Original Paper
`
` ORL 2011;73:260–265
` DOI: 10.1159/000330269
`
` Received: April 5, 2011
` Accepted after revision: June 8, 2011
` Published online: August 11, 2011
`
` A Multicenter Randomized Double-Blind 2-Week
`Comparison Study of Azelastine Nasal Spray
`0.1% versus Levocabastine Nasal Spray 0.05% in
`Patients with Moderate-to-Severe Allergic Rhinitis
`
` Demin Han a Lei Chen b Lei Cheng c Shixi Liu d Zheng Fu e Wei Zhang a
`Chengshuo Wang a Lin Xi a Luo Zhang a The Chinese Allergic Rhinitis
`Collaborative Research Group (C 2 AR 2 G)
`
` a Department of Otolaryngology, Head and Neck Surgery, Beijing Tong Ren Hospital, Capital Medical University,
`Beijing Institute of Otolaryngology, and b Department of Otolaryngology, Head and Neck Surgery, People’s
`Liberation Army General Hospital, Beijing , c Department of Otolaryngology, Head and Neck Surgery, First Affiliated
`Hospital, Nanjing Medical University, Nanjing , d Department of Otolaryngology, Head and Neck Surgery, West
`China Hospital of Sichuan University, Chengdu , and e Department of Otolaryngology, Head and Neck Surgery,
`Hainan Provincial People’s Hospital, Haikou City , China
`
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` Key Words
` Allergic rhinitis ⴢ Antihistamine ⴢ Azelastine ⴢ Chinese ⴢ
`Levocabastine
`
` Abstract
` Objective: To compare the onset of action, efficacy, and
`safety of azelastine and levocabastine in the treatment of al-
`lergic rhinitis. Subjects and Methods: In a multicenter, ran-
`domized, double-blind, parallel-group trial, 244 patients
`with moderate-to-severe allergic rhinitis were randomized
`to receive either azelastine hydrochloride nasal spray (ANS)
`0.1% or levocabastine hydrochloride nasal spray (LNS) 0.05%
`for 14 consecutive days. A visual analog scale was used to
`record total nasal symptom score (TNSS) changes. Indexes
`for further assessment included onset of action, total effec-
`tive rate, and evaluation of therapeutic effect. Results: Sta-
`tistically significant changes from baseline in TNSS were
`seen in both the LNS group and the ANS group. No signifi-
`cant differences were seen between the two groups in terms
`of evaluation of therapeutic effect, total effective rate, and
`
`onset of action, except for a higher symptom relief rate in the
`LNS group than in the ANS group within 30 min of adminis-
`tering the first dose. Adverse reactions were mild to moder-
`ate, with an incidence of 0.9% for LNS and 2.5% for ANS. Con-
`clusion: Both ANS and LNS were effective and safe in the
`treatment of moderate-to-severe persistent allergic rhinitis.
`Moreover, LNS reached a higher symptom relief rate within
`30 min of administering the first dose.
` Copyright © 2011 S. Karger AG, Basel
`
` Introduction
`
` Allergic rhinitis (AR) is a highly prevalent and worri-
`some inflammatory disease affecting about 10–40% of
`the global population [1] . Surveys suggest that AR affects
`about 23–30% of the population in Europe [2, 3] , and ac-
`
` Demin Han, Lei Chen, Lei Cheng, Shixi Liu, Zheng Fu, and Wei Zhang
`contributed equally to this work.
`
`Fax +41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
` © 2011 S. Karger AG, Basel
`0301–1569/11/0735–0260$38.00/0
`
` Accessible online at:
`www.karger.com/orl
`
` Luo Zhang, MD
` Beijing Institute of Otolaryngology
` No. 17 Hougouhutong
` Dong-Cheng District, Beijing 100005 (China)
` Tel. +86 10 6514 1136, E-Mail dr.luozhang   @   gmail.com
`
`Exhibit 1148
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

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`cording to data from the USA about 20–40 million people
`(10–30% of adults and up to 40% of children) are affected
`each year [4] , while a Chinese study demonstrated that
`the prevalence of self-reported AR in 11 cities across
`mainland China has wide variations, ranging from 10 to
`20% [5] . However, it is likely that the prevalence of AR is
`actually higher because the disease is often underdiag-
`nosed or unconfirmed by allergy testing in about 45–50%
`of AR sufferers in the general population [2, 6] . Although
`AR is not a life-threatening condition, it is a major cause
`of suffering, associated with impairments of quality of
`life, work and school productivity [7] , and substantial im-
`pact on the health and the economic burden of individu-
`als and society alike [8] .
