Evaluation of the Safety and Efficacy of Multiple Doses of Azelastine to Adult Patients with Bronchial Asthma over Time 1- 3
DAVID G. TINKElMAN, GERALD A. BUCHOLTZ, JAMES P. KEMP, JERALD W. KOEPKE, LAWRENCE H. REPSHER, SHELDON L. SPECTOR, WILLIAM W. STORMS, and ANDRE VAN AS
Introduction
Azelastine, a chemically novel, orally effective, long-acting antiallergic medication has recently been developed for the treatment of asthma. Its properties have been described as: H-l receptor blocker (1),leukotrienes C-3 and C-4 inhibitor (2), serotonin inhibitor (3), PCAinhibitor (4), and bradykinin inhibitor (2). In addition, azelastine was recently demonstrated to have bronchodilator properties in humans (5). Previous pharmacokinetic studies of azelastine in both animals and humans have indicated that this agent reaches its peak plasma concentration approximately 5 h after oral administration, with a biologic half-life of approximately 20 h after repeated administration (6). Various single- and multiple-dose tolerance studies in healthy human volunteers have demonstrated no clinically significant effects on the cardiovascular, hematopoietic, renal, or hepatic systems (6). Doses as great as 16 mg per day have been administered without significant adverse effects, comparable to that seen with lower doses (6). The most commonly reported adverse experiences have been transient drowsiness and altered taste. Clinical trials in the United States have shown azelastine at a dosage of 4 mg twice daily to be significantly better than placebo therapy in the treatment of bronchial asthma (6). These studies conducted in adult asthmatics were of short duration, but they indicated reduction in the number ofattacks and reduced use of back-up medication when compared with placebo therapy (6). In other studies, azelastine has been demonstrated effectivein treating the symptoms of allergic rhinitis while producing a low incidence of side effects (7). The purpose of this study was to evaluate the safety and efficacy of multiple doses of azelastine administered twice daily to a larger patient population and
SUMMARY Azelastine is a new oral antiasthma agent with bronchodilating and antiallergic properties. This 12-wk study compared azelastine (2, 4, 6, and 8 mg) and placebo given twice a day in asthmatics 12to 60 yr of age requiring daily bronchodilator therapy. Patients were allowed albuterol aerosol, short-acting theophylline, and pseudoephedrine only as needed. The stUdy was completed by 221 asthmatic subjects. No significant differences in symptoms, medication, or pulmonary function existed between groups at baseline. Analysis of the zero hour FEY1 before azelastine administration on eight occasions during the 12 wk of therapy indicated an increasing slope for azelastine 6 mg that was statistically different from that of placebo; similarly, the slope for azelastine 4 mg showed the same trend, but it did not reach statistical significance. All azelastine groups had significant reductions of as-needed medication after 1 wk; only in the 4-mg and &.mg groups was this reduction sustained for 12 wk. Asthma symptom scores and peak expiratory flow measurements remained stable in the azelastine groups despite significant reductions in concomitant medication administration. Side effects were minor and included: altered taste (30.1 to 51.9%), drowsiness (6.0 to 16.9%), and dry mouth (3.8 to 6.1%). The occurrence of these adverse events decreased with time throughout the study. Although azelastine 2 mg and 8 mg given twice a day were statistically better than placebo in some variables, there was no therapeutic consistency for these dosages. Overall evaluation suggests that azelastine at 4 mg and 6 mg twice a day are safe and effective for the treatment of chronic asthma in adults. AM REV RESPIR DIS 1990; 141:569-574
over a longer period of time than previously studied and to determine if a particular dose would be most effective and suitable for long-term administration. Methods Study Design This was a multicenter, 12-wk,double-blind, placebo-controlled, randomized trial involving parallel treatment groups. After a l-wk, single-blind, placebo-treatment baseline period, subjects received twice a day during the next 12 wk one of the following test drugs: 2, 4, 6, or 8 mg azelastine or placebo.
chodilators or with other illnesses considered to affect the study results. The study protocol was approved by an Institutional Review Board at each of the study sites. Subjects were apprised of the conduct of the study, and they signed an informed consent statement before entry into the baseline period.
(Received in original form April 3, 1989 and in revised form August 16, 1989)
1 From the Atlanta Allergy & Immunology Research Foundation, Atlanta, Georgia; the Division of Allergy/Immunology, University of South Florida, College of Medicine, Tampa, Florida; the Allergy & Asthma Medical Group & Research CenPatient Selection ter, San Diego, California; the Allergy Respiratory To participate in this study, patients had to . Institute of Colorado, Denver, and the Pulmonary be between 12 and 60 yr of age. All had a Consultants, P.A. Lutheran Medical Center, Wheathistory of moderate to moderately severe ridge, Colorado; the Allergy Research Foundation bronchial asthma and were able to demon- Inc., Los Angeles, California; Allergy Associates, strate a baseline FEV 1 between 40 and 80070 P.A., Colorado Springs, Colorado; and the Asthof predicted after withholding antiasthma ma & Allergy Research Center, Inc., Albuquerque, medications with improvementofat least 15070 New Mexico. 2 Supported by a grant from Wallace Laboratowithin 30 min after receiving two inhalations ries, Division of Carter-Wallace, Inc., Cranbury, of a beta-agonist bronchodilator. Women of New Jersey. child-bearing potential and those who were J Correspondence and requests for reprints pregnant or nursing were excluded from the should be addressed to Dr. David G. Tinkelman, study population, as werepatients with a his- Suite A-30, 6667 Vernon Woods Drive, Atlanta, GA tory of intolerance to antihistamines or bron- 30328.
