Antiallergika ■ Antiasthmatika • Antitussiva • Bronchodilatatoren •
`Bronchosekretolytika • Mukolytika
`
`ArzneimForschDrugRe
`
`Antiallergic Drugs ■ Antiasthmatics • Antitussives • Bronchodilators •
`Bronchosecretogogues • Mucolytics
`
`Comparative Efficacy and Safety
`of Azelastine and Levocabastine
`Nasal Sprays in Patients with Seasonal
`Allergic Rhinitis
`
`Norbert Falser3, Wolfgang Woberb 1, Volker W. Rahlfsc, and Martin Baehred
`
`Ear Nose Throat Specialist Practice3, Innsbruck (Austria), Institute for Medical Research13, Munich (Germany),
`idv-Datenanalyse und Versuchsplanungc, Gauting/Munich (Germany), and ASTA Medicad,
`Frankfurt/Main (Germany)
`
`Summary
`
`The aim o f the present investigation was
`to compare the efficacy and tolerability
`o f azelastine (CAS 58581-89-8) (1.12 mg/
`day) and levocabastine (CAS 79547-78-7)
`(0.4 mg/day) nasal spray administered
`twice daily to patients with seasonal aller­
`gic rhinitis. A total o f 180 patients parti­
`cipated in a 4-week, double-blind, paral­
`lel group (n = 90 each) study. Symptom
`severity o f nasal, ocular and other symp­
`toms were recorded, out o f which a total
`symptom score (TSS) was calculated.
`Physicians assessed symptoms at base­
`line and at days 7, 14, and 28, patients
`and physicians evaluated the efficacy and
`tolerability. After 4 weeks o f treatment
`with azelastine the mean overall TSS was
`reduced from a baseline score o f 18.7 to
`4.2, after levocabastine from 17.8 to 5.9.
`Patients m orning scores for treatment
`days 1 to 28 gave a mean total score o f
`
`Zusammenfassung
`
`212.4 for the azelastine group and 230.6
`for the levocabastine group; the equiva­
`lent evening scores yielded a mean total
`score o f 115.5 and 175.6 respectively.
`Global efficacy was judged by physicians
`as either ’very good’ or ’good’ for 90 % o f
`azelastine patients and for 74 % o f the le­
`vocabastine group; 92 % o f azelastine
`patients and 76 % o f levocabastine
`patients judged treatment to be either
`’very good’ or ’good’. No serious adverse
`events were reported, all adverse events
`were related to nasal symptoms. Both
`azelastine and levocabastine adminis­
`tered twice daily as a nasal spray provide
`effective and well tolerated symptomatic
`treatment o f seasonal allergic rhinitis. A z­
`elastine, however, was statistically super­
`ior in efficacy as well as in safety (PWei-
`Lachin < 0.0001, com bined results).
`
`Key words
`
`■ Azelastine, clinical study,
`nasal symptom score, safety
`■ CAS 58581-89-8
`■ CAS 79547-78-7
`■ Levocabastine, clinical study,
`nasal symptom score, safety
`■ Rhinitis, seasonal allergic
`
`Arzneim.-Forsch./Drug Res.
