Safety and efficacy of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with perennial allergic rhinitis DO NOT COPY

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1 Safety and efficacy of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with perennial allergic rhinitis Eli O. Meltzer, M.D., 1 Robert L. Jacobs, M.D., 2 Craig F. LaForce, M.D., 3 C. Leith Kelley, Ph.D., 4 Stephanie A. Dunbar, Ph.D., 4 and Sudeesh K. Tantry, Ph.D. 4 ABSTRACT Intranasal corticosteroids are recommended as first-line therapy for the treatment of the symptoms of persistent allergic rhinitis (AR). Since the phase-out of chlorofluorocarbon nasal aerosols, intranasal corticosteroids have been available only as aqueous nasal sprays. This study was designed to assess the efficacy, safety, and quality-of-life benefits of beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol in subjects with perennial AR (PAR). After a 7- to 21-day placebo run-in period, eligible subjects aged 12 years with PAR were randomized to 6 weeks of once-daily treatment with BDP nasal aerosol at 320 g or placebo. Reflective and instantaneous total nasal symptom scores (rtnss and itnss, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, and physician-assessed total nasal symptom score were evaluated. The primary end point was change from baseline in average morning (A.M.) and evening (P.M.) subject-reported rtnss over the 6-week treatment period. Safety and tolerability were also assessed. Treatment with BDP nasal aerosol showed significantly greater improvement in average A.M. and P.M. rtnss compared with placebo (mean treatment difference, 0.84; 95% confidence interval, 1.2, 0.5; p 01). Greater improvements in rtnss were reported as early as day 1 and were maintained throughout the 6-week treatment period with the exception of day 2. Greater improvements were seen for all four individual nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) with BDP nasal aerosol compared with placebo. Similarly, significant improvements were seen in average A.M. and P.M. itnss (p 01) and RQLQ score (p 01) with BDP nasal aerosol compared with placebo. In addition, BDP nasal aerosol treatment was well tolerated, and its safety profile was comparable to that of placebo. This clinical study indicated that treatment with BDP nasal aerosol provides statistically significant and clinically meaningful nasal symptom relief accompanied by improved quality of life in subjects with PAR. Additionally, treatment with BDP nasal aerosol was well tolerated with a safety profile comparable to that of placebo. This study was part of the clinical trial NCT registered in (Allergy Asthma Proc 33: , 2012; doi: /aap ) Allergic rhinitis (AR) is a common disease affecting 500 million people worldwide. 1 Among the 60 million people in the United States who suffer From the 1 Allergy and Asthma Medical Group and Research Center, San Diego, California, 2 Biogenics Research Institute, San Antonio, Texas, 3 North Carolina Clinical Research, Raleigh, North Carolina, and 4 Teva Branded Pharmaceutical Products R & D, Inc., Horsham, Pennsylvania Presented at the annual scientific meeting of the American College of Allergy, Asthma, and Immunology, Boston, Massachusetts, November 2011; and the annual scientific meeting of the American Academy of Allergy, Asthma and Immunology, Orlando, Florida, March 2012 Sponsored by Teva Branded Pharmaceutical Products R&D,Inc. EO Meltzer has received grant/research support (principal investigator or subinvestigator) from Alcon, Amgen, Apotex, AstraZeneca, Boehringer Ingelheim, Cephalon, Electrocore, GlaxoSmithKline, HRA, MedImmune, Novartis, Proctor & Gamble, Schering-Plough, Sunovion, and Teva; served as a consultant/advisory board for Alcon, Alexza, Allergan, AstraZeneca, Bausch Lomb, Boehringer Ingelheim, Dey, Forest, ISTA, Johnson & Johnson, Kalypsys, Meda, Merck, ONO, OptiNose, Proctor & Gamble, Rigel, Sanofi, Stallergenes, Sunovion, and Teva; and served as a speaker for the American College of Allergy, Asthma and Immunology, Alcon, Dey/Mylan, Florida Allergy Asthma and Immunology Society, Ista, Merck, Sunovion, and Teva. RL Jacobs has performed clinical trials as the principal investigator for Actelion, ISTA, Lek, Merck, MSD Consumer Care, Sanofi Pasteur, Schering-Plough, Sunovion, and Teva. CF LaForce has served as a speaker for Alcon, Genentech, and Merck. CL Kelley, SA Dunbar, and SK Tantry are employees and stockholders of Teva Branded Pharmaceutical Products R&D,Inc. Address correspondence and reprint requests to Eli O. Meltzer, M.D., Allergy and Asthma Medical Group and Research Center, 5776 Ruffin Road, San Diego, CA from AR, 2 nearly 20% have seasonal AR, 40% have perennial AR (PAR), and 40% have PAR with seasonal exacerbations. 