569
570
TINKElMAN, BUCHOLTZ, KEMP, KOEPKE, REPSHER, SPECTOR, STORMS, AND VAN AS
Study Medications Blinded-study medication (azelastine 2, 4, 6, and 8 mg or matching placebo) was randomly allocated to participants who met the qualification criteria. The study design called for the use of study medication as primary antiasthma medication. Albuterol aerosol was the first choice of back-up medication for increasing symptomatology. If subjects were not sufficiently controlled while receivingtheir study medication and albuterol aerosol, they were given short-acting theophylline, at a dose of approximately 4 mg/kg/ dose, as needed. In the event of poor control or a severeexacerbation of asthma, oral treatment with prednisone was allowed for a 6-day period. A maximum of two prednisone treatments were allowed prior to declaring the active treatment a failure. In addition, pseudoephedrine, 30 mg, was also provided to control exacerbations of rhinitis symptoms during the course of the study. When pseudoephedrine failed to control symptoms, antihistamines were allowed.
Variables Measured The safety of azelastine was assessed by monitoring the following items: history and physical examination, chest radiograph and EKG, a daily diary for adverse experiences, laboratory assessment of hematology, serum chemistry, renal function, periodic measures of vital signs, and body weight. Efficacy monitoring included: pulmonary function testing before and during the 8 h after administration of the first dose of test drug and after 1,4,8, and 12wk of therapy; diary card recording of back-up medication use, asthma symptoms, number of exacerbations of asthma, and twice-daily peak flow measurements. In addition, each subject and investigator independently assessed the asthma status and overall therapeutic response relative to baseline after 1, 4, 8, and 12 wk. The subject's status during the course of Week 1, during which the subject received placebo, was considered the baseline. Both the subject and the investigator provided a global evaluation of the treatment at the conclusion of the study. Plasma samples for the azelastine and desmethylazelastine assays were prepared from the blood samples drawn from subjects immediately before and at 4 h after ingestion of randomly assigned dose on the days on which pulmonary function testing was conducted. Samples were analyzed for azelastine and desmethylazelastine by a high performance liquid chromatography method developed at Wallace Laboratories (Cranbury, NJ). Presence of albuterol, theophylline, or pseudoephedrine did not interfere with the detection of azelastine or its metabolite (8, 9).
Statistical Methods The following efficacy variables were statistically analyzed. 1. Pulmonary function tests. Pulmonary function test data at one-half hour and at hourly intervals from 1 to 8 h after dosing
with study medication were calculated as a percent increase from a zero hour. The maximal pulmonary function test value, i.e., the maximal value of the half-hour and 1-through 8-h evaluations, was calculated as percent increase from zero hour for each subject. These calculations were made after the first dose of double-blind medication and after 1, 4, 8, and 12 wk of therapy. The slopes of the baseline (zero hour) values across all weeks of therapy were calculated by using least square means for each treatment group. 2. Subject symptoms. The total symptom score (sum of the scores: wheezing, dyspnea, cough, and chest tightness) at each visit and the differences from pretreatment were calculated. The number of asthma attacks as an average per day since the last evaluation visit and the differences from pretreatment were calculated. The differences during activetreatment for total symptom score and number of asthma attacks were compared with the differences during placebo therapy. 3. Peak expiratory flow (PEF). Subjects measured PEF using a Wright Mini-Peak Flow Meter soon after arising in the morning before using any antiasthma medication and again in the evening approximately 2 h after using any antiasthma medication. The best of three attempts recorded in the morning and in the evening were calculated as an average per day (separate averages for morning and evening) since the last evaluation visit. Differences were again compared with those during placebo therapy. 4. Back-up medication. The number of standardized doses of each medication, i.e., albuterol aerosol, theophylline, and pseudoephedrine, were calculated as an average per day according to the Drug Equivalence Scoring System (10). Usage of back-up therapy during active treatment was compared with the placebo baseline week. Each response variable was subjected to a two-way analysis of variance model. Pair-wise
comparisons with placebo were done using the residue mean square from the analysis of variance and testing against a two-sided alternative hypothesis. The proportions of subjects reporting the most frequently occurring adverse experiences were analyzed by chisquare test.
