Drug product: Drug substance(s): Document No.: Edition No.: 1 Study code: Accolate Zafirlukast (ZD9188) 9188IL/0138 Date: 02 May 2007 SYNOPSIS A Multicenter, Randomized, Double-blind, -controlled, Parallel group, 15-week Trial of Zafirlukast (ACCOLATE ) Versus Low dose Inhaled Corticosteroids After a 7-day Course of Oral Corticosteroids in Subjects With Asthma International co-ordinating investigator Dr. Michael Manning; Allergy & Immunology Associates, LTD; 7514 E Monterey Way; Scottsdale, AZ 858251, USA. Study centre(s) Study 9188IL/0138 was conducted at 39 centers in 1 country (USA). Publications There were no publications at the time of this report. Study dates Phase of development First subject enrolled 02 May 1996 Therapeutic confirmatory (III) Last subject completed 24 January 1997
Objectives The primary objectives of the study were To assess the efficacy of zafirlukast (20 mg BID) relative to that of low-dose ICS or placebo after a 7-day course of oral corticosteroids in patients with asthma. To assess the safety and tolerability of zafirlukast (20 mg BID) relative to that of low-dose ICS or placebo after a 7-day course of oral corticosteroids. Study design The multicenter study consisted of 3 parts: A 1-week observation/screening period. A 7- to 14-day single-blind placebo (double-dummy) run-in period. A 15-week, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety period comparing zafirlukast (20 mg BID) to beclomethasone dipropionate (BDP) (84 μg, 4 times daily [QID]) and to placebo. All patients were to receive a course of oral prednisone (40 mg, once per day [QD]) in addition to their assigned DB treatment for the first 7 days of the DB period. The DB period began at Visit 3, which was Day 0 on the study timeline. For the DB period, patients were randomized into 3 treatment groups. The patients in the group hereafter referred to as the zafirlukast group used active zafirlukast tablets and placebo BDP inhalers during the 15-week DB period. The patients in the group hereafter referred to as the BDP group used placebo zafirlukast tablets and active BDP inhalers during the 15-week DB period. The patients in the group hereafter referred to as the placebo group used placebo zafirlukast tablets and placebo BDP inhalers during the 15-week DB period. Target subject population and sample size Approximately 600 moderate-to-severe asthmatic patients 12 years of age were expected to receive study medications and undergo study procedures to achieve approximately 360 evaluable patients. 2
Investigational product and comparator(s): dosage, mode of administration and batch numbers Zafirlukast tablets (for oral use, BID) or matching placebo and BDP inhalation aerosol (2 puffs, 42 μg/puff, QID) or matching placebo were supplied for 15 weeks. Prednisone tablets (40 mg, QD) were supplied for use during the first 7 days of the DB period. Zafirlukast was labeled with instructions for proper use, including taking it 1 hour before or 2 hours after food. Instructions for use of BDP and prednisone were per package labeling. Albuterol inhalers were also supplied as rescue medication, and instructions for use, per package label, were given to patients. Duration of treatment The maximum duration of the DB treatment defined in the protocol was 15 weeks (105 days). Criteria for evaluation (main variables) Efficacy and pharmacokinetics There were no pharmacokinetic variables in this study. Primary variable: Mean daytime asthma symptoms score Mean morning peak expiratory flow rate (PEFR), before β 2 -agonist use Secondary variables: Office visit forced expiratory volume in 1 second (FEV 1 ) Total mornings with asthma Total nighttime awakenings Mean as needed (prn) β 2 -agonist use Treatment failure rates 3