`51 (I), 387-393 (2001)
`
`Vergleich der Wirksamkeit und Vertrag-
`lichkeit von Azelastin- und Levocabastin-
`Nasenspray bei Patienten mit saisonaler
`allergischer Rhinitis
`
`Ziel der vorliegenden Untersuchung
`war es, die Wirksamkeit und Vertraglich-
`
`keit von Azelastin (CAS 58581-89-8) (1,12
`mg/Tag) und Levocabastin (CAS 79547-
`78-7) (0,4 mg/Tag), jeweils in Form eines
`Nasensprays 2mal taglich appliziert, bei
`Patienten mit saisonaler allergischer Rhi­
`nitis zu vergleichen. Insgesamt 180 Pa­
`tienten nahmen an einer 4-wochigen,
`
`Exhibit 1015
`IPR2017-00807
`ARGENTUM
`
`Arzneim .-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`Falser et al. - Azelastine and levocabastine
`
`000001
`
`

`

`Antiallergika • Antiasthm atika • Antitussiva ■ Bronchodilatatoren • Bronchosekretolytika ■ Mukolytika
`
`doppelblinden Vergleichsstudie (parallele
`Gruppen zu je 90 Patienten) teil. ErfaRt
`wurde der Schweregrad von nasalen, oku-
`laren und anderen Symptomen, aus de-
`nen ein Symptomen-Score (Total Sym­
`ptom Score, TSS) errechnet wurde. Von
`den Priifarzten wurden an den Tagen 0,
`7, 14 und 28 die Symptome, von Patien­
`ten und Arzten die Wirksamkeit und Ver-
`traglichkeit beurteilt. Nach der 4-wochi-
`gen Therapie mit Azelastin war der TSS
`im Mittei von urspriingiich 18,7 auf 4,2
`gefallen, unter der Levocabastin-Behand-
`lung von 17,8 auf 5,9. Die morgendlichen
`
`Patienten-Werte liber die gesamten 28
`Tage der Studie ergaben einen mittleren
`Score von 212,4 fur die Azelastin-Gruppe
`respektive 230,6 fur die Levocabastin-
`Gruppe; die entsprechenden Abend-Sco-
`res erreichten mittlere Werte von 115,5
`bzw. 175,6. Die globale Wirksamkeit
`wurde von den Priifarzten entweder mit
`„sehr gut" oder „gut“ bei 90 % der Azela­
`stin- und bei 74 % der Levocabastin-Pa-
`tienten beurteilt; 92 % der Azelastin-Pa-
`tienten und 76 % der Levocabastin-Pa-
`tienten beurteilten ihre jeweilige Thera­
`pie mit „sehr gut" oder „gut“ . Schwerwie-
`
`gende unerwiinschte Ereignisse wurden
`nicht berichtet, alle unerwiinschten Er­
`eignisse bezogen sich auf nasale Sym­
`ptome. Sowohl Azelastin als auch Levoca-
`bastin, jeweils zweim al taglich als Nasen-
`spray appliziert, stellen eine wirksame
`und gut vertragliche Behandlung der sai-
`sonalen allergischen Rhinitis dar. Dabei
`zeigte sich Azelastin in bezug auf W irk­
`samkeit und Vertraglichkeit statistisch
`iiberlegen (PWei-Lachin < 0.0001, com ­
`bined results).
`
`1. Introduction
`Azelastine (CAS 58581-89-8) being an antiallergic agent
`has potent activity at a number of sites associated with
`the allergic reaction; these include potent and selective
`H! receptor antagonism [1], blockade of histamine re­
`lease from mast cells [2], and antagonism of leukotriene
`and platelet activating factor [3]. These activities com ­
`bine to make azelastine an extremely effective treat­
`ment in patients with seasonal and perennial allergic
`rhinitis.
`The efficacy of azelastine nasal spray in controlling
`the symptoms associated with seasonal allergic rhinitis
`is well established and has been confirmed in a series
`of large controlled clinical trials comparing azelastine
`0.56 mg/day with oral agents such as terfenadine 120
`mg/day [4] and cetirizine 10 mg/day [5].
`In addition, these studies confirmed the favourable
`safety profile of azelastine. Sedation, commonly associ­
`ated with first generation antihistamines, is not evident
`with nasally administered azelastine, even in children.
`Levocabastine (CAS 79547-78-7) is a selective LL re­
`ceptor antagonist which is marketed in many European
`countries and is waiting for marketing approval in the
`United States. Levocabastine can be administered by
`nasal spray and provides a rapid onset of action [6].
`Previous clinical studies have demonstrated that levo­
`cabastine nasal spray administered twice daily is an ef­
`fective and well tolerated treatment of ragweed-induced
`seasonal allergic rhinitis [7].