Results
There were eight clinical centers across the United States. Two hundred seventyseven subjects wereenrolled into the l-wk, single-blind placebo baseline evaluation period. 1\venty-one of these subjects did not receive double-blind medication at the end of the single-blind placebo baseline evaluation period. Of the 254 subjects who did receive double-blind medication, 33 did not complete the 12 wk of treatment. Twelve of these discontinued because of lack of efficacy, 13because of adverse experiences, and eight because of administrative reasons. The case record of one subject was unavailable for analysis because of a shipping error. The 253 evaluable subjects consisted of 70 females and 183 males, 12 to 61 yr of age, and weighing 80 to 246 pounds; table 1 summarizes, by treatment group, the nature of the subject populations at baseline as reflected by asthma symptoms, number of asthma attacks, morning and eveningpeak flow measurements, and spirometric pulmonary function values for FEV t and FEF2s - 1s • Both clinically and statistically, the treatment groups were comparable relative to these parameters.
Efficacy At the end of the baseline evaluation period, the first dose of double-blind medi-
TABLE 1 DEMOGRAPHIC INFORMATION AND BASELINE PULMONARY FUNCTION PARAMETERS BY TREATMENT GROUP Azelastine
Number per group M/F Mean age, yr Age range, yr Mean weight, Ibs Mean FEV L " - 75 , L/min Mean FEF25 Mean PEFR, L/min Mean FVC, L Mean % predicted FEV1 Mean % reversibility Mean asthma attacks, n Mean peak flow rates A.M. P.M.
Mean total symptoms
Placebo
2 mg
4 mg
6 mg
8 mg
49 36/13 29.2 12-58 148.7 2.30 1.65 5.97 3.47 61.8 30.5 0.55
53 33/20 33.7 13-57 154.3 2.11 1.46 5.71 3.26 60.7 31.8 0.62
50 36/14 29.9 12-61 157.0 2.30 1.79 5.85 3.32 65.8 28.0 0.37
52 39/13 30.3 12-59 143.2 2.19 1.54 5.76 3.34 61.1 30.6 0.83
49 39/10 31.3 13-60 158.2 2.34 1.71 6.16 3.39 62.4 28.5 0.26
380.15 400.59 4.91
351.43 371.92 4.80
353.46 373.47 4.49
346.60 377.52 4.53
401.81 421.37 4.65
571
AZELASTlNE EFRCACY IN LONG-TERM MANAGEMENT OF ASTHMA
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Fig. 1. Mean FEV, for the zero hour measurement at each pulmonary funct ion test (least squares line) during treatment for 12wk. - - = 8 mg azelastine; ~ . - = 6 mg azelastine ; _t - = 4 mg azelastine ; . ... = 2 mg azelastine; - = placebo; t = pulmonary function test.
12 wk of treatment with azelastine or placebo is shown in figure 2. The improvement in FEV. when measured 12 h after the last dose of study medication was statistically significant for all azelastine treatments (p < 0.05), but not for placebo when compared with their respective baseline values. Bronchodilation occurred after the first dose of azelastine. The mean FEV. for each treatment group during the initial 8-h pulmonary function testing after administration of the first oral dose of blinded medication is shown in figure 3. The azelastine 4 mg group achieved statistically significant improvement in FEV., which was begun 2 h after dosing (p = 0.029) and was generally sustained at Hours 4,6,7, and 8. Similar improvement in FEF 2 5 - 75 for the azelastine 4 mg group was observed beginning 3 h after dosing (p = 0.052) and sustained at Hours 4, 6, 7, and 8. Only the azelastine 4 mg group achieved statistically significant and maintained clinically relevant improvement in the pulmonary function measurements throughout the course of the 8-h testing period.
cation was administered, and pulmonary function testing was performed for as long as 8 hr. Subsequent pulmonary function testing was performed after I, 4, 8, and 12 wk of therapy. On these test days, baseline pulmonary function was performed after withholding concomitant medication for at least 8 h and test medication for 12 h. The baseline (zero Backup Medications hour) least squares lines for FEV. for Subjects wereinstructed to use A/butero/. each treatment group across the 12 wk of active drug therapy are demonstrated their backup medication to maintain in figure 1.The slope of the line for FEV. their asthma and/or rhinitis at a tolerafor the azelastine 6 mg treatment group ble level. The azelastine 4 mg group was statistically different from that of achieved statistically significant (p = placebo treatment group (p = 0.043).Al- 0.034) reduction in the use of aerosolthough the slopes of the lines for FEV. ized albuterol during the first month of for other dosage levels were not statis- therapy. These reductions were sustained tically different from placebo therapy, throughout the remainder of the trial the slope of the line for FEV. of the (p = 0.011). The azelastine 2 mg group azelastine 4 mg showed a trend similar also achieved statistically significant reduction after 1 month of therapy, but the to that of the 6 mg group. The actual increase in zero hour FEV. magnitude of the reductions was more (12 h after last study medication) after variable during subsequent weeks. The JOO
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Fig. 3. Mean FE'/, over 8 h after the first dose. -6- = 8 mg azelastine; -0- = 6 mg azelastine; - - . - - = 4 mg azelastine; .. 6 . . = 2 mg azelastine ; -0- = placebo. 'p .. 0.05.