` AR is characterized by inflammation of the nasal mu-
`cosa. Sneezing, rhinorrhea, nasal itching as well as itch-
`ing of the palate and eyes occur as a result of the release
`of mediators of inflammation, such as histamine, leukot-
`rienes, prostaglandin D 2 , tryptase, and kinins. Hista-
`mine plays an important role in the pathophysiology of
`AR through its neural and vascular effects, resulting in
`nasal itching, rhinorrhea and nasal obstruction [9] .
` Treatment strategies for AR include topical corticoste-
`roids, oral or topical antihistamines, allergen-specific
`immunotherapy, and other methods, among which anti-
`histamines are an essential cornerstone, although the na-
`sal steroid spray should be most effective among several
`types of nasal sprays. Compared with oral antihistamines
`that are currently widely used, topical administration of
`antihistamines directly to the nasal passages has several
`advantages including lower risk of systemic side effects
`and drug interactions.
` Azelastine nasal spray (ANS) and levocabastine nasal
`spray (LNS) are currently the most widely used topical
`antihistamine products in the treatment of seasonal AR.
`Both agents are potential and selective H 1 receptor an-
`tagonists with no appreciable affinity in vitro for H 2 , do-
`paminergic, adrenergic, serotoninergic, or cholinergic
`receptors. When administered nasally, ANS and LNS
`have been demonstrated to be effective against nasal itch-
`ing, sneezing, and rhinorrhea. There are two direct, pro-
`spective studies comparing the efficacy and tolerability
`of these two agents [10, 11] . It is not surprising that both
`ANS and LNS provided effective and well-tolerated
`symptomatic treatment of seasonal AR [1, 2] . ANS was
`reported to be statistically superior in efficacy as well as
`in safety in a 4-week treatment of 180 patients [11] , while
`LNS was found to be at least as effective as, but better tol-
`erated than, ANS in a 1-week treatment of 123 patients
` [10] . As no direct comparison of these two topical anti-
`
`histamines for the treatment of persistent AR has been
`undertaken to date, the present study was initiated to
`compare the onset of action, efficacy, and tolerability of
`either ANS or LNS as monotherapy for moderate-to-se-
`vere persistent AR.
`
` Subjects and Methods
`
` Subjects
` A total of 244 patients aged 18–65 years met the criteria for en-
`rolment in this study. All subjects were required to have a history
`of at least 2 years of moderate or severe symptoms of perennial AR,
`according to the Allergic Rhinitis and its Impact on Asthma
`(ARIA) guidelines [1] . Each subject needed to have a positive skin
`prick test and had to be in good general health as indicated by
`physical examination (heart rate, breathing, systolic blood pres-
`sure, and diastolic blood pressure) and clinical laboratory values.
` Exclusion criteria included: (1) seasonal AR; (2) non-allergic
`rhinitis; (3) other nasal diseases that might interfere with the re-
`sults; (4) upper respiratory tract inflammation; (5) severe rhinoste-
`nosis resulting from deflection of the nasal septum; (6) severe asth-
`ma; (7) treatment with other nasal drops, nasal or oral antihista-
`mine medications, or vasoconstrictors within the previous 7 days;
`(8) severe cardiac disease, liver or renal function failure; (9) preg-
`nancy or lactation; (10) hypersensitivity to levocabastine or azelas-
`tine; (11) AIDS, venereal disease, alcohol abuse or alcohol depen-
`dence, and (12) operation scheduled during the study period.
`
` Study Design
` This was a multi-center, randomized, double-blind, parallel-
`group study, conducted in five hospitals in four cities across Chi-
`na. The study was performed from December 2008 to October
`2009. Written informed consent was obtained from each patient.
`This study was approved by the Ethic Committees of all centers
`involved in the study and performed in accordance with the ICH
`and Good Clinical Practice regulations and the principles of the
`Declaration of Helsinki.
` During the 1-week screening period before final enrolment,
`the patients’ general information and medical history were re-
`corded, and a nasal symptom assessment and general physical ex-
`amination were undertaken, including measurements of vital
`signs, such as heart rate, breathing, and blood pressure, and a
`urine pregnancy test for female participants.