Safety The safety variables were: Extent of exposure Categories of Aes Most common Aes Clinical laboratory tests Zafirlukast is known to affect markers of liver function, this report identifies all patients with potentially significant abnormalities for alanine aminotransferase (ALT 5 x the upper limit of normal [ULN]) or for bilirubin ( 3 mg/dl, which is 51 µmol/l) or for both. These clinically significant abnormalities were retrospectively categorized as OAEs if they were reported as AEs by the investigator. Vital signs, ECG, and physical examinations Subjective symptoms, diaries Statistical methods All patients who received study treatment were to be included in the safety analyses. Analyses of efficacy were to be performed on 2 populations, the intention to treat (ITT) population and the per protocol (PP) population. The ITT population was to include all patients randomized to receive the trial drug. The PP population excluded patients who had selected protocol violations or who deviated from procedures as described in the protocol. Safety results from this study were analyzed using summary statistics only. The efficacy analyses were selected to demonstrate that zafirlukast 20 mg BID is at least as efficacious as BDP 84 μg QID (ie, non-inferior to BDP). Subject population All treated patients (N=420) were included in the safety analyses. The number of patients included in the efficacy analyses was 408. The characteristics for the individual treatment groups were similar. 4
Table S1 Demographic and baseline characteristics for treated patients Zafirlukast 20 mg BID BDP 84 μg QID Total (N=420) Sex Female, n (%) 74 (53.6) 88 (62.4) 79 (56.0) 241 (57.4) Male, n (%) 64 (46.4) 53 (37.6) 62 (44.0) 179 (42.6) Age at entry, years Mean (SD) 34.9 (13.1) 34.7 (14.0) 34.5 (14.4) 34.7 (13.8) Range 12 to 70 12 to 86 12 to 74 12 to 86 Race Caucasian, n (%) 124 (89.9) 128 (90.8) 127 (90.1) 379 (90.2) Black, n (%) 9 (6.5) 11 (7.8) 7 (5.0) 27 (6.4) Asian, n (%) 1 (0.7) 1 (0.7) 1 (0.7) 3 (0.7) Hispanic, n (%) 4 (2.9) 1 (0.7) 6 (4.3) 11 (2.6) FEV 1 % predicted at baseline Mean (SD) 67.0 (10.2) 66.5 (10.4) 67.6 (11.5) 67.1 (10.7) Range 43.0 to 87.0 44.0 to 91.5 34.0 to 92.0 34.0 to 92.0 Data from Table T1.2 and T1.3 (Section 8). BID: Twice daily; FEV 1 : Forced expiratory volume in 1 second; SD: Standard deviation. Table S2 Patient completion and withdrawal for double-blind period Zafirlukast 20 mg BID BDP 84 μg QID n (%) n (%) n (%) Completed study 103 (74.6) 116 (82.3) 88 (62.4) Missing completion/ 1 (0.7) 0 0 withdrawal form Withdrew from study 34 (24.6) 25 (17.7) 53 (37.6) Asthma became 12 (8.7) 2 (1.4) 23 (16.3) worse a Adverse event b 3 (2.2) 5 (3.5) 3 (2.1) Lost to follow up 6 (4.3) 6 (4.3) 7 (5.0) 5
Table S2 Patient completion and withdrawal for double-blind period Protocol noncompliance Zafirlukast 20 mg BID BDP 84 μg QID n (%) n (%) n (%) 5 (3.6) 5 (3.5) 12 (8.5) Other reasons 8 (5.8) 7 (5.0) 8 (5.7) Data from Table T2.1 (Section 8). a Includes exacerbations reported as adverse events. b Excludes asthma. BID: Twice daily. Efficacy results Primary variable: Daytime asthma symptoms score All 3 treatment groups had a reduction in their mean daytime symptoms score at endpoint as compared to baseline. The mean change at endpoint was -0.22 for the zafirlukast 20 mg BID group, -0.56 for the BDP group, and -0.11 for the placebo group. Zafirlukast 20 mg BID is at least as efficacious as placebo (but not statistically significantly different from placebo) and not equivalent to BDP with respect to asthma symptoms scores, See Figure 2. 6
Figure 1 Mean change from baseline over time in daytime asthma symptoms scores (ITT population) Note: 20 MG BID data were obtained using zafirlukast 20 mg twice a day. BDP data were obtained using beclomethasone dipropionate 84 μg QID. 7
Figure 2 Ninety-five percent confidence intervals between treatments for daytime asthma symptoms scores at end of treatment (ITT population) Note: The 20 MG BID data were obtained using zafirlukast 20 mg twice a day. BDP data were obtained using beclomethasone dipropionate 84 μg QID. The mean difference between BDP and placebo was 0.42 with a 95% CI of 0.27 to 0.57. Thus, BDP was superior to placebo with respect to asthma symptoms scores. Morning peak expiratory flow rate before β 2 -agonist use The zafirlukast 20 mg BID group showed a slight improvement in their mean morning PEFR values at endpoint (7.14 L/min), the BDP group had considerable improvement (32.69 L/min), while the placebo group had a slight deterioration (-7.64 L/min) in their morning PEFR values at endpoint. The mean difference between BDP and placebo was 39.14 with a 95% CI of 27.48 to 50.80. A plot of the mean changes from baseline over time is presented in Figure 3. A plot of the 95% CIs for the mean differences between treatments in changes from baseline at the end of treatment is presented in Figure 3. 8
