PHARMACY LIBRARY
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`en Arzneimittel
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`&5 ~ Forschung
`b b.O Drug Research
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`Eel
`Q.)
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`t:::!
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`\
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`s_p_e_c_ial_ S_e_c_ti_o_n _______________ _
`Biotechnology in Drug Research
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`■
`
`5/2001
`
`UN10~~~CY LIBRARY
`.
`OF WISCONSIN
`JUN O 6 2001
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`Madison, WI 53705
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`Vol. 51 (I) • No. 5 pages 383-450 (2001)
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`

`

`■ Herz-Kreislauf-Therapeutika · Kardiaka ·
`Koronar-Therapeuti ka
`■ Cardiac Drugs · Cardiac Stimulants •
`Coronary Drugs
`
`E 383
`
`Uchida, T., Toki, Y., Fukami, Y., Kamiya, H.,
`Matsui, H., Okumura, K., Ito T., Hayakawa, T.
`Relative Bedeutung von Kalzium-aktivierten
`Kalium-Kanfilen fiir die Nipradilol-induzierte
`Erschlaffung der Aorta bei Ratten
`Relative Importance of Calcium-activated
`Potassium Channels in Nipradilol-induced Aortic
`Relaxation in Rats
`
`■ Antiallergika • Antiasthmatika • Antitussiva •
`Bronchodilatatoren • Bronchosekretolytika • Mukolytika
`■ Antiallergic Drugs • Antiasthmatics • Antitussives •
`Bronchodilators • Bronchosecretogogues • Mucolytics
`
`■ Antiemetika · Magen-Darm-Therapeutika • Urologika
`■ Antiemetics · Gastrointestinal Drugs · Urologic Drugs
`
`E 394
`
`Dalrymple, P. D., Beeby, T. L., Mukai, H.,
`Chasseaud, L. F.
`Pharmakokinetik von NS-49, einem alA(cid:173)
`Adrenozeptor-Agonisten der Phenethylamin(cid:173)
`Gruppe / 4. Mitteilung; Gewebeverteilung,
`Plazentatransfer und Milchsekretion von Radio(cid:173)
`aktivitat bei Ratten nach einmaliger oraler
`Verabreichung von 14C-NS-49 sowie Auswirkun(cid:173)
`gen wiederholter Verabreichung auf die Pharma(cid:173)
`kokinetik
`Pharmacokinetics of NS-49, a Phenethylamine
`Class a1AAdrenoceptor Agonist I 4th Communica(cid:173)
`tion: Tissue distribution, placental transfer and
`milk secretion of radioactivity in rats after a
`single oral administration of 14C-NS-49, and ef(cid:173)
`fects of repeated administration on its pharmaco(cid:173)
`kinetics
`
`Falser, N., Wober, W., Rahlfs, V. W., Baehre, M. E 387
`Vergleich der Wirksamkeit und Vertraglichkeit
`von Azelastin- und Levocabastin-Nasenspray bei
`Patienten mit saisonaler allergischer Rhinitis
`Comparative Efficacy and Safety of Azelastine
`and Levocabastine Nasal Sprays in Patients with
`Seasonal Allergic Rhinitis
`
`Koike, T., Kitazumi, H., Mukai, H.
`Gewebeverteilung von NS-49, einem a 1A(cid:173)
`Adrenozeptor-Agonisten der Phenethylamin-
`Klasse, bei Pigment-Ratten
`Tissue Distribution of NS-49, a Phenethylamine
`Class a1A-Adrenoceptor Agonist, in Pigmented
`Rats
`
`E 402
`
`■ Analgetika • Antiphlogistika · Antirheumatika
`■ Analgesics • Antiphlogistics • Antirheumatic Drugs
`
`E 408
`
`Fang, J.-Y., Sung, K. C., Hu, 0. Y.-P.,
`Chen, H.-Y.
`Transdermale Permeation von Nalbuphin und
`Nalbuphinpivalat aus Hydrogelen durch passive
`Diffusion und Iontophorese
`Transdermal Delivery of Nalbuphine and
`Nalbuphine Pivalate from Hydrogels by Passive
`Diffusion and Iontophoresis
`
`E = Publication in English. G = Publication in German.
`
`