` In this study, 244 patients, aged 18–65 years, passed screening
`and were finally enrolled and randomized to one of the two treat-
`ment groups, which either undertook 2 weeks of treatment with
`two sprays of LNS in each nostril twice daily (equal to a daily dose
`of 0.40 mg) or one spray of ANS in each nostril twice daily (equal
`to a daily dose 0.56 mg), as a positive control. Three follow-ups
`were conducted in both groups, including visits on day 0 (base-
`line) and day 14, and one telephone follow-up on day 7. On day 0,
`all eligible patients were asked to complete a visual analog scale
`(VAS) evaluation of their nasal symptoms and were then provided
`with the study medications and a diary card to record nasal symp-
`tom changes, onset of action after first dose, and adverse events
`(AEs). The second follow-up was via telephone and focused on
`patients’ compliance with treatment and any AEs. During the fi-
`
` Two Topical Antihistamines in AR
`Treatment
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`nal visit, patients were again required to complete a VAS assess-
`ment in addition to compliance and AE reports as on day 0. At the
`end of the study, the patients and investigators were asked to give
`a general evaluation of the treatment they had received or admin-
`istered, respectively.
`
` Efficacy Analysis
` A total nasal symptom score (TNSS) based on a scale from 0
`(‘nasal symptoms, not at all bothersome’) to 10 (‘nasal symptoms,
`extremely bothersome’) VAS was the main data source required
`for primary efficacy analysis. TNSS indicated a combination sta-
`tus of a patient’s nasal symptoms, including sneezing, running
`nose (rhinorrhea), nasal itching, and nasal blockage. Secondary
`efficacy indexes included onset of action, total effective rate, and
`evaluation of clinical therapeutic effects by patients and investiga-
`tors, respectively.
`
` Onset of Action
` The first dose was given on day 1. The onset of action after the
`first dose and symptom relief were recorded at different time
`points (5, 15, and 30 min, 1, 1.5 and 2 h after first application) for
`each patient.
`
` Evaluation of Clinical Therapeutic Effect
` At the end of the 14-day study, patients and investigators, re-
`spectively, gave a general evaluation of therapeutic effects for each
`patient’s treatment. Evaluations were rated as not good, general,
`good, excellent or ideal. The last 4 evaluations were considered as
`a clinical therapeutic effect for analysis.
`
` Total Effective Rate
` We defined a no-effect case as a patient having no change or
`even worsening of TNSS after the 2-week treatment. Total effec-
`tive rate was calculated according to the following formula: (the
`number of total cases – the number of no-effect cases)/the number
`of total cases ! 100%.
`
` Compliance
` Compliance with the treatments was assessed by checking the
`returned medication bottles and diary cards. Those patients who
`did not use the study medications or complete the cards according
`to our protocol were considered non-compliant.
`
` Safety Evaluation
` Heart rate, respiration, blood pressure, and AEs were recorded
`during each visit. Severity of each AE as well as whether or not it
`was related to the study medication was documented carefully.
`AE rate = (the number of cases of AEs/total number of patients)
` ! 100%.
`
` Population Samples and Statistical Analysis
` Three population samples were introduced for statistical anal-
`ysis: (1) FAS, the full population, which included all patients with
`diary data for at least 1 efficacy evaluation during a scheduled
`visit; (2) PPS, the per-protocol population (or efficacy popula-
`tion), which included all patients who completed the study with-
`out major protocol violation and patients who withdrew within 2
`weeks because of being cured or finding no therapeutic effect at
`all, and (3) SS, the safety population, comprising all patients who
`were randomized and received at least 1 dose of study medication
`
`with diary data for at least 1 efficacy evaluation during a sched-
`uled visit. Data from the PPS and SS populations are further dis-
`cussed in this paper.
` For measurement data, a t test or Wilcoxon rank sum test was
`used to compare groups. For count data, the Fisher exact probabil-
`ity test was used.
`
` Results
`
` Of the 298 patients entering the screening period of
`the study, 244 patients (FAS) were finally enrolled and
`randomized to either the LNS group (122 patients, 60
`males and 62 females) or the ANS group (122 patients, 63
`males and 59 females) for the 2-week treatment period.
`Among them, 224 patients (PPS) completed the efficacy
`evaluation (112 patients in the LNS group, 112 patients in
`the ANS group) and 238 patients (SS) completed the safe-
`ty evaluation (117 patients in the LNS group, 121 patients
`in the ANS group).