`The present investigation was performed as a con­
`trolled double blind randomized study in order to de­
`termine the equivalence or superiority of azelastine in
`efficacy and tolerability in comparison to levocabastine
`in the treatment of seasonal allergic rhinitis [8].
`
`2. Patients and methods
`2.1. Patients
`A total of 180 outpatients were recruited at two ENT (Ear Nose
`Throat) centres in Austria during the 1996 hay fever season.
`
`Consenting male and female patients were to be between 18
`and 65 years of age and were to be suffering from seasonal
`allergic rhinitis, as confirmed by a positive prick-test (vs. hist­
`amine-positive control 10 HEP). Prior to admission to the
`study, patients underwent an allergy test, physical examina­
`tion, and rhinoscopy.
`The symptom rating scale (total symptom score, or TSS) on
`entry to the study was to be at least 8 out of a maximum of 30.
`Patients excluded from the study were those with asthma in
`need of treatment, those with non-allergic rhinitis, perennial
`allergic rhinitis, obstructive nasal adenoids or acute infection
`of the upper respiratory tract. Prior to the start of the study
`patients were not to have received anti-allergic therapy or psy-
`chopharmacologic agents for 14 days, topical steroids for 15
`days and systemic corticosteroids for 4 weeks.
`The following concomitant medications were not permitted
`during the trial period: oral or topical steroids, antihistamines,
`sympathicomimetics, selfmedication with any drug influencing
`nasal respiration or any drug which might influence the judge­
`ment about the efficacy or safety of the test compounds. After
`verbal instruction, a written explanation of the study was pro­
`vided to each patient and informed written consent was ob­
`tained. Patients were allocated to treatment groups by a prede­
`termined, computer-generated blockrandom code.
`The severity of symptoms was documented by each patient
`in diary cards each morning before drug application and each
`evening 15 min after drug application by means of a four-point
`scale (0 = not present; 1 = mild, symptoms noticeable; 2 = mod­
`erate, detrimental to daily activities; 3 = severe, permanent de­
`traction). The following ten symptoms were assessed:
`Nasal symptoms: sneezing
`itching of the nose
`rhinorrhoea
`stuffy nose
`disorded or defective sense of smell
`Ocular symptoms itching of eyes
`lacrimation
`photophobia
`itching of the throat
`cough.
`Patients returned to the clinic for assessment after 7, 14,
`and 28 days. At the end of the study patients and physicians
`separately judged both the efficacy and the tolerability of the
`treatment according to a five-point scale (1 = very good; 2 =
`good; 3 = satisfactory; 4 = insufficient; 5 = not assessable).
`
`Other symptoms
`
`Falser et al. - Azelastine and levocabastine
`
`Arzneim .-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
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`
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`Antiallergic Drugs ■ Antiasthm atics ■ Antitussives • Bronchodilators • Bronchosecretogogues • Mucolytics
`
`As to safety and tolerability patients were questioned about
`the occurrence of any adverse events at each visit. Tolerance
`was rated as either 'very good’, ’good’, ’satisfacory’, or ’insuffici­
`ent’.
`
`2.2. Methods
`2.2.1. Study design
`The parallel group randomized, double-blind, bicentric study
`compared azelastine nasal spray (azelastine) with levocabas­
`tine nasal spray (levocabastine). The attending physician, the
`principal investigator, the study coordinator and the statisti­
`cian were blinded until the code was broken after double data
`entry. The study was conducted in compliance with the ICH/
`GCP guidelines and the Declaration of Helsinki and its revi­
`sions (Hong Kong 1989). Written approval of the International
`Freiburger Ethical Committee was obtained prior to the start
`of the study.
