across treatment groups. The incidence of ALT level elevations 3 times the ULN or greater was similar in the zileuton CR (2.5%) and zileuton IR groups (2.1%) and similar to that reported in previous zileuton IR studies (1.9%).11 The results of this study establish that treatment with zileuton CR, 1,200 mg twice daily, is effective in providing beneficial improvements in pulmonary function measurements compared with placebo in patients with moderate persistent asthma. Furthermore, data from this study show that zileuton CR, taken as 2 CR 600-mg tablets twice daily, offers

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an efficacy and safety profile similar to that observed with zileuton IR, 600 mg 4 times daily (Zyflo).11 REFERENCES 1. MacGlashan DW, Schleimer RP, Peters SP, et al. Generation of leukotrienes by purified human lung mast cells. J Clin Invest. 1982;70:747–751. 2. Fels AO, Pawlowski NA, Cramer EB, Kin TK, Cohn ZA, Scott WA. Human alveolar macrophages produce leukotriene B4. Proc Natl Acad Sci U S A. 1982;79:7866 –7870. 3. Weller PF, Lee CW, Foster DW, Corey EJ, Austern KF, Lewis RA. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4. Proc Natl Acad Sci U S A. 1983;80:7626 –7630. 4. Henderson WR. The role of leukotrienes in inflammation. Ann Intern Med. 1994;121:684 – 697. 5. Currie GP, Lee DKC, Srivastava P. Long-acting bronchodilator or leukotriene modifier as add-on therapy to inhaled corticosteroids in persistent asthma? Chest. 2005;128:2954 –2962. 6. Dworski R, Fitzgerald GA, Oates JA, et al. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med. 1994;149:953–959. 7. Dempsey OJ. Leukotriene receptor antagonist therapy. Postgrad Med J. 2000;76:767–773. 8. Dube LM, Swanson LJ, Awni WM, Bell RL, Carter GW, Ochs RF. Zileuton: the first leukotriene synthesis inhibitor for use in the management of chronic asthma. In: Drazen JM, Dahlen S-E, Lee TH, eds. Five-Lipoxygenase Products in Asthma. New York, NY: Marcel Dekker Inc; 1998:391– 428. 9. Israel E, Cohn J, Dube´ L, Drazen JM; for the Zileuton Clinical Trial Group. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: a randomized controlled trial. JAMA. 1996;275:931–936. 10. Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax. 1992;46:76 – 83. 11. Zyflo [product label]. Lexington, MA: Critical Therapeutics Inc; 2005. 12. Liu MC, Dube LM, Lancaster J; and the Zileuton Study Group. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized study. J Allergy Clin Immunol. 1996;98:859 – 871. Requests for reprints should be addressed to: Karen Walton-Bowen Critical Therapeutics Inc 60 Westview St Lexington, MA 02421 E-mail: [email protected]

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