`

`• Hamostyptika
`• Haemostyptic Drugs
`
`■ Patentinformationen
`■ Information on Patents
`
`Habernickel, V. J.
`E 439
`Der Pharmamarkt im Spiegel der Patente / Wirk-
`stoffe zur Behandlung von Diabetes und Folge(cid:173)
`erkrankungen, Antiinflammatorika, Arthritis-
`rnittel
`The Pharma Market as Reflected by Patents I
`Agents for treating diabetes and related diseases,
`agents for the treatment of inflammation, agents
`for the treatment of arthritis
`
`■ AnkOndigungen
`■ Announcements
`
`■ Buchbesprechungen
`■ Book Reviews
`
`444
`
`444
`
`Bianchini, P., Parma, B.
`Studie zur immunologischen Sicherheit einer
`hamostatisch wirksamen Wundauflage aus
`Pferdecollagen
`Immunological Safety Evaluation of a Horse
`Collagen Haemostatic Pad
`
`E 414
`
`■ Antibiotika • Chemotherapeutika • Virustatika ·
`Zytostatika
`■ Antibiotics • Antiviral Drugs • Chemotherapeutics ·
`Cytostatics
`
`Kii<till<bay, H., Durmaz, R., Giiven, M.,
`Giinal, S.
`Synthese von Benzimidazol-Derivaten und ihre
`antibakterielle und antimykotische Aktivitat
`Synthesis of Some Benzimidazole Derivatives and
`their Antibacterial and Antifungal Activities
`
`E 420
`
`E 425
`
`Guzman, A., Garcia, C., Paz Marin, A.,
`Demestre, I.
`4-wochige orale Toxizitatsstudien rnit dem
`neuen antibakteriell wirksamen Chinolon
`Cetefloxacintosylat an Ratten und Krallenaffen
`Four-week Oral Toxicity Studies of the New
`Quinolone Antibacterial Agent Cetefloxacin
`Tosylate in Rats and Marmoset Monkeys
`
`E 433
`
`Poli, G., Dall'Ara, P., Binda, S., Santus, G.,
`Poli, A., Cocilovo, A., Ponti, W
`Auswertung des Meerschweinchenriickenhaut(cid:173)
`modells bei der Auswahl topischer Virustatik fiir
`die Behandlung von rezidivierendem Herpes
`simplex Typ 1
`Value of the Dorsal Cutaneous Guinea Pig Model
`in Selecting Topical Antiviral Formulations for
`the Treatment of Recurrent Herpes simplex Type 1
`Disease
`
`