3 Nasal congestion, nasal itching, rhinorrhea, sneezing, and frequent ocular complaints are the major symptoms associated with AR. 3,4 In the United States, the direct cost of this disease was estimated to be $11.2 billion in Allergen avoidance, pharmacologic therapy, and immunotherapy have been used to treat the symptoms of AR. 1,2,6 Intranasal corticosteroids are recommended as first-line therapy because they have been shown to provide greater nasal symptom relief compared with other pharmacologic agents. 2,6,7 However, intranasal corticosteroids are currently available only as aqueous formulations. Undesirable side effects of aqueous nasal sprays can be troublesome for some patients. 8 Two national surveys among adult patients with AR, Aller- address: eomeltzer@aol.com Published online April 2, 2012 Copyright 2012, OceanSide Publications, Inc., U.S.A. Allergy and Asthma Proceedings 249

2 gies in America and the Nasal Allergy Survey Assessing Limitations, highlight the bothersome side effects associated with currently available AR medications. 9,10 The Nasal Allergy Survey Assessing Limitations survey reported that approximately one-third of patients with AR named dripping down the throat as a moderately or extremely bothersome side effect associated with aqueous corticosteroid nasal sprays. 9 Thus, there is an unmet need for the development of nonaqueous intranasal corticosteroid formulations for the treatment of AR. Furthermore, the availability of both nonaqueous (aerosol) and aqueous formulations of intranasal corticosteroids provides treatment options for patients. As a result, patients may be more likely to comply with their treatment regimen, leading to improved outcomes, especially in patients with chronic AR symptoms. 8 Beclomethasone dipropionate (BDP) is a potent antiinflammatory corticosteroid indicated for the treatment of asthma and AR. BDP has previously been developed for the treatment of AR in both aqueous formulations (Beconase [GlaxoSmithKline, Research Triangle Park, NC] and Vancenase AQ [Schering, Kenilworth, NJ]) and nonaqueous (dry) aerosol formulations (as chlorofluorocarbon [CFC] metered-dose inhaler nasal aerosols [Beconase and Vancenase Pockethaler]). As mandated by the Montreal Protocol, all CFC-containing nasal aerosols were withdrawn from the market because of concerns regarding the adverse effect of CFCs on the environment and thus are not currently available for patient use. 11 BDP hydrofluoroalkane inhalation aerosol (QVAR [Teva Respiratory, LLC, Horsham, PA]), an improved CFC-free formulation of BDP, has been approved in the United States for maintenance treatment of asthma in patients 5 years of age since BDP nasal aerosol, a nonaqueous, hydrofluoroalkane-containing, non-cfc formulation of BDP, has recently been developed for the treatment of AR to address the unmet need for an aerosol corticosteroid formulation. The primary objective of this study was to establish the efficacy of BDP nasal aerosol (320 g/day once daily) in adolescent and adult subjects with PAR. Quality of life, safety, and tolerability were also evaluated. METHODS Study Design and Treatment This was a randomized, double-blind, placebocontrolled, parallel-group, multicenter study conducted at 35 centers throughout the United States. After a 7- to 21-day placebo run-in period, eligible subjects were randomized (1:1 ratio) to receive once-daily treatment with either BDP nasal aerosol (320 g/day: 80 g/actuation, 2 actuations/nostril) or placebo nasal aerosol (vehicle: 2 actuations/nostril) for 6 weeks. Subjects self-administered the study medication (2 actuations/nostril) once daily (morning [A.M.]) and assessed their nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) twice daily (A.M. and evening [P.M.]). Each symptom was evaluated on a severity scale ranging from 0 (no signs/symptoms) to 3 (severe signs/symptoms) and reported as reflective (symptoms over the previous 12 hours) and instantaneous (symptoms at the time of evaluation [over the last 10 minutes prior to dosing]). All subjects provided written informed consent or assent, as age appropriate, before study participation. The study was approved by Quorum Review (Seattle, WA) and was conducted in accordance with the principles of the revised version of the Declaration of Helsinki. Subjects Subjects 12 years of age who were in good health with at least a 2-year history of PAR were eligible for entry into the study. The PAR must have been severe enough that it required continuous or intermittent treatment in the past and would require continuous treatment throughout the study. Skin-prick tests were used to indicate sensitivity to at least one relevant allergen known to induce PAR. Sensitivity was defined as a wheal diameter at least 3 mm larger than the control. A subject s positive allergen test result had to be consistent with the medical history of PAR and the subject had to be expected to be exposed to the positive PAR allergen for the entire duration of the study. Excluded from the study were subjects with nasal structural pathology, subjects allergic to a seasonal aeroallergen with seasonal exacerbation anticipated to occur during the study, and subjects with evidence of a respiratory tract infection or respiratory disorder other than AR within 14 days before screening. Subjects with active asthma who required treatment with inhaled or systemic corticosteroids or any other controller drugs or routine use of -agonists were excluded. Subjects who received prohibited medications during various washout periods before the study were not eligible for study participation. No rescue medications were allowed during the study. Treatment with short-acting antihistamines was discontinued 7 days before the screening visit, while treatment with long-acting antihistamines was discontinued 10 days before the screening visit; both short- and long-acting antihistamines were withheld for the duration of the study. To qualify for randomization, subjects must have achieved an average minimum reflective total nasal symptom score (rtnss) of 6 (maximum, 12) and an average minimum reflective nasal congestion score of 2 (maximum, 3) on the last 4 days of the placebo run-in period (baseline), including the A.M. assessment on the day of randomization; adequately completed their AR assessment diary; and taken their single-blind study medication at least 80% of the time during the placebo run-in period. 250 May June 2012, Vol. 33, No. 3

3 Figure 1. Study flow and subject disposition. Includes 1 subject in each treatment group who reported an adverse event during the placebo run-in period but discontinued from the study during the treatment period due to these adverse events., beclomethasone dipropionate hydrofluoroalkane. 236 subjects allocated to 320 µg/day 15 subjects discontinued 6 subjects Withdrew consent 5 subjects Lost to follow-up 1 subject Adverse event 1 subject Pregnancy 1 subject Protocol violation/ noncompliance 1 subject Other Efficacy Assessments Baseline for efficacy assessments was defined as the average of responses obtained during the last 4 days before randomization, including the A.M. assessment on the day of randomization. The primary efficacy end point was the change from baseline in average A.M. and P.M. subject-reported rtnss over the 6-week treatment period. Average A.M. and P.M. subject-reported instantaneous TNSS (itnss) over the 6-week treatment period was a secondary efficacy end point. Individual symptom components of the TNSS (nasal congestion, nasal itching, rhinorrhea, and sneezing) were additional end points. An additional secondary end point was the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score 13 at week 6 for adult subjects with impaired quality of life at baseline (defined as a RQLQ score of 3.0 at randomization). The RQLQ, a disease-specific quality-of-life questionnaire developed to measure the functional problems (physical, emotional, and social) troublesome to subjects with AR, was completed by all English-speaking adult subjects ( 18 years of age). The RQLQ consists of 28 questions in seven domains (activities, sleep, nonnose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) subjects screened for eligibility 574 subjects enrolled and entered placebo run-in period 474 subjects randomized 238 subjects allocated to placebo 22 subjects discontinued 