`
`2.2.2. Treatment
`Study medications were labelled according to the German Drug
`Law. Azelastine (batch number: 015042; supplied by ASTA
`Medica11) was administered using a nasal spray which deliv­
`ered 0.14 mg/actuation. Levocabastine nasal spray (purchased
`in a local pharmacy) delivered 0.05 mg/actuation. Patients
`were requested to administer 2 puffs of study drug into each
`nostril in the morning and evening. Thus, the daily dose of
`levocabastine was 0.4 mg and that of azelastine was 1.12 mg.
`Patients were asked to return used containers so that an assess­
`ment of compliance could be made.
`
`2.2.3. Primary end points
`Five primary efficacy variables were defined in the protocol:
`the nasal symptom sum-score calculated out of 3 nasal symp­
`toms (sneezing, itching of the nose, and rhinorrhea) as well as
`the sum of all 10 symptom scores (total symptom score, TSS)
`as recorded in the patient diaries, each at morning and even­
`ing. In addition, the global judgement of efficacy by the investi­
`gator was also a primary variable.
`
`2.2.4. Secondary end points
`Secondary efficacy criteria were changes of the individual
`symptoms as recorded both in the patient diaries and by the
`investigators on the case report forms from baseline through
`days 7, 14, and 28. Also included were changes in rhinoscopic
`findings (anterior rhinoscopy) from baseline through days 7,
`14, and 28, as manifested by macroscopic assessment of in­
`flammation, edema and secretion (0 = absent, 1 = slight, 2 =
`moderate, 3 = severe).
`
`2.2.5. Sample size determination and statistical
`evaluation
`The hypothesis to be tested was the one-sided test for equiva­
`lence within the framework of the Wilcoxon-Mann-Whitney
`test. The sample size calculation was based on a test for equi­
`valence (one-sided) with the lower bound of the equivalence
`region defined as MW = 0.36, a medium-sized difference of two
`
`11 ASTA Medica AG, Frankfurt/Main (Germany).
`
`distributions. Alpha was defined as 0.025 (one-sided), beta as
`0.1. The resulting sample size was N1 = N2 = 91, thus a total of
`180 seemed to be an adequate number.
`All five primary efficacy variables, the two indices for the
`time periods and the global judgement of the efficacy, were
`planned to be tested as an ensemble with the highly efficient
`directional test (test for stochastic ordered alternatives) of the
`generalized multivariate Wilcoxon-Mann-Whitney Test of Wei
`and Lachin [8]. A one-sided test for non-inferiority was per­
`formed. Equivalence was tested for an equivalence bound of
`MW = 0.4. In addition the degree of equivalence was described
`by means of a one-sided confidence interval (LB-CI) [9], If
`equivalence was accepted a test for superiority was to be per­
`formed in addition, with the same alpha in a confirmatory
`manner according to the closed testing principle [10]. The
`Mann-Whitney estimator for the so called stochastic superior­
`ity of the test group in comparison to the reference group is a
`useful statistic with a range from 0 to 1 (0.5 indicating equiva­
`lence, > 0.5 indicating superiority of azelastine, < 0.5 indicating
`inferiority of azelastine). It denotes the probability, that a ran­
`domly selected patient of the test group achieves a better result
`than a randomly selected patient of the reference group. For
`all Mann-Whitney estimators the one sided 95 % confidence
`intervals have been calculated. Demographic and historical
`data were summarized for descriptive purposes and analysed
`for differences by means of the Mann-Whitney statistic and its
`confidence intervals.
`The first line analysis of efficacy was the intention-to-treat
`(ITT) data set.
`
`3. Results
`3.1. Patients
`Validated data were obtained for a total of 180 patients
`(90 each group). The ITT data set comprised n = 179
`patients, the safety data set n = 180 patients. The two
`treatment groups were comparable with respect to the
`following demographic parameters: age, weight, height,
`and sex; no significant differences were found for any
`of these parameters. Demographic details and baseline
`characteristics are given in Table 1.
`
`Table 1: Patients demographic and baseline characteristics.