Figure 3 Mean change from baseline over time in morning peak expiratory flow rate (ITT population) Note: The 20 MG BID data were obtained using zafirlukast 20 mg twice a day. BDP data were obtained using beclomethasone dipropionate 84 μg QID. A plot of the 95% CIs for the mean differences between treatments in changes from baseline at the end of treatment is presented in Figure 4. 9
Figure 4 Ninety-five percent confidence intervals between treatments for morning peak expiratory flow rate at end of treatment (ITT population) Note: The 20 MG BID data were obtained using zafirlukast 20 mg twice a day. BDP data were obtained using beclomethasone dipropionate 84 μg QID. Secondary variables: Evening peak expiratory flow rate before β 2 -agonist use Only the BDP group had a mean improvement in evening PEFR over baseline. The patients treated with zafirlukast 20 mg BID or placebo had a mean deterioration in their evening PEFR from baseline. Mean changes in evening PEFR at endpoint as compared to baseline were -4.11 L/min for zafirlukast 20 mg BID, 21.51 L/min for BDP, and -8.79 L/min for placebo. Forced expiratory volume in 1 second The BDP group showed a mean improvement from baseline in FEV 1, while the zafirlukast 20 mg BID and placebo groups showed almost no change from baseline. The mean changes from baseline FEV 1 at endpoint were 0.05 L for zafirlukast 20 mg BID, 0.32 L for BDP, and -0.01 L for placebo. 10
Percent of predicted forced expiratory volume in 1 second The BDP group showed a marked improvement in mean percent of predicted FEV 1 from baseline, while the zafirlukast 20 mg BID group showed only a small improvement and the placebo group had almost no change. Mean change from baseline for percent of predicted FEV 1 was 2.19 for zafirlukast 20 mg BID, 9.39 for BDP, and 0.28 for placebo. Mornings with asthma symptoms All 3 groups showed a decrease in the mean number of mornings with asthma symptoms. The mean change from baseline in number of mornings with asthma symptoms at endpoint was -0.8 for zafirlukast 20 mg BID, -1.51 for BDP, and -0.48 for placebo. Nighttime awakening The mean change from baseline in number of nighttime awakenings at endpoint was 0.33 for zafirlukast 20 mg BID, -1.50 for BDP, and 0.80 for placebo. β 2 -agonist use The mean change from baseline in β 2 -agonist use at endpoint (puffs/day) was -0.03 for zafirlukast 20 mg BID, -1.47 for BDP, and 0.54 for placebo. Treatment failure rates The criteria for treatment failure were: an asthma exacerbation reported as an adverse event, patient need for oral steroids, or withdrawal for the reason asthma became worse. Eighty-four patients (32 zafirlukast 20 mg BID, 12 BDP, and 40 placebo) had treatment failures. Table S3 summarizes the treatment failures by treatment group. (Note that patients could have had more than 1 reason for treatment failure.) Treatment failures were significantly less common (p<0.001) in the BDP group than in the zafirlukast or placebo treatment groups. The difference between zafirlukast and placebo was not statistically significant. Table S3 Number of patients with treatment failure Zafirlukast 20 mg BID, N=134 BDP, 84 μg QID N=137, N=137 Reason for failure n (%) n (%) n (%) Asthma exacerbation reported as AE 14 (10.4) 4 (2.9) 14 (10.2) Withdrew due to worsening asthma 12 (9.0) 2 (1.5) 23 (16.8) Patient took oral steroids 27 (20.1) 8 (5.8) 30 (21.9) Total unique patients (any reason) 32 (23.9) 12 (8.8) 40 (29.2) AE: Adverse event; BDP: Beclomethasone dipropionate; BID: Twice daily. 11
Safety results Table S4 presents an overview of exposure for patients in each treatment group in terms of duration of treatment and total zafirlukast exposure. Table S4 Duration of treatment, days Overview of exposure by duration for double-blind patients Zafirlukast 20 mg BID BDP 84 μg QID Mean (SD) 91.1 (29.9) 94.4 (28.0) 83.0 (34.2) Range 1 to 120 1 to 114 6 to 120 Total zafirlukast exposure a, mg Mean (SD) 3643.2 (1197.3) NA NA Range 40 to 4800 NA NA Data from Table T2.2 (Section 8). a Includes exposure to oral corticosteroid (prednisone) during the first week of the DB period. BDP: Beclomethasone dipropionate; BID: Twice daily; NA: Not applicable; SD: Standard deviation. The maximum duration of DB exposure defined in the protocol was 15 weeks (105 days). Exposure data indicate the mean duration for the zafirlukast 20 mg BID group was 91.1 days (range 1 to 120 days), compared to means of 94.4 days and 83.0 days for the BDP and placebo groups, respectively. Table S5 presents the number of patients from the study that had an AE in any category. Note that the AEs summarized in this report were those AEs with onset after the first DB dose. Table S5 Patients Number (%) of adverse events experienced in any category Zafirlukast 20 mg BID BDP 84 μg QID n (%) n (%) n (%) Patients with AEs 89 (64.5) 89 (63.1) 96 (68.1) Patient deaths due to AEs 0 0 0 Patient with SAEs 4 (2.9) 8 (5.7) 5 (3.5) Patients withdrawn due to AEs a 13 (9.4) 7 (5.0) 22 (15.6) Patients with drug-related AEs 10 (7.2) 18 (12.8) 11 (7.8) 12