7 subjects Adverse event 6 subjects Withdrew consent 6 subjects Other 2 subjects Lost to follow-up 1 subject Protocol violation/ noncompliance 221 subjects completed the study 216 subjects completed the study 101 subjects did not meet screening criteria 100 subjects excluded 89 subjects Randomization criteria failure 11 subjects Other Physician-assessed TNSS (PNSS) 14 was also assessed. At each study visit (screening, randomization, week 2, and week 6), physicians assessed the severity of each subject s nasal symptoms using the same scale as described previously for subject-reported nasal symptoms. The PNSS was obtained by summing the individual physician-assessed nasal symptom scores, which were determined via questioning the subject (overall feeling since their last visit) as well as via ear, nose, and throat examinations. Safety Assessments Safety was monitored by physical examinations, electrocardiograms, and safety laboratory assessments at various visits throughout the study. Treatmentemergent adverse events (AEs) were also monitored. Statistical Methods Using a standard deviation of 2.0, it was estimated that 235 subjects/treatment group would provide 90% power to detect a difference between the treatment groups of 0.6 in the change from baseline in average A.M. and P.M. subject-reported rtnss with a two-sided -level of 5. The primary end point (average A.M. and P.M. subject-reported rtnss) was Allergy and Asthma Proceedings 251

4 Table 1 Subject demographics and baseline characteristics (ITT population) analyzed using a repeated-measures analysis of covariance (ANCOVA) model with covariate adjustment for baseline, day, treatment, and the treatmentby-day interaction using the intent-to-treat (ITT) population. The ITT population included all randomized subjects who received at least 1 dose of study medication and had at least 1 postbaseline efficacy measurement. Day was treated as an unordered categorical variable. A first-order autoregressive structure was used to model intrasubject correlation, in conjunction with treating subject as a random effect. Estimated treatment differences and 95% confidence intervals (CI) for the treatment differences were calculated. The secondary end point, average A.M. and P.M. subject-reported itnss, was analyzed in a similar fashion to the primary end point. The RQLQ score at week 6 was analyzed using an ANCOVA model with factors for treatment, baseline, and center using the RQLQ population, which included only English-speaking adult subjects ( g/day (n 232) (n 234) Total (n 466) Age, yr Mean (SD) 36.8 (14.5) 37.2 (13.7) 37.0 (14.1) Median Minimum maximum Gender, n (%) Female 158 (68.1) 161 (68.8) 319 (68.5) Male 74 (31.9) 73 (31.2) 147 (31.5) Race, n (%) White 186 (80.2) 185 (79.1) 371 (79.6) Black or African American 40 (17.2) 40 (17.1) 80 (17.2) Asian 6 (2.6) 5 (2.1) 11 (2.4) American Indian or Alaskan Native 1 (0.4) 2 (0.9) 3 (0.6) Other 1 (0.4) 6 (2.6) 7 (1.5) Ethnicity, n (%) Hispanic or Latino 26 (11.2) 30 (12.8) 56 (12.0) Neither Hispanic nor Latino 206 (88.8) 204 (87.2) 410 (88.0) Baseline values, mean (SD) Average A.M. and P.M. rtnss 8.9 (1.70) 9.0 (1.73) A.M. rtnss 8.8 (1.75) 9.0 (1.74) P.M. rtnss 8.9 (1.74) 9.0 (1.84) Average A.M. and P.M. itnss 8.1 (1.98) 8.3 (1.96) A.M. itnss 8.2 (2.03) 8.3 (2.05) P.M. itnss 8.0 (2.09) 8.2 (2.05) PNSS 8.4 (2.24) 8.6 (2.05) RQLQ# 4.2 (0.74) 4.2 (0.81) Subjects were able to select more than one race. #RQLQ population (n 132 at 320 g/day and n 125 placebo ). A.M. morning; beclomethasone dipropionate hydrofluoroalkane; itnss instantaneous total nasal symptom score; ITT intent-to-treat; PNSS physician-assessed total nasal symptom score; P.M. evening; RQLQ Rhinoconjunctivitis Quality of Life Questionnaire; rtnss reflective total nasal symptom score; SD standard deviation. years of age) with impaired quality of life at baseline (defined as a RQLQ score of 3.0 at randomization). Additional efficacy end points, including change from baseline in A.M. rtnss and itnss, P.M. rtnss and itnss, and individual subject-reported nasal symptom scores, were analyzed using the method described for the primary end point. The PNSS, individual physician-assessed nasal symptom scores, RQLQ score at week 2, and individual domains of the RQLQ score were analyzed using an ANCOVA model with factors for treatment, baseline, and center. A fixed-sequence step-down multiplicity procedure was used to test the primary and secondary end points (in the following order: average A.M. and P.M. rtnss, average A.M. and P.M. itnss, and RQLQ score at week 6) while controlling the familywise error rate at 5%. Safety data were summarized by incidence, means, changes, and shifts depending on the measure for the safety population, which included all random- 252 May June 2012, Vol. 33, No. 3