` Reasons for cases withdrawing during the study includ-
`ed 11 with poor compliance (6 patients in the LNS group,
`5 patients in the ANS group), 4 who were lost to follow-up
`(2 patients in the LNS group, 2 patients in the ANS group),
`and 5 who withdrew due to other reasons (2 patients in the
`LNS group, 3 patients in the ANS group). Patients random-
`ized to the two medication groups were well matched in
`terms of age, sex, and severity of symptoms.
`
` Nasal Symptom Control
` Individual TNSSs were seen to be significantly re-
`duced in both the LNS group (reduced by a value of 2.90
` 8 1.98, p ! 0.01) and the ANS group (reduced by a value
`of 3.21 8 2.13, p ! 0.01) from baseline, respectively. No
`significant differences were seen between the two groups
`( fig. 1 ).
`
` Onset of Action
` More cases in the LNS group than in the ANS group
`reported onset of action within 15 and 30 min after ad-
`ministration of the first dose of study medication (15
`min: LNS 59% vs. ANS 41%, p ! 0.05; 30 min: LNS 80%
`vs. ANS 65%, p ! 0.05). At 2 h after the first dose, the two
`groups were comparable (LNS: 90%, ANS: 92%; fig. 2 ).
`
` Evaluation of Therapeutic Effect
` At the end of the 2-week treatment period, overall
`evaluations were made by both the investigators and the
`patients. The investigators gave a positive assessment of
`the treatment for 95% of patients in the LNS group versus
`92% of patients in the ANS group, while 88% of patients
`
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`LNS
`ANS
`
`150
`
`100
`
`50
`
`0
`
`Patients (%)
`
`p < 0.01
`
`p > 0.05
`
`p < 0.01
`
`LNS
`ANS
`
`p > 0.05
`
`10
`
`468
`
`02
`
`TNSS
`
`Baseline
`
`Treatment
`
`5 min
`
`15 min
`
`30 min
`
`1 h
`
`1–2 h
`
`2 h
`
` Fig. 1. Comparison of TNSSs in the LNS and ANS groups. Sig-
`nificant reductions were seen in both the LNS group (reduced by
`a value of 2.90 8 1.98, p ! 0.01) and the ANS group (reduced by
`a value of 3.21 8 2.13, p ! 0.01), respectively. No significant dif-
`ferences were seen between the two groups.
`
` Fig. 2. Comparison of symptom control by LNS and ANS at dif-
`ferent time points. Ratio of cases with improved TNSS at sched-
`uled time points (from 5 min to 2 h) are shown. LNS was more
`effective than ANS at 15 and 30 min after the first dosage (p !
`0.05), but both sprays were similar after 1 h.
`
`p > 0.05
`
`p > 0.05
`
`88.4%
`
`91.1%
`
`94.6%
`
`92.0%
`
`Moderate
`Good
`Excellent
`Ideal
`
`150
`
`100
`
`50
`
`0
`
`Patients (%)
`
`LNS (P)
`
`ANS (P)
`
`LNS (I)
`
`ANS (I)
`
` Fig. 3. Comparison of overall therapeutic effects in the LNS and
`ANS groups at the end of the 2-week treatment period evaluated
`by the investigators (I) or the patients (P). The investigators gave
`a positive assessment of the treatment for 95% of patients in the
`LNS group versus 92% of patients in the ANS group, while 88% of
`patients in the LNS group versus 91% of patients in the ANS group
`assessed themselves positively. No significant difference was seen
`between the groups.
`
` Discussion
`
` AR is a common health problem globally. The short-
`term expectation of pharmacotherapy for AR is symptom
`control with minimal impact on daily functioning, and
`little or no sedation and associated cognitive impairment.
`
`in the LNS group versus 91% of patients in the ANS group
`assessed themselves positively. No significant difference
`was seen between the groups. Overall, both the investiga-
`tors and the patients were satisfied with each of the two
`treatments ( fig. 3 ).
`
` Total Effective Rate
` Clinical effectiveness was recorded for 103 patients out
`of 112 in the LNS group and 104 patients out of 112 in the
`ANS group (92 vs. 93%) with no significant difference
`between groups in terms of symptom control.
`
` Compliance
` Patient compliance was similar in both the LNS (6 in-
`compliant cases) and ANS (5 incompliant cases) treat-
`ment groups in this study.
`
` Adverse Events
` Of the 238 patients randomized to either treatment,
`2.6% from the LNS group and 3.3% from the ANS group
`experienced an AE, among which 0.9% (1 case, mycte-
`roxerosis) of LNS-treated patients’ AEs and 2.5% (3 cases,
`1 each of nasal obstruction, epistaxis, and nasal burning)
`of ANS-treated patients’ AEs were medication related.