azelastine 6 mg group also achieved a statistically significant (p = 0.004 and p = 0.(06) reduction during the second and third month of therapy. The overall change in aerosolized albuterol use is summarized in figure 4. In this figure, one unit is equivalent to one puff. The results of the azelastine 2, 4, and 6 mg groups, but not the azelastine 8 mg group, were statistically significant when use over the 3 months of the study was compared with that of the placebo group (p = 0.006, p = 0.002, p = 0.0006, respectively). Theophylline. When subjects were not controlled with aerosolized albuterol, short-acting theophylline was used as the next back-up medication. The azelastine 4 mg group showed a significant reduction in theophylline use during the first month and a statistically significant reduction during the third month (p = 0.018)of treatment (figure 5). In this figure, one unit is equivalent to 200 mg short-acting theophylline.Over the course of study treatment, the azelastine 4 mg
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Fig. 2. Improvement in zero hour FEV, after 12 wk of treatment. I'ZZZll = 8 mg azelast ine; IilllJ = 6 mg azelastine; _ = 4 mg azelastine; ~ = 2 mg azelastine; ~ = placebo. 'p ~ 0.05 (change from baseline).
Fig. 4. Average daily use of a1buterol aerosol as a backup medication during treatment (one unit equivalent 10one pUff). 1'ZZZll = 8 mg azelastine ; ~ = 6mgazelastine;_ = 4mgazelastine; Illll5ll = 2 mg azelastine; ~ = placebo. 'p = .. 0.05 (all comparisons versus placebo).
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Weeks of Therapy
Overall
572
nNKELMAN, BUCHOLTZ, KEMp, KOEPKE, REPSHER, SPECTOR, STORMS, AND VAN AS
420 410
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Fig. 5. Averagedailyuseof short-actingtheophylline (oneunit equivalentto 200 mg short-acting theophylline).17lzz::l = 8 mg azelastine; IffiD = 6 = 4 mg azelastine; c:=J = mg azelastine; _ 2 mg azelastine; c:=J = placebo. 'p = .;; 0.05 (all comparisons versus placebo).
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9- 12
Overall
Weeks of Therapy
group achieved statistically significant (p = 0.036) reduction in the use of theophylline.The 6 mg group showeda trend toward statistical significance for overall use (P = 0.09). Decongestant tablets. All azelastine dosage groups showed numerically greater decreases than did placebo in the daily number of tablets through 12wk of therapy (figure 6). In this figure, one unit equals one 30-mg pseudoephedrine. Although pseudoephedrine use in most azelastine-treated groups was 20 to 35070 less than that of the placebo-treated group, these differences were not statistically significant.
Total Symptom Scores Total symptom scores did not change in any of the azelastine groups even though the use of aerosolized albuterol and immediate release theophylline was statistically lessthan that of the placebo-treated group. In contrast, clinical symptomatic stability in the placebo group was maintained through increased use ofantiasthma therapeutic agents. Change in Morning and Evening Peak Expiratory Flow The mean PEF for each treatment group
averaged over the number of days between office visits for the morning and evening measurements, respectively, are shown in figures 7 and 8. Morning mean PEF for the azelastine 6 mg group showed a trend toward statistical improvement after 10 and 12 wk of therapy, but it did not reach statistical significance (P = 0.11). A similar trend was shown for azelastine 4 mg after 12 wk (P = 0.06). For the evening PEF measurements, the difference from placebo was statistically significant for the azelastine 4 mg dosage (p = 0.02) after 1 and 12 wk of treatment. A similar trend was observed for the azelastine 8 mg dosage, but it did not achieve statistical significance (p = 0.052). For the azelastine 4 mg group, the PEF was higher and achieved statistical significance after 12 wk (p = 0.017).
Safety No serious or unexpected adverse experiences were noted (table 2). The most frequently reported adverse experiences weredrowsiness (somnolence), alteration in taste (metallic or bitter taste), dry mouth, and headache. Drowsiness was reported at frequencies of 6.0 to 16.9% among the azelastine-treated groups . In
. Rg . 7. Pre-A.M. dosepeak flow ratesduring 12wk of treatment. -D.- = 8 mg azelastine; -0- = 6 mg azelastine; --.-- = 4 mg azelastine; . . 0 . . = 2 mg azelastine; -0- = placebo.
comparison, 2% of the placebo-treated group experienced somnolence. Somnolence in the azelastine 2, 6, and 8 mg groups, but not in the azelastine 4 mg group, was statistically different from that in the placebo group (p < 0.05). The incidence of reported drowsiness decreased during continued therapy during the course of the trial. Altered taste occurred at frequencies of 30.1 to 51.9% among azelastine-treated groups. In comparison, none of the placebo group experienced bitter or altered taste. All azelastine-treated groups werestatistically different when compared with placebo therapy (p < 0.001) for this adverse experience. The incidence of complaints of altered taste also decreased during continued therapy. Dry mouth occurred at frequency of 3.8 to 6.1% among azelastine groups . The azelastine groups were not statistically significantly different from the placebo group. Headache occurred at frequencies comparable to the placebo-treated groups.