5 A Change From Baseline rtnss n = 232 n = p < µg/day ized subjects who received at least 1 dose of study medication. RESULTS Subject Demographics and Baseline Characteristics A total of 675 subjects were screened, and 574 subjects who met the eligibility criteria were enrolled in the placebo run-in period. A total of 474 subjects were randomized (236 subjects to BDP nasal aerosol and 238 subjects to placebo). The most common reason for nonrandomization was failure of randomization criteria (89 subjects). Thirty-seven subjects withdrew from the study: 15 (6.4%) from the BDP nasal aerosol group and 22 (9.2%) from the placebo group. The most common reason for discontinuation was withdrawal of consent (total of 12 subjects, 6 in each treatment group). In the B Change From Baseline rtnss 320 µg/day (n = 232) (n = 234) p < Time (day) Figure 2. (A) Treatment with at 320 g/day resulted in a significantly greater improvement in average A.M. and P.M. subject-reported rtnss compared with placebo (ITT population). LS mean treatment difference from placebo. Values represent LS mean ( SE). (B) Greater improvements (p 5) in average A.M. and P.M. subject-reported rtnss were observed with at 320 g/day as early as day 1 of treatment (ITT population). A.M., morning;, beclomethasone dipropionate hydrofluoroalkane; ITT, intent-to-treat; LS, least squares; P.M., evening; rtnss, reflective total nasal symptom score; SE, standard error. A Change From Baseline itnss n = 232 n = p < µg/day B Change From Baseline itnss p < Time (day) 320 µg/day (n = 232) (n = 234) Figure 3. (A) Treatment with at 320 g/day resulted in a significantly greater improvement in average A.M. and P.M. subject-reported itnss compared with placebo (ITT population). LS mean treatment difference from placebo. Values represent LS mean ( SE). (B) Greater improvements (p 5) in average A.M. and P.M. subject-reported itnss with at 320 g/day were observed as early as day 3 of treatment (ITT population). A.M., morning;, beclomethasone dipropionate hydrofluoroalkane; itnss, instantaneous total nasal symptom score; ITT, intent-to-treat; LS, least squares; P.M., evening; SE, standard error. placebo group, 7 subjects withdrew because of AEs, compared with only 1 subject in the BDP nasal aerosol group (Fig. 1). Overall, 92.2% of subjects completed the study. Eight randomized subjects (4 in each treatment group) were excluded from the ITT population because they had no postbaseline rtnss values. Hence, the ITT population included 466 subjects (232 subjects treated with BDP nasal aerosol and 234 subjects treated with placebo). Demographics and baseline characteristics (for all efficacy and quality-of-life measures evaluated) were similar between the treatment groups (Table 1). Efficacy Average A.M. and P.M. Subject-Reported TNSS. At baseline, the average A.M. and P.M. rtnss was similar between the BDP nasal aerosol and placebo groups (8.9 Allergy and Asthma Proceedings 253

6 Table 2 Treatment comparison of A.M. subject-reported TNSS and P.M. subject-reported TNSS at week 6 (ITT population) Change From Baseline Nasal Congestion 0.18 Nasal Itching Rhinorrhea Sneezing Reflective µg/day (n = 232) (n = 234) Nasal Congestion g/day (n 232) (n 234) A.M. rtnss LS mean change from baseline (SE) 2.5 (0.14) 1.6 (0.14) Treatment difference (95% CI) 0.82 ( 1.2, 0.4) p Value 01 P.M. rtnss LS mean change from baseline (SE) 2.5 (0.14) 1.6 (0.14) Treatment difference (95% CI) 0.87 ( 1.3, 0.5) p Value 01 A.M. itnss LS mean change from baseline (SE) 2.1 (0.13) 1.3 (0.13) Treatment difference (95% CI) 0.81 ( 1.2, 0.4) p value 01 P.M. itnss LS mean change from baseline (SE) 2.1 (0.14) 1.4 (0.14) Treatment difference (95% CI) 0.76 ( 1.1, 0.4) p Value 01 A.M. morning; beclomethasone dipropionate hydrofluoroalkane; CI confidence interval; itnss instantaneous total nasal symptom score; ITT intent-to-treat; LS least squares; P.M. evening; rtnss reflective total nasal symptom score; SE standard