`

`Antiallergika - Antiasthmatika · Antitussiva · Bronchodilatatoren ·
`Bronchosekretolytika · Mukolytika
`
`Antiallergic Drugs · Antiasthmatics · Antitussives · Bronchodilators
`Bronchosecretogogues · Mucolytics
`
`Arznei m ForschDrugRe
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Comparative Efficacy and Safety
`of Azelastin e and Levocabastine
`Nasal Sprays in Patients with Seasonal
`Allergic Rhinitis
`
`Norbert Falser 3, Wolfgang Woberh t, Volker W. Rahlfsc, and Martin Baehred
`
`Ear Nose Throat Specialist Practicea, Innsbruck (Austria), Institute for Medical Researchb, Munich (Germany),
`idv-Datenanalyse und Versuchsplanungc, Gauting/Munich (Germany), and ASTA Medica<l,
`Frankfurt/Main (Germany)
`
`Summary
`
`The aim of the present investigation was
`to compare the efficacy and tolerability
`of 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(cid:173)
`gic rhinitis. A total of 180 patients parti(cid:173)
`cipated in a 4-week, double-blind, paral(cid:173)
`lel group (n = 90 each) study. Symptom
`severity of nasal, ocular and other symp(cid:173)
`toms were recorded, out of which a total
`symptom score (TSS) was calculated.
`Physicians assessed symptoms at base(cid:173)
`line and at days 7, 14, and 28, patients
`and physicians evaluated the efficacy and
`tolerability. After 4 weeks of treatment
`with azelastine the mean overall TSS was
`reduced from a baseline score of 18.7 to
`4.2, after levocabastine from 17 .8 to 5.9.
`Patients morning scores for treatment
`days 1 to 28 gave a mean total score of
`
`Zusammenfassung
`
`212.4 for the azelastine group and 230.6
`for the levocabastine group; the equiva(cid:173)
`lent evening scores yielded a mean total
`score of 115.5 and 175.6 respectively.
`Global efficacy was judged by physicians
`as either 'very good' or 'good' for 90 % of
`azelastine patients and for 74 % of the le(cid:173)
`vocabastine group; 92 % of azelastine
`patients and 76 % of 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(cid:173)
`tered twice daily as a nasal spray provide
`effective and well tolerated symptomatic
`treatment of seasonal allergic rhinitis. Az(cid:173)
`elastine, however, was statistically super(cid:173)
`ior in efficacy as well as in safety (PWei(cid:173)
`Lachin < 0.0001, combined results).
`
`Keywords
`
`■ Azelastine, clinical study,
`nasal symptom score, safety
`■ CAS 58581-89-8
`■ CAS 79547-78-7
`• Levocabastine, clinical study,
`nasal symptom score, safety
`11111 Rhinitis, seasonal allergic
`
`Arzneim.-Forsch./Drug Res.
`51 (1), 387-393 (2001)
`
`Vergleich der Wirksamkeit und Vertrlig(cid:173)
`lichkeit von Azelastin- und Levocabastin(cid:173)
`Nasenspray bei Patienten mit saisonaler
`allergischer Rhinitis
`
`Ziel der vorliegenden Untersuchung
`war es, die Wirksamkeit und Vertrliglich-
`
`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 tliglich appliziert, bei
`Patienten mit saisonaler allergischer Rhi(cid:173)
`nitis zu vergleichen. Insgesamt 180 Pa(cid:173)
`tienten nahmen an einer 4-wochigen,
`
`

`

`doppelblinden Vergleichsstudie (parallele
`Gruppen zu je 90 Patienten) tell. Erfa8t
`wurde der Schweregrad von nasalen, oku(cid:173)
`laren und anderen Symptomen, aus de(cid:173)
`nen ein Symptomen-Score (Total Sym(cid:173)
`ptom Score, TSS) errechnet wurde. Von
`den Priifarzten wurden an den Tagen 0,
`7, 14 und 28 die Symptome, von Patien(cid:173)
`ten und Arzten die Wirksamkeit und Ver(cid:173)
`triiglichkeit beurteilt. Nach der 4-wiichi(cid:173)
`gen Therapie mit Azelastin war der TSS
`im Mittel von urspriinglich 18, 7 auf 4,2
`gefallen, unter der Levocabastin-Behand(cid:173)
`lung von 17,8 auf 5,9. Die morgendlichen
`
`Patienten-Werte tiber die gesamten 28
`Tage der Studie ergaben einen mittleren
`Score von 212,4 fiir die Azelastin-Gruppe
`respektive 230,6 fiir die Levocabastin(cid:173)
`Gruppe; die entsprechenden Abend-Sco(cid:173)
`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(cid:173)
`stin- und bei 74 % der Levocabastin-Pa(cid:173)
`tienten beurteilt; 92 % der Azelastin-Pa(cid:173)
`tienten und 76 % der Levocabastin-Pa(cid:173)
`tienten beurteilten ihre jeweilige Thera(cid:173)
`pie mit ,,sehr gut" oder ,.gut". Schwerwie-
`
`gentle unerwtinschte Ereignisse wurden
`nicht berichtet, alle unerwtinschten Er(cid:173)
`eignisse bezogen sich auf nasale Sym(cid:173)
`ptome. Sowohl Azelastin als auch Levoca(cid:173)
`bastin, jeweils zweimal tiiglich als Nasen(cid:173)
`spray appliziert, stellen eine wirksame
`und gut vertriigliche Behandlung der sai(cid:173)
`sonalen allergischen Rhinitis dar. Dabei
`zeigte sich Azelastin in bezug auf Wirk(cid:173)
`samkeit und Vertriiglichkeit statistisch
`tiberlegen (PWei-Lachin < 0.0001, com(cid:173)
`bined results).
`
`I. 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 1 receptor antagonism [l], blockade of histamine re(cid:173)
`lease from mast cells [2], and antagonism of leukotriene
`and platelet activating factor [3]. These activities com(cid:173)
`bine to make azelastine an extremely effective treat(cid:173)
`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(cid:173)
`ated with first generation antihistamines, is not evident
`with nasally administered azelastine, even in children.
`Levocabastine (CAS 79547-78-7) is a selective H 1 re(cid:173)
`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(cid:173)
`cabastine nasal spray administered twice daily is an ef(cid:173)
`fective and well tolerated treatment ofragweed-induced
`seasonal allergic rhinitis [7].
`The present investigation was performed as a con(cid:173)
`trolled double blind randomized study in order to de(cid:173)
`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 froIIl seasonal
`allergic rhinitis, as confirmed by a positive prick-test (vs. hist(cid:173)
`amine-positive control 10 HEP). Prior to admission to the
`study, patients underwent an allergy test, physical examina(cid:173)
`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(cid:173)
`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(cid:173)
`ment about the efficacy or safety of the test compounds. After
`verbal instruction, a written explanation of the study was pro(cid:173)
`vided to each patient and informed written consent was ob(cid:173)
`tained. Patients were allocated to treatment groups by a prede(cid:173)
`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(cid:173)
`erate, detrimental to daily activities; 3 = severe, permanent de(cid:173)
`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
`
`3 8 8 Falser et al. - Azelastine and levocabastine
`
`Arzneim.-Forsclt./Drug Res. 51 (I}, 387- 393 (2001)
`© ECV · Editio Cantor Verlag, ,\ulendorf (Germany)
`
`