450 440
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Fig. 6. Average daily useof standardizeddoses of Sudafed!' (one unit equals one 3O-mg tablet). I7lzz::l = 8 mg azelastine; IffiD = 6 mg azelastine; _ = 4mgazelast ine;1l!i!2l = 2mgazelastine ; c:=J = placebo.
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DAVID G. TINKElMAN, GERALD A. BUCHOLTZ, JAMES P. KEMP, JERALD W. KOEPKE, LAWRENCE H. REPSHER, SHELDON L. SPECTOR, WILLIAM W. STORMS, and ANDRE VAN AS
Introduction
Azelastine, a chemically novel, orally effective, long-acting antiallergic medication has recently been developed for the treatment of asthma. Its properties have been described as: H-l receptor blocker (1),leukotrienes C-3 and C-4 inhibitor (2), serotonin inhibitor (3), PCAinhibitor (4), and bradykinin inhibitor (2). In addition, azelastine was recently demonstrated to have bronchodilator properties in humans (5). Previous pharmacokinetic studies of azelastine in both animals and humans have indicated that this agent reaches its peak plasma concentration approximately 5 h after oral administration, with a biologic half-life of approximately 20 h after repeated administration (6). Various single- and multiple-dose tolerance studies in healthy human volunteers have demonstrated no clinically significant effects on the cardiovascular, hematopoietic, renal, or hepatic systems (6). Doses as great as 16 mg per day have been administered without significant adverse effects, comparable to that seen with lower doses (6). The most commonly reported adverse experiences have been transient drowsiness and altered taste. Clinical trials in the United States have shown azelastine at a dosage of 4 mg twice daily to be significantly better than placebo therapy in the treatment of bronchial asthma (6). These studies conducted in adult asthmatics were of short duration, but they indicated reduction in the number ofattacks and reduced use of back-up medication when compared with placebo therapy (6). In other studies, azelastine has been demonstrated effectivein treating the symptoms of allergic rhinitis while producing a low incidence of side effects (7). The purpose of this study was to evaluate the safety and efficacy of multiple doses of azelastine administered twice daily to a larger patient population and
SUMMARY Azelastine is a new oral antiasthma agent with bronchodilating and antiallergic properties. This 12-wk study compared azelastine (2, 4, 6, and 8 mg) and placebo given twice a day in asthmatics 12to 60 yr of age requiring daily bronchodilator therapy. Patients were allowed albuterol aerosol, short-acting theophylline, and pseudoephedrine only as needed. The stUdy was completed by 221 asthmatic subjects. No significant differences in symptoms, medication, or pulmonary function existed between groups at baseline. Analysis of the zero hour FEY1 before azelastine administration on eight occasions during the 12 wk of therapy indicated an increasing slope for azelastine 6 mg that was statistically different from that of placebo; similarly, the slope for azelastine 4 mg showed the same trend, but it did not reach statistical significance. All azelastine groups had significant reductions of as-needed medication after 1 wk; only in the 4-mg and &.mg groups was this reduction sustained for 12 wk. Asthma symptom scores and peak expiratory flow measurements remained stable in the azelastine groups despite significant reductions in concomitant medication administration. Side effects were minor and included: altered taste (30.1 to 51.9%), drowsiness (6.0 to 16.9%), and dry mouth (3.8 to 6.1%). The occurrence of these adverse events decreased with time throughout the study. Although azelastine 2 mg and 8 mg given twice a day were statistically better than placebo in some variables, there was no therapeutic consistency for these dosages. Overall evaluation suggests that azelastine at 4 mg and 6 mg twice a day are safe and effective for the treatment of chronic asthma in adults. AM REV RESPIR DIS 1990; 141:569-574
over a longer period of time than previously studied and to determine if a particular dose would be most effective and suitable for long-term administration. Methods Study Design This was a multicenter, 12-wk,double-blind, placebo-controlled, randomized trial involving parallel treatment groups. After a l-wk, single-blind, placebo-treatment baseline period, subjects received twice a day during the next 12 wk one of the following test drugs: 2, 4, 6, or 8 mg azelastine or placebo.
chodilators or with other illnesses considered to affect the study results. The study protocol was approved by an Institutional Review Board at each of the study sites. Subjects were apprised of the conduct of the study, and they signed an informed consent statement before entry into the baseline period.
(Received in original form April 3, 1989 and in revised form August 16, 1989)
1 From the Atlanta Allergy & Immunology Research Foundation, Atlanta, Georgia; the Division of Allergy/Immunology, University of South Florida, College of Medicine, Tampa, Florida; the Allergy & Asthma Medical Group & Research CenPatient Selection ter, San Diego, California; the Allergy Respiratory To participate in this study, patients had to . Institute of Colorado, Denver, and the Pulmonary be between 12 and 60 yr of age. All had a Consultants, P.A. Lutheran Medical Center, Wheathistory of moderate to moderately severe ridge, Colorado; the Allergy Research Foundation bronchial asthma and were able to demon- Inc., Los Angeles, California; Allergy Associates, strate a baseline FEV 1 between 40 and 80070 P.A., Colorado Springs, Colorado; and the Asthof predicted after withholding antiasthma ma & Allergy Research Center, Inc., Albuquerque, medications with improvementofat least 15070 New Mexico. 2 Supported by a grant from Wallace Laboratowithin 30 min after receiving two inhalations ries, Division of Carter-Wallace, Inc., Cranbury, of a beta-agonist bronchodilator. Women of New Jersey. child-bearing potential and those who were J Correspondence and requests for reprints pregnant or nursing were excluded from the should be addressed to Dr. David G. Tinkelman, study population, as werepatients with a his- Suite A-30, 6667 Vernon Woods Drive, Atlanta, GA tory of intolerance to antihistamines or bron- 30328.