Table S5 Number (%) of adverse events experienced in any category Events Zafirlukast 20 mg BID BDP 84 μg QID Total AEs 171 NA 201 NA 189 NA Drug-related AEs 15 NA 32 NA 19 NA Data from Table T3.1 (Section 8). a Includes asthma AEs. AE: Adverse event; BID: Twice daily; NA: Not applicable; SAE: Serious adverse event. The percentage of patients in the study who experienced AEs was similar among the 3 treatment groups (between 63.1% and 68.1%). The percentage of patients with SAEs was highest in the BDP group (5.7%), and the percentage with DAEs was highest in the placebo group (15.6%). In addition, 18 patients from the BDP group experienced 32 drug-related AEs, compared to lower numbers in the zafirlukast 20 mg BID and placebo groups (10 patients and 11 patients experienced 15 AEs and 19 AEs, respectively). Table S6 presents the AEs experienced by the highest number of patients, including the entire study population and all study periods. Table S6 Adverse event Number (%) of patients with the most commonly reported adverse events ( 3% of patients in any group) sorted by decreasing order of frequency Zafirlukast 20 mg BID BDP 84 μg QID (COSTART preferred term) n (%) n (%) n (%) Pharyngitis 31 (22.5) 33 (23.4) 28 (19.9) Headache 14 (10.1) 15 (10.6) 12 (8.5) Aggravation reaction a 14 (10.1) 4 (2.8) 16 (11.3) Sinusitis 10 (7.2) 12 (8.5) 14 (9.9) Accidental injury 6 (4.3) 4 (2.8) 1 (0.7) Rash 5 (3.6) 4 (2.8) 1 (0.7) Back pain 4 (2.9) 2 (1.4) 6 (4.3) Dyspepsia 1 (0.7) 6 (4.3) 4 (2.8) 13
Table S6 Adverse event Number (%) of patients with the most commonly reported adverse events ( 3% of patients in any group) sorted by decreasing order of frequency Zafirlukast 20 mg BID BDP 84 μg QID (COSTART preferred term) n (%) n (%) n (%) Cough increased 1 (0.7) 5 (3.5) 1 (0.7) a For all aggravation reactions reported in this table, the reported text was related to asthma exacerbation, with the exception of 1 patient (0028/2809), whose AE reported text was exacerbation of depression. Data from Table T3.3 (Section 8). BDP: Beclomethasone dipropionate; BID: Twice daily. There were no deaths and no OAEs during this study. The frequency and nature of the non-fatal SAEs and DAEs did not raise any new safety concerns. Clinical laboratory results Laboratory results were retrospectively examined to identify patients with marked abnormalities indicative of abnormal liver function, specifically ALT levels 5 x ULN and/or bilirubin levels 3 mg/dl (51 µmol/l). No patients met the criteria during the DB period. No meaningful deviations from the known safety profile of zafirlukast were identified from the clinical laboratory results. Vital signs, ECG, physical findings, and other observations related to safety No meaningful deviations from the known safety profile of zafirlukast were identified from these results. Conclusion(s) This 420-patient, 15-week, double-blind study of moderate-to-severe asthmatic patients 12 years of age had as its objective comparing the efficacy, safety, and tolerability of zafirlukast with those of low-dose ICS (BDP 84 μg QID) or placebo after a 7-day course of oral corticosteroids. 14
This study failed to demonstrate that zafirlukast 20 mg BID is at least as efficacious as BDP 84 μg QID. The primary efficacy variables were daytime asthma symptoms scores (zafirlukast not statistically significantly better than placebo and not equivalent to BDP) and morning PEFR (zafirlukast at least as efficacious as placebo but not equivalent to BDP). For other efficacy variables (evening PEFR, FEV 1, percent of predicted FEV 1, mornings with asthma symptoms, nighttime awakenings, β 2 -agonist use, and treatment failure rates), BDP was superior to both zafirlukast 20 mg BID and placebo. During this study, zafirlukast 20 mg BID was well tolerated. The AE profile and other safety variable findings were consistent with the known safety profile. Date of the report 30 November 2006 15