`None of the AEs was serious, and there were no cases of
`early withdrawal due to AEs in either group. No clini-
`cally significant differences in vital signs were seen with-
`in the groups and between groups.
`
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`Treatment
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`Administration of antihistamines directly to the nasal
`passages has several advantages over oral administration.
`Given the fact that the potential for systemic adverse ef-
`fects is lowered when a drug is delivered directly to the
`target organ, higher concentrations of the drug can be
`used for better symptom control. Azelastine and levoca-
`bastine are the only two nasal antihistamines currently
`available in China. ANS (0.1%) [12] and LNS (0.05%) [13]
`are selective histamine H1 receptor antagonists with no
`appreciable affinity in vitro for H 2 , dopaminergic, adren-
`ergic, serotoninergic, or cholinergic receptors. Although
`in general, nasal antihistamines are less effective at re-
`lieving total nasal symptoms than topical steroids, cur-
`rent treatment guidelines for AR recommend nasal anti-
`histamines as a first-line treatment, probably due to rap-
`id onset of action and safety.
` Noble and McTavish [13] reported that topical levo-
`cabastine could provide a rapid onset of action, a marked
`effect on nasal symptoms, and fewer side effects. This is
`consistent with the results we have obtained in this
`study. Recently, 335 patients with moderate-to-severe
`perennial AR in Japan were treated with 2 doses of levo-
`cabastine (0.025 or 0.05%) or placebo for 2 weeks, re-
`spectively. Significant improvement of nasal symptoms
`was observed in the levocabastine groups, while there
`were no significant differences of efficacy between the
`high-dose and low-dose levocabastine groups. On the
`other hand, there was no significant difference in the oc-
`currence of adverse effects among the three groups (16,
`17, and 20%) [14] .
` The safety profiles of both ANS and LNS have been
`extensively evaluated in clinical trials. Nasal irritation,
`headache, somnolence, and fatigue were the most fre-
`quently reported AEs of LNS [13, 15–17] , but these were
`mostly mild or moderate. In our study, only a few mild
`side effects such as nasal cavity dryness, epistaxis, nasal
`obstruction, and nasal cavity irritation were reported, in-
`dicating that both LNS and ANS were well tolerated. A
`review of the AEs reported by 1,758 patients undertaking
`levocabastine treatment identified the following most
`common AEs: headache (4%), nasal irritation (3%), som-
`nolence (3%), and fatigue (2%) [18] . In another post-mar-
`keting survey of 4,002 patients treated with azelastine for
`1 month, the most common adverse effects reported were
`rhinitis (4%), taste disturbance (2.5%), and nasal irrita-
`tion (1.2%) [19] .
` In our multicenter study, both nasal sprays provided
`rapid and effective symptomatic relief. Total nasal symp-
`tom control was similar in both the LNS and ANS group
`(LNS 92% and ANS 93%). These results are consistent
`
`with those of other investigators [10, 11] . In terms of onset
`of action, both LNS [10, 13] and ANS [12, 13] for treat-
`ment of AR had a rapid onset of effect. Generally, more
`than 50% of patients reported symptom relief within 30
`min of administration of LNS [10] . In our study, onset of
`action favored LNS over ANS within 30 min of receiving
`the first dose of medication. The rapid onset of action in-
`dicated a potential for administration on an as-needed
`basis for relief and control of AR symptoms. In addition,
`both the investigators and patients involved in this study
`were highly satisfied with the treatments, indicating a po-
`tential for wider use of these two nasal antihistamines in
`the treatment of persistent AR.
` In conclusion, both nasal antihistamines employed in
`this study are effective and safe for the treatment of mod-
`erate-to-severe perennial AR. LNS is superior in terms of
`onset of action compared with ANS. Further studies are
`required to assess the effectiveness of symptom control
`and the safety of long-term administration of these
`agents.
`
` Acknowledgments
`
` This work was supported by grants from the National Science
`Fund for Distinguished Young Scholars (81025007), National
`Natural Science Foundation of China (30872846 and 30973282),
`Beijing Science and Technology Program (KZ200910025008),
`Beijing Natural Science Foundation (7102030), and the Special
`Fund of Sanitation Elite Reconstruction of Beijing (2009-2-007)
`to L.Z.
`
` Disclosure Statement
`
` The authors declare that they have no conflicts of interest.
`
`
`
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