569
570
TINKElMAN, BUCHOLTZ, KEMP, KOEPKE, REPSHER, SPECTOR, STORMS, AND VAN AS
Study Medications Blinded-study medication (azelastine 2, 4, 6, and 8 mg or matching placebo) was randomly allocated to participants who met the qualification criteria. The study design called for the use of study medication as primary antiasthma medication. Albuterol aerosol was the first choice of back-up medication for increasing symptomatology. If subjects were not sufficiently controlled while receivingtheir study medication and albuterol aerosol, they were given short-acting theophylline, at a dose of approximately 4 mg/kg/ dose, as needed. In the event of poor control or a severeexacerbation of asthma, oral treatment with prednisone was allowed for a 6-day period. A maximum of two prednisone treatments were allowed prior to declaring the active treatment a failure. In addition, pseudoephedrine, 30 mg, was also provided to control exacerbations of rhinitis symptoms during the course of the study. When pseudoephedrine failed to control symptoms, antihistamines were allowed.
Variables Measured The safety of azelastine was assessed by monitoring the following items: history and physical examination, chest radiograph and EKG, a daily diary for adverse experiences, laboratory assessment of hematology, serum chemistry, renal function, periodic measures of vital signs, and body weight. Efficacy monitoring included: pulmonary function testing before and during the 8 h after administration of the first dose of test drug and after 1,4,8, and 12wk of therapy; diary card recording of back-up medication use, asthma symptoms, number of exacerbations of asthma, and twice-daily peak flow measurements. In addition, each subject and investigator independently assessed the asthma status and overall therapeutic response relative to baseline after 1, 4, 8, and 12 wk. The subject's status during the course of Week 1, during which the subject received placebo, was considered the baseline. Both the subject and the investigator provided a global evaluation of the treatment at the conclusion of the study. Plasma samples for the azelastine and desmethylazelastine assays were prepared from the blood samples drawn from subjects immediately before and at 4 h after ingestion of randomly assigned dose on the days on which pulmonary function testing was conducted. Samples were analyzed for azelastine and desmethylazelastine by a high performance liquid chromatography method developed at Wallace Laboratories (Cranbury, NJ). Presence of albuterol, theophylline, or pseudoephedrine did not interfere with the detection of azelastine or its metabolite (8, 9).
Statistical Methods The following efficacy variables were statistically analyzed. 1. Pulmonary function tests. Pulmonary function test data at one-half hour and at hourly intervals from 1 to 8 h after dosing
with study medication were calculated as a percent increase from a zero hour. The maximal pulmonary function test value, i.e., the maximal value of the half-hour and 1-through 8-h evaluations, was calculated as percent increase from zero hour for each subject. These calculations were made after the first dose of double-blind medication and after 1, 4, 8, and 12 wk of therapy. The slopes of the baseline (zero hour) values across all weeks of therapy were calculated by using least square means for each treatment group. 2. Subject symptoms. The total symptom score (sum of the scores: wheezing, dyspnea, cough, and chest tightness) at each visit and the differences from pretreatment were calculated. The number of asthma attacks as an average per day since the last evaluation visit and the differences from pretreatment were calculated. The differences during activetreatment for total symptom score and number of asthma attacks were compared with the differences during placebo therapy. 3. Peak expiratory flow (PEF). Subjects measured PEF using a Wright Mini-Peak Flow Meter soon after arising in the morning before using any antiasthma medication and again in the evening approximately 2 h after using any antiasthma medication. The best of three attempts recorded in the morning and in the evening were calculated as an average per day (separate averages for morning and evening) since the last evaluation visit. Differences were again compared with those during placebo therapy. 4. Back-up medication. The number of standardized doses of each medication, i.e., albuterol aerosol, theophylline, and pseudoephedrine, were calculated as an average per day according to the Drug Equivalence Scoring System (10). Usage of back-up therapy during active treatment was compared with the placebo baseline week. Each response variable was subjected to a two-way analysis of variance model. Pair-wise
comparisons with placebo were done using the residue mean square from the analysis of variance and testing against a two-sided alternative hypothesis. The proportions of subjects reporting the most frequently occurring adverse experiences were analyzed by chisquare test.