`
`Sex
`male
`female
`Age (years
`mean
`median
`Weight (kg)
`mean
`median
`Hieght (cm)
`mean
`median
`Duration of acute phase (days)
`mean
`median
`
`Azelastine
`
`Levocabastine
`
`64 (27 %)
`25 (28 %)
`
`57 (63 %)
`33 (37 %)
`
`30
`25
`
`79
`81
`
`178
`179
`
`12
`10
`
`29
`25
`
`77
`80
`
`176
`179
`
`12
`10
`
`Arzneim .-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`Falser et al. - Azelastine and levocabastine
`
`000003
`
`

`

`Antiallergika • Antiasthm atika • Antitussiva ■ Bronchodilatatoren • Bronchosekretolytika • Mukolytika
`
`Fig. 1: Disposition o f patients throughout the study.
`
`Compliance with the medication regimen was asses­
`sed by checking the returned medication bottles. All
`patients were considered compliant (data were incom­
`plete for only 2 patients). One hundred and seventy-
`seven of the 180 patients completed the 4-week treat­
`ment period according to the study protocol. Three
`patients (all receiving azelastine) did not complete the
`treatment period. This was due to early recovery in one
`patient, lack of efficacy in another, and a third patient
`was lost to follow-up. Only one patient was excluded
`from the intention-to-treat efficacy analysis as there
`were no data for the primary criteria for visit 2. There
`were no other major protocol violations. Disposition of
`patients is shown in Fig. 1. All patients who received at
`least one dose o f study medication were included in the
`safety analysis.
`The first patient was included in the study on April
`20, 1996 and the last visit of the last patient took place
`on August 7, 1996. During this time period airborne pol­
`len counts were regularly recorded [11]. Most widely
`found pollen during the the study-period were Betula,
`Platanus, Quercus, Pinus, Poaceae, and Urtica.
`
`3.2. Efficacy
`3.2.1. Primary end points
`With regard to baseline pre-treatment efficacy criteria,
`the azelastine group showed more severe symptoms (p=
`0.0441) compared with the levocabastine group. In both
`groups, there was a marked reduction in TSS as re­
`corded at the visits. At all three follow-up visits, the re­
`duction of TSS is more pronounced in the azelastine
`group than in the levocabastine group (Fig. 2). After 4
`weeks of treatment with azelastine, the mean overall
`TSS was reduced from a baseline score of 18.7 to 4.2 at
`the final visit. In the levocabastine group the mean TSS
`was reduced from a baseline score of 17.8 to 5.9 at the
`final visit.
`
`Fig. 2: Total Symptom Score (TSS) (means and standard devia­
`tions) at clinical assessments (N = 179).
`
`When considering morning diary card symptoms re­
`corded by patients from treatment day 1 to 28, there
`was a mean TSS o f 212.4 for the azelastine group and
`230.6 for the levocabastine group. For the equivalent
`evening scores, there was a mean total score of 115.5
`for the azelastine group and 175.6 for the levocabastine
`group (Fig 3). Thus, the evening patient diary data
`showed lower total scores (and hence milder symp­
`toms) in the azelastine group.
`The nasal symptom sum-score was defined as the
`sum o f three symptoms: sneezing, itching of the nose,
`and rhinorrhoea. Fig. 4. shows a mean nasal symptom
`score for each of the clinical visits. In both treatment
`groups, the nasal symptom sum-score initially was at
`a moderate to severe level with a mean of 7.3 for the
`azelastine group and 7.1 for the levocabastine group.
`After 4 weeks of treatment with azelastine, the nasal
`symptom sum-score was reduced by a mean of 6.1 to
`1.2; in the levocabastine group the mean nasal symp­
`tom score was reduced to 2.1, equivalent to a reduction
`by a mean o f 5.0.