error. Nasal Itching Rhinorrhea Sneezing Instantaneous Figure 4. Greater improvements (p 03) in average A.M. and P.M. subjectreported reflective and instantaneous individual nasal symptom scores with BDP HFA at 320 g/day compared with placebo (ITT population). LS mean treatment difference from placebo. Values represent LS mean ( SE; p 03 for all). A.M., morning;, beclomethasone dipropionate hydrofluoroalkane; ITT, intent-to-treat; LS, least squares; P.M., evening; SE, standard error. and 9.0, respectively; Table 1). Across the 6-week treatment period, subjects treated with BDP nasal aerosol reported a significantly greater improvement from baseline in average A.M. and P.M. rtnss compared with subjects treated with placebo (least squares [LS] mean [SE] change from baseline, 2.46 [0.14] and 1.63 [0.14], respectively; LS mean treatment difference, 0.84; 95% CI, 1.2, 0.5; p 01; Fig. 2 A). Greater improvements in average A.M. and P.M. rtnss were reported with BDP nasal aerosol as early as day 1 (p 5) and were maintained throughout the 6-week treatment period with the exception of day 2 (Fig. 2 B). As seen for rtnss, treatment with BDP nasal aerosol resulted in a significantly greater improvement in average A.M. and P.M. itnss across the 6-week treatment period compared with placebo. The LS mean (SE) change from baseline over the 6-week treatment period was 2.14 (0.13) for BDP nasal aerosol and 1.36 (0.13) for placebo, resulting in an LS mean treatment difference of May June 2012, Vol. 33, No. 3

7 (95% CI, 1.1, 0.4; p 01; Fig. 3 A). Greater improvements in average A.M. and P.M. itnss were reported for subjects treated with BDP nasal aerosol by day3(p 5) and were maintained throughout the 6-week treatment period (Fig. 3 B). A.M. Subject-Reported TNSS and P.M. Subject-Reported TNSS. When analyzed separately, greater improvements were seen in A.M. rtnss (p 01) as well as P.M. rtnss (p 01) with BDP nasal aerosol compared with placebo over the entire 6-week treatment period (Table 2). Similar results were observed with itnss across the 6-week treatment period (Table 2). Individual Subject-Reported Nasal Symptom Scores. As seen with overall nasal symptom improvement, treatment with BDP nasal aerosol resulted in greater improvements from baseline in average A.M. and P.M. subject reported reflective and instantaneous individual nasal symptom scores for all four of the component symptoms of the TNSS compared with placebo. Improvements in all four individual components (nasal congestion, nasal itching, rhinorrhea, and sneezing) contributed to the significant improvement observed in average A.M. and P.M. rtnss and itnss with BDP nasal aerosol (Fig. 4). Physician-Assessed Nasal Symptom Scores. At baseline, the mean PNSS was comparable between the treatment groups (Table 1). The change from baseline in PNSS was greater with BDP nasal aerosol than with placebo at week 2 (LS mean treatment difference, 0.55; 95% CI, 1.0, 0.1; p 12) and week 6 (LS mean treatment difference, 1.22; 95% CI, 1.7, 0.7; p 01; Fig. 5). Additionally, greater improvements (p 01) were reported for each of the individual physicianassessed nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) for subjects treated with BDP nasal aerosol compared with subjects treated with placebo at week 6 (data not shown). Rhinoconjunctivitis Quality of Life Questionnaire. At baseline, the mean RQLQ score was comparable between the treatment groups (Table 1). Improvements in quality of life, as measured by the RQLQ score, were significantly greater with BDP nasal aerosol than with placebo at week 6 (LS mean treatment difference, 0.58; 95% CI, 0.9, 0.2; p 01 in subjects with impaired quality of life at baseline [RQLQ population]; Fig. 6). The improvements in quality of life in the BDP nasal aerosol group were clinically relevant. 