Results
There were eight clinical centers across the United States. Two hundred seventyseven subjects wereenrolled into the l-wk, single-blind placebo baseline evaluation period. 1\venty-one of these subjects did not receive double-blind medication at the end of the single-blind placebo baseline evaluation period. Of the 254 subjects who did receive double-blind medication, 33 did not complete the 12 wk of treatment. Twelve of these discontinued because of lack of efficacy, 13because of adverse experiences, and eight because of administrative reasons. The case record of one subject was unavailable for analysis because of a shipping error. The 253 evaluable subjects consisted of 70 females and 183 males, 12 to 61 yr of age, and weighing 80 to 246 pounds; table 1 summarizes, by treatment group, the nature of the subject populations at baseline as reflected by asthma symptoms, number of asthma attacks, morning and eveningpeak flow measurements, and spirometric pulmonary function values for FEV t and FEF2s - 1s • Both clinically and statistically, the treatment groups were comparable relative to these parameters.
Efficacy At the end of the baseline evaluation period, the first dose of double-blind medi-
TABLE 1 DEMOGRAPHIC INFORMATION AND BASELINE PULMONARY FUNCTION PARAMETERS BY TREATMENT GROUP Azelastine
Number per group M/F Mean age, yr Age range, yr Mean weight, Ibs Mean FEV L " - 75 , L/min Mean FEF25 Mean PEFR, L/min Mean FVC, L Mean % predicted FEV1 Mean % reversibility Mean asthma attacks, n Mean peak flow rates A.M. P.M.
Mean total symptoms
Placebo
2 mg
4 mg
6 mg
8 mg
49 36/13 29.2 12-58 148.7 2.30 1.65 5.97 3.47 61.8 30.5 0.55
53 33/20 33.7 13-57 154.3 2.11 1.46 5.71 3.26 60.7 31.8 0.62
50 36/14 29.9 12-61 157.0 2.30 1.79 5.85 3.32 65.8 28.0 0.37
52 39/13 30.3 12-59 143.2 2.19 1.54 5.76 3.34 61.1 30.6 0.83
49 39/10 31.3 13-60 158.2 2.34 1.71 6.16 3.39 62.4 28.5 0.26
380.15 400.59 4.91
351.43 371.92 4.80
353.46 373.47 4.49
346.60 377.52 4.53
401.81 421.37 4.65
571
AZELASTlNE EFRCACY IN LONG-TERM MANAGEMENT OF ASTHMA
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Fig. 1. Mean FEV, for the zero hour measurement at each pulmonary funct ion test (least squares line) during treatment for 12wk. - - = 8 mg azelastine; ~ . - = 6 mg azelastine ; _t - = 4 mg azelastine ; . ... = 2 mg azelastine; - = placebo; t = pulmonary function test.
12 wk of treatment with azelastine or placebo is shown in figure 2. The improvement in FEV. when measured 12 h after the last dose of study medication was statistically significant for all azelastine treatments (p < 0.05), but not for placebo when compared with their respective baseline values. Bronchodilation occurred after the first dose of azelastine. The mean FEV. for each treatment group during the initial 8-h pulmonary function testing after administration of the first oral dose of blinded medication is shown in figure 3. The azelastine 4 mg group achieved statistically significant improvement in FEV., which was begun 2 h after dosing (p = 0.029) and was generally sustained at Hours 4,6,7, and 8. Similar improvement in FEF 2 5 - 75 for the azelastine 4 mg group was observed beginning 3 h after dosing (p = 0.052) and sustained at Hours 4, 6, 7, and 8. Only the azelastine 4 mg group achieved statistically significant and maintained clinically relevant improvement in the pulmonary function measurements throughout the course of the 8-h testing period.
cation was administered, and pulmonary function testing was performed for as long as 8 hr. Subsequent pulmonary function testing was performed after I, 4, 8, and 12 wk of therapy. On these test days, baseline pulmonary function was performed after withholding concomitant medication for at least 8 h and test medication for 12 h. The baseline (zero Backup Medications hour) least squares lines for FEV. for Subjects wereinstructed to use A/butero/. each treatment group across the 12 wk of active drug therapy are demonstrated their backup medication to maintain in figure 1.The slope of the line for FEV. their asthma and/or rhinitis at a tolerafor the azelastine 6 mg treatment group ble level. The azelastine 4 mg group was statistically different from that of achieved statistically significant (p = placebo treatment group (p = 0.043).Al- 0.034) reduction in the use of aerosolthough the slopes of the lines for FEV. ized albuterol during the first month of for other dosage levels were not statis- therapy. These reductions were sustained tically different from placebo therapy, throughout the remainder of the trial the slope of the line for FEV. of the (p = 0.011). The azelastine 2 mg group azelastine 4 mg showed a trend similar also achieved statistically significant reduction after 1 month of therapy, but the to that of the 6 mg group. The actual increase in zero hour FEV. magnitude of the reductions was more (12 h after last study medication) after variable during subsequent weeks. The JOO
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Fig. 3. Mean FE'/, over 8 h after the first dose. -6- = 8 mg azelastine; -0- = 6 mg azelastine; - - . - - = 4 mg azelastine; .. 6 . . = 2 mg azelastine ; -0- = placebo. 'p .. 0.05.