`Efficacy was judged globally by physicians at the end
`of the study as either 'very good’ or ’good’ in 80/89
`
`•— • Azelastine (n=89)
`■—• Levocabastine (n=90)
`
`300
`
`'CO
`S' 250
`"D
`CO
`— 200
`V/J<D
`§ 150
`
`E 100
`
`50
`
`0 ■
`
`all symptoms all symptoms nasal symptoms nasal symptoms
`at morning
`at evening
`at morning
`at evening
`
`Fig. 3: Total Symptom Score (TSS) and nasal symptom sum-score
`(means and standard deviations) over 4 weeks (N = 179).
`
`Falser et al. - Azelastine and levocabastine
`
`Arzneim .-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`000004
`
`

`

`Antiallergic Drugs • Antiasthm atics ■ Antitussives ■ Bronchodilators ■ Bronchosecretogogues ■ Mucolytics
`
`The results of anterior rhinoscopy showed greater
`improvements from baseline with azelastine for all
`three criteria (inflammation, edema, nasal secretion).
`The lower bounds of the univariate one-sided 95 %-
`confidence intervals were above the 0.5-line of equiva­
`lence for all three single criteria. The most responsive
`criteria was nasal secretion (MW > 0.64).
`
`3.2.3. Drug tolerability
`Adverse events were reported by two patients in the az­
`elastine group and by 20 patients in the levocabastine
`group. All events were related to nasal symptoms. Sev­
`enty-eight percent o f levocabastine adverse events were
`deterioration of nasal symptoms, the remainder were
`stuffy nose. Azelastine events were cough at night, itch­
`ing, and sneezing attacks after administration. All but
`two of the adverse events (one in each group) were clas­
`sified as severe. None of the adverse events was con­
`sidered serious.
`Tolerance was rated as either ’very good’ or ’good’ by
`87/89 (98 %) of azelastine patients and by 63/90 (70 %)
`of levocabastine patients. ’Insufficient’ tolerance was
`reported by one patient in the azelastine group and by
`17 patients in the Levocabastine group. Investigators
`rated tolerance as either ’very good’ or ’good’ in 88/89
`(99 %) of cases in the azelastine group and in 70/90
`(78 %) of cases in the levocabastine group. There was a
`clear superiority in the azelastine group with regard to
`judgements of tolerance by patients and investigators
`(p < 0001).
`
`3.2.4. Benefit risk analysis
`In addition to the analyses of the primary and second­
`ary as well as the safety parameters a special benefit
`risk analysis has been performed using the global judg­
`ments of efficacy and tolerance by the patient and the
`investigator as criteria for ’benefit’ and ’risk’; all test re­
`sults have to be interpreted in an explorative manner.
`This analysis shows a clear superiority of azelastine
`with respect to the four criteria mentioned and to all
`criteria combined. Fig. 5 shows Mann-Whitney statistics
`and confidence intervals for this benefit-risk analysis.
`
`4. Discussion
`The results indicate that both azelastine and levocabas­
`tine administered nasally provide effective relief of the
`symptoms of seasonal allergic rhinitis as demonstrated
`by significant reductions in symptom scores recorded
`on patient diary cards and by physicians at clinic as­
`sessments. When comparing efficacy, i.e. symptom
`scores between the two treatment groups, consistent
`advantages were seen for the azelastine group which
`obtained a significantiy greater relief of symptoms dur­
`ing the course of the study.
`This is particularly true for the total symptom score
`as well as for the nasal sum-score: patients in the azela­
`stine group were slightly more severely diseased, i.e.
`
`Fig. 4: Nasal Symptom Sum-Score (means and standard devia­
`tions) at clinical assessments (N = 179).
`
`(90 %) of azelastine patients and as either ’very good’
`or ’good’ in 67/90 (74 %) patients in the levocabastine
`group.
`
`3.2.1.1. Confirmatory analysis of primary end points
`Equivalence (’equal’ or ’better’) of the two treatments
`with respect to the combined criteria of efficacy (TSS
`and nasal sum-score morning and evening as well as
`global efficacy judgement by the investigator) was con­
`firmed: the Mann-Whitney estimator being 0.6180 and
`the lower bound of the confidence interval of the
`Mann-Whitney estimator LB-CI being 0.5679, well
`above the critical level of 0.4. Since equivalence was ac­
`cepted a test for superiority o f azelastine with regard to
`the combined efficacy criteria was performed. This test
`demonstrated a statistically significant result (p < 0.0001).