`

`Antiallergic Drugs - Antiasthmatics - 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(cid:173)
`ent'.
`
`2.2. Methods
`2.2.1. Study design
`The parallel group randomized, double-blind, bicentric study
`compared azelastine nasal spray (azelastine) with levocabas(cid:173)
`tinc nasal spray (levocabastine). The attending physician, the
`principal investigator, the study coordinator and the statisti(cid:173)
`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(cid:173)
`sions (Hong Kong 1989). Written approval of the International
`FreiL,;rger 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
`Medica1l) was administered using a nasal spray which deliv(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`ing. In addition, the global judgement of efficacy by the investi(cid:173)
`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(cid:173)
`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(cid:173)
`lence within the framework of the Wilcoxon-Mann-Whitney
`test. The sample size calculation was based on a test for equi(cid:173)
`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 Nl = 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(cid:173)
`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(cid:173)
`formed in addition, with the same alpha in a confirmatory
`manner according to the closed testing principle [10] . The
`M_ann-Whitney estimator for the so called stochastic superior(cid:173)
`ity of the test group in comparison to the reference group is a
`useful statistic with a range from O to 1 (0.5 indicating equiva(cid:173)
`lence, > 0.5 indicating superiority of azelastine, < 0.5 indicating
`inferiority of azelastine). It denotes the probability, that a ran(cid:173)
`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. I. 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
`
`