13 Similar results were observed when RQLQ was analyzed for the ITT population (LS mean treatment difference, 0.56; 95% CI, 0.8, 0.3; p 01). In addition, greater improvements Change From Baseline PNSS 3.5 n = 232 n = 234 n = 232 n = Week 2 Week 6 5 p = µg/day were observed in all seven domains of the RQLQ score with BDP nasal aerosol than with placebo (p 5 for all; Fig. 7). Safety There were no clinically meaningful differences between BDP nasal aerosol and placebo in terms of incidence, type, and severity of AEs. Of the 574 subjects who were included in the safety population, the incidence of AEs was numerically lower in subjects treated with BDP nasal aerosol (n 48 [20.3%]) than in subjects treated with placebo (n 64 [26.9%]). In the BDP nasal aerosol and placebo groups, respectively, nasal discomfort (5.9% versus 5.0%) was the most commonly reported treatment-emergent AE followed by epistaxis (1.7% versus 1.7%) and headache (1.3% versus 2.1%; 1.22 p < 01 Figure 5. Subjects treated with at 320 g/day showed greater improvement (p 12) in PNSS compared with placebo at both week 2 and week 6 (ITT population). LS mean treatment difference from placebo. Values represent LS mean ( SE). BDP HFA, beclomethasone dipropionate hydrofluoroalkane; ITT, intentto-treat; LS, least squares; PNSS, physician-assessed total nasal symptom score; SE, standard error. Change From Baseline RQLQ Score n = p = 01 n = µg/day Figure 6. Treatment with at 320 g/day resulted in a significantly greater clinically relevant improvement in RQLQ score at week 6 compared with placebo (RQLQ population). LS mean treatment difference from placebo. Values represent LS mean ( SE)., beclomethasone dipropionate hydrofluoroalkane; LS, least squares; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SE, standard error. Allergy and Asthma Proceedings 255

8 Activities Emotional Eye Symptoms Nasal Non-Nose/Eye Symptoms Symptoms Practical Problems Sleep Change From Baseline µg/day (n = 132) (n = 125) Table 3 Treatment-emergent AEs with incidence of >1% in either treatment group (safety population) Adverse Event, n (%) 320 g/day (n 236) 1.4 (n 238) Nasal discomfort 14 (5.9) 12 (5.0) Epistaxis 4 (1.7) 4 (1.7) Headache 3 (1.3) 5 (2.1) Upper respiratory 3 (1.3) 4 (1.7) tract infection Sinus headache 3 (1.3) 0 Oropharyngeal pain 2 (0.8) 4 (1.7) Worsening allergic rhinitis 0 5 (2.1) AEs adverse events; beclomethasone dipropionate hydrofluoroalkane. Table 3). The majority of AEs were of mild or moderate intensity. Nasal discomfort (reported as severe in two subjects in each treatment group) was the only severe AE reported in more than two subjects overall. One subject who was treated with BDP nasal aerosol had a serious AE (arrhythmia) that occurred 8 days after the subject completed the study and was not considered by the investigator to be related to study treatment. Six subjects, all of whom were randomized to placebo, discontinued from the study because of AEs. Only 1 subject withdrew from the study because of AEs that were considered treatment related (cough and postnasal drip). There were no clinically relevant changes from baseline or differences between the BDP nasal aerosol and placebo groups in findings from physical examinations, electrocardiograms, or laboratory evaluations Figure 7. Treatment with at 320 g/day resulted in a greater improvement (p 5) in each of the seven individual domains of the RQLQ score at week 6 compared with placebo (RQLQ population). LS mean treatment difference from placebo. Values represent LS mean ( SE; p 5 for all)., beclomethasone dipropionate hydrofluoroalkane; LS, least squares; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SE, standard error. DISCUSSION The efficacy and safety of previous BDP formulations have been well established for the treatment of AR. 15 However, the efficacy and safety of the recently developed nasal aerosol formulation of BDP in subjects with PAR has not been previously reported. Results reported here indicate that once-daily administration of BDP nasal aerosol provided statistically significant and clinically meaningful improvement in the symptoms of PAR compared with placebo, as measured using subject-reported efficacy end points. 13,16 Importantly, treatment with BDP nasal aerosol resulted in greater improvements in all four nasal symptoms that compose the TNSS (nasal congestion, nasal itching, rhinorrhea, and sneezing) while showing a safety profile comparable with that of placebo. Thus, the results from this study clearly suggest that BDP nasal aerosol at a dose of 320 g/day is an effective and well-tolerated treatment option for subjects with PAR. All efficacy outcomes evaluated in the present study indicate improved nasal symptom scores in subjects receiving BDP nasal aerosol compared with subjects receiving placebo. The improvements observed with BDP nasal aerosol were evident early in treatment (as early as day 1 for rtnss and day 