`When the individual efficacy criteria were tested for
`superiority, the Mann-Whitney estimators denoted a
`superiority of azelastine for 3 of the 5 criteria, namely:
`The TSS recorded in the evening (p < 0.0001) and the
`nasal symptom sum-score recorded in the evening (p <
`0.0001), the lower bounds o f the confidence interval LB-
`CI being 0.6385 and 0.6214, respectively, again well
`above the line of equivalence of 0.5. The global judge­
`ment o f efficacy by the investigator showed also signifi­
`cant group differences (p = 0.0007, LB-CI = 0.5574).
`
`3.2.2. Secondary end points
`When looking at the reduction in scores for individual
`symptoms, it was seen that the morning values of the
`azelastine group showed superiority (MW > 0.5); the
`most responsive symptoms with regard to change from
`baseline at the end of the study were lacrimation,
`rhinorrhoea, and itching of the nose. For the evening
`values, azelastine showed superiority for seven symp­
`toms (MW = 0.5622). The most responsive symptoms
`were itching of the nose, rhinorrhoea, and disordered
`or defective sense of smell.
`Efficacy was judged globally by patients at the end
`of the study as either ’very good’ or ’good’ in 92 % of
`azelastine patients and as either ’very good’ or ’good’
`in 76 % of levocabastine patients.
`
`Arzneim .-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`Falser et al. - Azelastine and levocabastine
`
`000005
`
`

`

`Antiallergika • Antiasthm atika • Antitussiva • Bronchodilatatoren ■ Bronchosekretolytika ■ Mukolytika
`
`1.0
`
`0.9
`
`0-8
`
`0.6
`
`0 5
`
`0.4
`
`0.3
`
`0.1
`
`0.0
`
`* < 0.0001 (Combined Results, Directional Test for Difference, one-sided, alpha=0.05)
`
`superiority of Azelastine
`
`P = 0.0007
`
`P < 0.0001
`
`P < 0.0001
`
`1
`
`P < 0.0001
`
`L
`
`^
`
`P < 0.0001
`
`^
`
`inferiority of Azelastine
`
`G.eff.pat
`
`G.tol.inv
`
`G.tol.pat
`
`Combined Result
`
`G.eff.inv = global judgement of efficacy by investigator
`G.eff.pat = global judgement of efficacy by patient
`G.tol.inv = global judgement of tolerance by investigator
`G.tol.pat = global judgement of tolerance by patient
`
`1.0
`
`0.9
`
`0 8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.3
`
`0.1
`
`0.0
`
`Fig. 5: Mann-Whitney statistics and confidence intervals (95 %-CI, one-sided) for the benefit risk analysis, univariate results (Wilcoxon
`tests) and combined result (Wei-Lachin); Mann-Whitney estimator: 0.29 / 0.71 = large difference, 0.36 / 0.64 = medium sized difference,
`0.44 / 0.56 = small difference, 0.5 = equal (N = 179).
`
`had higher symptom scores, than those in the levocaba­
`stine group; and yet, after 4 weeks treatment the symp­
`tom scores were lower after azelastine.
`Symptom relief was particularly evident after the
`daily evening administration of azelastine; patients
`were asked to make this recording into their diary cards
`just 15 minutes after administration o f treatment. Thus,
`the results suggest an extremely rapid onset of azelas­
`tine action as reported in a previous study [12]. The impor­
`tance of immediate symptom relief cannot be over­
`estimated in seasonal allergic rhinitis where treatments
`are often used by patients on a demand schedule.
