Before initiating the study, comparative dissolution testing was performed to determine whether over-encapsulation would affect the bioequivalence of the blinded zafirlukast tablets. The dissolution profiles were the same for the over-encapsulated (blinded drug) and the trade product. Empty capsules were also tested, and complete dissolution and disintegration of the capsules occurred within 5 minutes.
Patients were instructed to inhale 2 puffs from their study MDI each morning and evening and to swallow 1 study capsule each morning at least 1 hour before breakfast, and each evening at least 2 hours following dinner. The timing of administration of study capsules was based on the limited absorption of zafirlukast when given with food. Patients were instructed to rinse their mouths with water after using the MDI. Patients were not allowed to take any asthma medication during the study other than the study medication, albuterol (Ventolin Inhalation Aerosol) as needed for symptom relief, or oral or parenteral corticosteroids for asthma exacerbations. The use of medications that interact with inhaled corticosteroids or leukotriene modifiers was not allowed. Patients who experienced 2 exacerbations (eg, required a second burst of oral corticosteroids) or received oral or parenteral corticosteroids for more than 14 consecutive days were withdrawn from the study.
Assessments of Efficacy and Safety
The primary physiologic efficacy measure was morning predose FEV1. Other efficacy measures included patient-recorded morning (am) and evening (pm) peak expiratory flow (PEF). Patient-oriented outcomes included asthma symptom scores, percentage of symptom-free days, albuterol use, percentage of albuterol-free days, and nighttime awakenings due to asthma symptoms; physicians’ overall assessment of medication effectiveness, and patient questionnaires concerning asthma-specific quality of life, productivity, and satisfaction with study medication. Safety assessments included the incidences of asthma exacerbations, adverse events, and pre-defined, clinically significant, laboratory test results.
FEV1 was assessed at each clinic visit between 6 am and 10 am.6 Morning doses of study medications were withheld before each clinic visit, and the visit was rescheduled if the patient used albuterol within 6 hours preceding the visit. Before taking study medications, patients recorded on a diary card any asthma symptoms experienced, using a 6-point scale (where 0 = no symptoms and 5 = symptoms caused severe discomfort and prevented normal activities). After recording symptoms, patients measured and recorded their PEF, along with the number of puffs of albuterol used and the number of nighttime awakenings due to asthma. Patients reported study medication compliance daily on the diary card. Adverse events, concurrent medications, and diary cards were reviewed at each clinic visit. Laboratory tests were performed at the beginning of the run-in period and at the patient’s last visit.
At the last clinic visit, following a review of diary cards and the status of each patient, physicians rated the overall effectiveness of each patient’s blinded study medication using a 4-point scale (where 0 = ineffective and 3 = very effective). At weeks 2 and 12, patients assessed their overall satisfaction with study medication using a 7-point scale (where 0= very dissatisfied and 6 = very satisfied) and completed the Asthma Quality of Life Questionnaire (AQLQ),7 which measures the impact of asthma on patients’ daily functioning. At weeks 2, 4, 6, 8, and 12, patients documented their productivity (days missed from work or school and days with symptoms at work or school) over the previous 2 weeks.
Statistical Analyses
The sample size (Ž100 patients completing each treatment) provided Ž80% power to detect a difference in FEV1 of 0.25 L between treatment groups, according to a 2-sample t test with a significance level of 0.05 and a standard deviation of 0.55 L.
All patients randomly assigned to the study drug were included in the safety analyses. Nine patients at 1 site were excluded from the efficacy analyses because of significant deviations from good clinical practice standards.
Change from baseline was calculated at each clinic visit and at the last available observation for FEV1. For each subject-recorded assessment from the diary card, weekly means were calculated for each patient, and change from baseline (baseline = mean of last 7 days’ data from run-in) was calculated at each week and at the endpoint (endpoint = mean of last available weekly data). Onset of effect was evaluated as change in daily am PEF from day of randomization. Changes from baseline in global AQLQ and the individual domain scores were computed at the endpoint (endpoint = last available questionnaire). Analyses of covariance adjusted for investigator effect and included the baseline value as a covariate. Analysis of covariance F tests were used to evaluate treatment differences in all change from baseline values.