3 for itnss) and were maintained for the duration of the study. Additionally, improvements in A.M. rtnss and A.M. itnss were similar to those observed for P.M. rtnss and P.M. itnss, respectively, over the 6-week treatment period, suggesting that BDP nasal aerosol is an effective oncedaily treatment for PAR. It is important to also note that improvements in physician-assessed nasal symptom scores were greater after 2 weeks of treatment with BDP nasal aerosol relative to placebo, and the greater benefits of BDP nasal aerosol were maintained at week 6. As seen with efficacy, subjects treated with BDP nasal aerosol also reported greater improvements in 256 May June 2012, Vol. 33, No. 3

9 quality of life as assessed by RQLQ score compared with placebo-treated subjects. At week 6, the improvement in RQLQ score observed after treatment with BDP nasal aerosol versus placebo in both the RQLQ and the ITT populations was statistically significant and clinically relevant. 13 The safety profile of BDP nasal aerosol was similar to that of placebo in this study. The most frequently reported AEs were nasal discomfort followed by epistaxis and headache occurring in similar proportions of subjects in each treatment group. None of the subjects who received BDP nasal aerosol discontinued from the study because of an AE, and only one subject experienced a serious AE (arrhythmia), which occurred 8 days after the subject completed the study and was not considered by the investigator to be related to study treatment. In conclusion, treatment with BDP nasal aerosol (320 g/day) resulted in statistically significant and clinically meaningful improvements in nasal symptoms associated with PAR. The improvements in PAR symptoms were observed early in treatment and were maintained over the entire 6-week treatment period. BDP nasal aerosol was well tolerated, and the safety profile was similar to that of placebo in adolescent and adult subjects. These results, in conjunction with the significant benefit reported in subjects with SAR, 17 provide convincing evidence of the overall effectiveness of BDP nasal aerosol for the treatment of the full spectrum of AR. ACKNOWLEDGMENTS The authors acknowledge the technical and editorial support provided by ApotheCom (Yardley, PA). REFERENCES 1. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 63(suppl 86):8 160, Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin Immunol 122(suppl):S1 S84, Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol 108(suppl):S2 S8, Greiner AN, Hellings PW, Rotiroti G, et al. Allergic rhinitis. Lancet 378: , Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31: , Bousquet J, and the ARIA Workshop Group. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 108:S147 S334, Weiner JM, Abramson MJ, and Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: Systematic review of randomised controlled trials. BMJ 317: , Luskin AT. Is there a role for aerosol nasal sprays in the treatment of allergic rhinitis. Allergy Asthma Proc 32: , Fromer LM, Ortiz G, Ryan SF, et al. Insights on allergic rhinitis from the patient perspective. J Fam Pract 61(suppl):S16 S22, Naclerio RM, Hadley JA, Stoloff S, et al. Patient and physician perspectives on the attributes of nasal allergy medications. Allergy Asthma Proc 28:S11 S17, Montreal Protocol. Available online at intpol/; accessed January 26, QVAR 40 g (beclomethasone dipropionate HFA, 40 g) inhalation aerosol for oral inhalation only; QVAR 80 g (beclomethasone dipropionate HFA, 80 g) inhalation aerosol for oral inhalation only package insert. Teva Respiratory, LLC, Horsham, PA; Juniper EF, Guyatt GH, Griffith LE, et al. Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol 98: , Kim K, Weiswasser M, and Nave R. Safety of once-daily ciclesonide nasal spray in children 2 to 5 years of age with perennial allergic rhinitis. Pediatr Asthma Allergy Immunol 20: , Blaiss MS. Safety update regarding intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc 32: , Barnes ML, Vaidyanathan S, Williamson PA, et al. The minimal clinically important difference in allergic rhinitis. Clin Exp Allergy 40: , van Bavel J, Amar NJ, Melchior A, et al. nasal aerosol 320 g once daily is safe and effective in the treatment of nasal symptoms associated with seasonal allergic rhinitis (SAR). Ann Allergy Asthma Immunol 105:A121, e Allergy and Asthma Proceedings 257