`All adverse events were related to nasal symptoms,
`there were no systemic events, and no serious adverse
`events. Concerning the trial medications, azelastine was
`better tolerated than levocabastine expressed by a ten­
`fold lower adverse events rate. This was confirmed by
`the judgments of tolerance by both patients and inves­
`tigators which clearly indicate a superiority of azelas­
`tine.
`No reports of sedation were obtained for either drug.
`First generation antihistamines have been associated
`since long with CNS-related adverse events, particularly
`with sedation, which is probably due to the ability of
`antihistamines to cross the blood-brain barrier [13]. In
`animal models azelastine has shown to have only poor
`access to the CNS [14,15]. In clinical studies with azela­
`stine sedation was slightly more frequently reported
`than after placebo [16-19], whereas in other trials sed­
`ation was not reported at all [20, 21]. On the other hand,
`somnolence and fatigue have been reported as two of
`the most commonly occurring adverse events with in­
`tranasal levocabastine [6].
`Surprisingly enough not a single case of taste dis­
`turbance was reported, despite this is one of the most
`frequently reported adverse events after azelastine [12,
`16-18, 22, 23]. Since this taste disturbance, often re­
`
`corded as ’bitter taste’, is usually mild and transient [16,
`18], the patients in our study most likely did not men­
`tion such an event because they had been informed
`about this potential side effect upfront.
`Both drugs belong to a class o f highly potent H, anti­
`histamines which have recently been developed for
`local administration as a viable alternative to the oral
`antihistamines. The long half life of these drugs permits
`twice daily dosing and local application facilitates a
`rapid onset of action [24]. Previous studies have shown
`both drugs to be as effective as other second-generation
`oral antihistamines [24],
`A previous study in seasonal allergic rhinitis has also
`compared azelastine and levocabastine [25], however,
`the dose of azelastine was half that o f the current study
`(0.56 mg/day). The treatment period was 7 days only,
`and the symptom scores showed similar decreases for
`the two drugs. However, the efficacy results differed
`from those of the present study in that no significant
`advantages were reported for the azelastine group. This
`could have been due to the lower dose of azelastine
`used and also might have been influenced by the
`shorter treatment period [25].
`In the same study levocabastine showed a better tol­
`erance with an 11 % incidence of adverse events com­
`pared to an incidence of 19 % in the azelastine group.
`By comparison, in the current study the incidence of
`adverse events was lower for azelastine than for levoca­
`bastine despite the fact that the dose of azelastine was
`twice that in the study by Mosges et al [25]. This is sup­
`posedly due to the fact that bitter taste has not been
`reported by the patients, thus resulting in the given low
`overall incidence of adverse events after azelastine.
`The significance ot the reported results might have
`been even increased by incorporating a placebo-group
`in the study design; however, we felt such a procedure
`
`Falser et al. - Azelastine and levocabastine
`
`Arzneim .-Forsch./Drug Res. 51 (1), 387-393 (2001)
`© ECV • Editio Cantor Verlag, Aulendorf (Germany)
`
`000006
`
`

`

`Antiallergic Drugs • Antiasthm atics • Antitussives • Bronchodilators • Bronchosecretogogues Mucolytics
`
`inappropriate and unethical towards our patients, par­
`ticularly since in a couple of earlier studies azelastine
`showed superiority over placebo [16-19, 26].
`In conclusion, this study demonstrates that azelas­
`tine, administered twice daily as a nasal spray, was as
`effective as levocabastine in treating the symptoms of
`seasonal allergic rhinitis. Both drugs can be recom­
`mended for the topical treatment of seasonal allergic
`rhinitis, especially since the drug dosages are low and
`sedative effects as a rule are not seen which is impor­
`tant for the alertness of school children, car drivers and
`operators of machinery.
`Overall, the efficacy and tolerance reported by
`patients favoured azelastine. The reduced potential for
`sedation, combined with the rapid onset of action and
`minimal overall dosage of the nasal spray may be con­
`sidered an advantage over other antihistamines, par­
`ticularly first-generation compounds, and warrants fur­
`ther investigations with azelastine.
`
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