azelastine 6 mg group also achieved a statistically significant (p = 0.004 and p = 0.(06) reduction during the second and third month of therapy. The overall change in aerosolized albuterol use is summarized in figure 4. In this figure, one unit is equivalent to one puff. The results of the azelastine 2, 4, and 6 mg groups, but not the azelastine 8 mg group, were statistically significant when use over the 3 months of the study was compared with that of the placebo group (p = 0.006, p = 0.002, p = 0.0006, respectively). Theophylline. When subjects were not controlled with aerosolized albuterol, short-acting theophylline was used as the next back-up medication. The azelastine 4 mg group showed a significant reduction in theophylline use during the first month and a statistically significant reduction during the third month (p = 0.018)of treatment (figure 5). In this figure, one unit is equivalent to 200 mg short-acting theophylline.Over the course of study treatment, the azelastine 4 mg
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Fig. 2. Improvement in zero hour FEV, after 12 wk of treatment. I'ZZZll = 8 mg azelast ine; IilllJ = 6 mg azelastine; _ = 4 mg azelastine; ~ = 2 mg azelastine; ~ = placebo. 'p ~ 0.05 (change from baseline).
Fig. 4. Average daily use of a1buterol aerosol as a backup medication during treatment (one unit equivalent 10one pUff). 1'ZZZll = 8 mg azelastine ; ~ = 6mgazelastine;_ = 4mgazelastine; Illll5ll = 2 mg azelastine; ~ = placebo. 'p = .. 0.05 (all comparisons versus placebo).
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Weeks of Therapy
Overall
572
nNKELMAN, BUCHOLTZ, KEMp, KOEPKE, REPSHER, SPECTOR, STORMS, AND VAN AS
420 410
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Fig. 5. Averagedailyuseof short-actingtheophylline (oneunit equivalentto 200 mg short-acting theophylline).17lzz::l = 8 mg azelastine; IffiD = 6 = 4 mg azelastine; c:=J = mg azelastine; _ 2 mg azelastine; c:=J = placebo. 'p = .;; 0.05 (all comparisons versus placebo).
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Overall
Weeks of Therapy
group achieved statistically significant (p = 0.036) reduction in the use of theophylline.The 6 mg group showeda trend toward statistical significance for overall use (P = 0.09). Decongestant tablets. All azelastine dosage groups showed numerically greater decreases than did placebo in the daily number of tablets through 12wk of therapy (figure 6). In this figure, one unit equals one 30-mg pseudoephedrine. Although pseudoephedrine use in most azelastine-treated groups was 20 to 35070 less than that of the placebo-treated group, these differences were not statistically significant.
Total Symptom Scores Total symptom scores did not change in any of the azelastine groups even though the use of aerosolized albuterol and immediate release theophylline was statistically lessthan that of the placebo-treated group. In contrast, clinical symptomatic stability in the placebo group was maintained through increased use ofantiasthma therapeutic agents. Change in Morning and Evening Peak Expiratory Flow The mean PEF for each treatment group
averaged over the number of days between office visits for the morning and evening measurements, respectively, are shown in figures 7 and 8. Morning mean PEF for the azelastine 6 mg group showed a trend toward statistical improvement after 10 and 12 wk of therapy, but it did not reach statistical significance (P = 0.11). A similar trend was shown for azelastine 4 mg after 12 wk (P = 0.06). For the evening PEF measurements, the difference from placebo was statistically significant for the azelastine 4 mg dosage (p = 0.02) after 1 and 12 wk of treatment. A similar trend was observed for the azelastine 8 mg dosage, but it did not achieve statistical significance (p = 0.052). For the azelastine 4 mg group, the PEF was higher and achieved statistical significance after 12 wk (p = 0.017).
Safety No serious or unexpected adverse experiences were noted (table 2). The most frequently reported adverse experiences weredrowsiness (somnolence), alteration in taste (metallic or bitter taste), dry mouth, and headache. Drowsiness was reported at frequencies of 6.0 to 16.9% among the azelastine-treated groups . In
. Rg . 7. Pre-A.M. dosepeak flow ratesduring 12wk of treatment. -D.- = 8 mg azelastine; -0- = 6 mg azelastine; --.-- = 4 mg azelastine; . . 0 . . = 2 mg azelastine; -0- = placebo.
comparison, 2% of the placebo-treated group experienced somnolence. Somnolence in the azelastine 2, 6, and 8 mg groups, but not in the azelastine 4 mg group, was statistically different from that in the placebo group (p < 0.05). The incidence of reported drowsiness decreased during continued therapy during the course of the trial. Altered taste occurred at frequencies of 30.1 to 51.9% among azelastine-treated groups. In comparison, none of the placebo group experienced bitter or altered taste. All azelastine-treated groups werestatistically different when compared with placebo therapy (p < 0.001) for this adverse experience. The incidence of complaints of altered taste also decreased during continued therapy. Dry mouth occurred at frequency of 3.8 to 6.1% among azelastine groups . The azelastine groups were not statistically significantly different from the placebo group. Headache occurred at frequencies comparable to the placebo-treated groups.
450 440
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