`

`Eligible patients
`(n=180)
`
`Randomised (n=180)
`
`Allocated to receive azelastine
`(n=90)
`
`Allocated to receive levocabastine
`(n=90)
`
`Completed 4 weeks treatment
`and follow-up as per protocol
`(n~a1)
`
`Completed 4 weeks lrealment
`and follow-up as per protocol
`(n=90)
`
`25
`
`20
`
`~ 15
`" (/)
`E
`;;l 10
`
`5
`
`0
`
`.......... Azelastine (n=89)
`.......... Levocabastine (n=90)
`
`Visit 1
`
`Visit 2
`
`Visit 3
`
`Visit 4
`
`Premature discontinuation (n=3)
`lack of efficacy (n=1)
`early recovery
`(n=1)
`lost to follow-up (n=1)
`
`Premature discontinuation (n=0)
`
`Fig. 2: Total Symptom Score (TSS) (means and standard devia(cid:173)
`tions) at clinical assessments (N = 179).
`
`Fig. 1: Disposition of patients throughout the study.
`
`Compliance with the medication regimen was asses(cid:173)
`sed by checking the returned medication bottles. All
`patients were considered compliant (data were incom(cid:173)
`plete for only 2 patients). One hundred and seventy(cid:173)
`seven of the 180 patients completed the 4-week treat(cid:173)
`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 of 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(cid:173)
`len counts were regularly recorded [ll]. 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(cid:173)
`corded at the visits. At all three follow-up visits, the re(cid:173)
`duction of TSS is more pronounced in the azelastine
`group th~n 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.
`
`When considering morning diary card symptoms re(cid:173)
`corded by patients from treatment day 1 to 28, there
`was a mean TSS of 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(cid:173)
`toms) in the azelastine group.
`The nasal symptom sum-score was defined as the
`sum of 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(cid:173)
`tom score was reduced to 2.1, equivalent to a reduction
`by a mean of 5.0.
`Efficacy was judged globally by physicians at the end
`of the study as either 'very good' or 'good' in 80/89
`
`300
`
`'in
`~ 250
`'O
`a,
`~ 200
`(/)
`~
`0
`~ 150
`0
`E 100
`:::,
`(/)
`'" 2 50
`
`0
`
`.......... Azelastine (n=89)
`........., Levocabastine (n=90)
`
`rI
`
`L-a-11 -sy_m_p-to_m_s_ a_ll_s_ym- pt_o_m_s _n_asa_ l s-ym- pt_om_s-nasa_ l_s_ym_p_to_m_s
`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).
`
`3 90
`
`Falser et al. - Azelastine and levocabastine
`
`Arzneim.-Forsch./Drug Res. 51 (I), 387-393 (2001)
`© ECV. Editio Cantor Verlag. Aulendorf (Germany)
`
`

`

`Antiallergic Drugs · Antiasthmatics • Antitussives · Bronchodilators • Bronchosecretogogues . Mucolytics
`
`....._. Azelastine (n=89)
`._.. Levocabastine (n=90)
`
`10
`
`9
`
`8
`
`7
`
`~ 6
`0
`~ 5
`E
`5l 4
`3
`
`2
`
`DL--- -- -- - -- -- - - -- -'-----
`Visit 4
`Visit 3
`Visit 2
`Visit 1
`
`Fig. 4: Nasal Symptom Swn-Score (means and standard devia(cid:173)
`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(cid:173)
`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(cid:173)
`cepted a test for superiority of 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 of the confidence interval LB(cid:173)
`CI being 0.6385 and 0.6214, respectively, again well
`above the line of equivalence of 0.5. The global judge(cid:173)
`ment of efficacy by the investigator showed also signifi(cid:173)
`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(cid:173)
`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.
`
`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 %(cid:173)
`confidence intervals were above the 0.5-line of equiva(cid:173)
`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(cid:173)
`elastine group and by 20 patients in the levocabastine
`group. All events were related to nasal symptoms. Sev(cid:173)
`enty-eight percent of levocabastine adverse events were
`deterioration of nasal symptoms, the remainder were
`stuffy nose. Azelastine events were cough at night, itch(cid:173)
`ing, and sneezing attacks after administration. All but
`two of the adverse events (one in each group) were clas(cid:173)
`sified as severe. None of the adverse events was con(cid:173)
`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(cid:173)
`ary as well as the safety parameters a special benefit
`risk analysis has been performed using the global judg(cid:173)
`ments of efficacy and tolerance by the patient and the
`investigator as criteria for 'benefit' and 'risk'; all test re(cid:173)
`. suits 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(cid:173)
`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(cid:173)
`sessments. When comparing efficacy, i.e. symptom
`scores between the two treatment groups, consistent
`advantages were seen for the azelastine group which
`obtained a significantly greater relief of symptoms dur(cid:173)
`ing the course of the study.
`This is particularly tru