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The add-on effect of an intranasal antihistamine with an intranasal corticosteroid in Japanese cedar pollinosis

  • Takenori Haruna
    Affiliations
    Department Otorhinolaryngology-Head & Neck Surgery, Himeji St. Mary's Hospital, Himeji, Japan
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  • Shin Kariya
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Takaya Higaki
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Aya Murai
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Kengo Kanai
    Affiliations
    Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
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  • Aiko Oka
    Affiliations
    Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
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  • Maki Akamatsu
    Affiliations
    Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
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  • Mizuo Ando
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Kazunori Nishizaki
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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  • Mitsuhiro Okano
    Correspondence
    Corresponding author at: Department Otorhinolaryngology, International University of Health and Welfare Graduate School of Medicine, 4-3 Kozunomori, Narita 286-8686, Japan.
    Affiliations
    Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Department of Otorhinolaryngology, International University of Health and Welfare School of Medicine, Narita, Japan
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      Abstract

      Objective

      Combination intranasal drugs with a corticosteroid and antihistamine are available in several countries with better effect than treatments with single agents. However, it remains unclear whether this effect is also seen in Japanese cedar pollinosis (JCP), the most prevalent seasonal allergic rhinitis in Japan. We investigated the effect of an add-on intranasal antihistamine with an intranasal corticosteroid in JCP during the pollen dispersal period. (UMIN000025508)

      Methods

      We performed a double-blinded, randomized, placebo-controlled trial from March 1 to 14, 2017. Patients (n = 20 per group) received either a mometasone furoate nasal spray (MFNS) plus a levocabastine nasal spray (levocabastine group) or MFNS plus a placebo nasal spray (placebo group). The primary endpoint was the difference in the total nasal symptom score (TNSS) after treatment between the two groups. Differences in the total ocular symptom score, total symptom score, total medication score, total symptom-medication score, and five individual symptoms as well as safety were the secondary endpoints.

      Results

      The change in the TNSS from baseline was significantly greater in the levocabastine group than in the placebo group. A significant reduction in the TNSS was observed more than 6 days earlier in the levocabastine group than in the placebo group. Such add-on effects were also seen in the secondary endpoints. Both treatments were well-tolerated.

      Conclusion

      The intranasal antihistamine provided better control of not only nasal symptoms, but also of ocular symptoms, and decreased the need for rescue medications when added to intranasal corticosteroid treatment in JCP patients.

      Key words

      1. Introduction

      Intranasal corticosteroids (INS) are an effective treatment for seasonal allergic rhinitis (SAR), especially when used as a prophylactic treatment to suppress pre-onset minimal persistent inflammation induced by exposure to a low amount of pollen before the continuous pollen dispersal period [
      • Canonica GW
      • Compalati E.
      Minimal persistent inflammation in allergic rhinitis: implications for current treatment strategies.
      ,
      • Noyama Y
      • Okano M
      • Fujiwara T
      • Kariya S
      • Makihara S
      • Haruna T
      • et al.
      Effect of intranasal corticosteroid on pre-onset activation of eosinophils and mast cells in experimental Japanese cedar pollinosis.
      . For example, we previously reported that prophylactic treatment with INS delayed the onset and reduced the symptom severity of Japanese cedar pollinosis (JCP) as compared to a placebo as well as to post-onset treatment with INS. JCP is the most prevalent SAR in Japan, where it is considered a national affliction [
      • Noyama Y
      • Okano M
      • Fujiwara T
      • Kariya S
      • Makihara S
      • Haruna T
      • et al.
      Effect of intranasal corticosteroid on pre-onset activation of eosinophils and mast cells in experimental Japanese cedar pollinosis.
      ,
      • Makihara S
      • Okano M
      • Fujiwara T
      • Kimura M
      • Higaki T
      • Haruna T
      • et al.
      Early interventional treatment with intranasal mometasone furoate in Japanese cedar/cypress pollinosis: a randomized placebo-controlled trial.
      ,
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ,
      • Yamada T
      • Saito H
      • Fujieda S.
      Present state of Japanese cedar pollinosis: the national affliction.
      ,
      • Haruna T
      • Kariya S
      • Higaki T
      • Makihara S
      • Kanai K
      • Komatsubara Y
      • et al.
      Determining an appropriate time to start prophylactic treatment with intranasal corticosteroids in Japanese cedar pollinosis.
      ].
      In the real world, many patients receive conventional post-onset treatment [
      • Bousquet J
      • Schunemann HJ
      • Togias A
      • Bachert C
      • Erhola M
      • Helling PW
      • et al.
      Next-generation allergic rhinitis and its impact on asthma (ARIA) guidelines for allergic rhinitis based on Grading of recommendations assessment, development and evaluation (GRADE) and real-world evidence.
      ]. Although post-onset treatment with INS is effective as compared to the placebo treatment, more symptoms persist as compared to the use of prophylactic treatment, especially for ocular symptoms [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ]. Several reports have shown that combination treatment of INS and intranasal antihistamine (INAH) is effective as a post-onset treatment for SAR, and intranasal formulations of azelastine hydrochloride-fluticasone propionate and olopatadine hydrochloride-mometasone furoate are available in the United States and several other countries [
      • Prenner BM.
      A review of the clinical efficacy and safety of MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate, in clinical studies conducted during different allergy seasons in the US.
      ,
      • Seresirikachorn K
      • Chitsuthipakorn W
      • Kanjanawasee D
      • Khattiyawittayakun L
      • Snidvongs K.
      Effects of H1 antihistamine addition to intranasal corticosteroid for allergic rhinitis: a systemic review and meta-analysis.
      ,
      • Hampel FC
      • Pedinoff AJ
      • Jacobs RL
      • Caracta CF
      • Tantry SK.
      Olapatadine-mometasone combination nasal spray: evaluation of efficacy and safety in patients with seasonal allergic rhinitis.
      ].
      Since little is known about the efficacy of INAH for JCP, especially in combination with INS, we sought to determine the efficacy and safety of the add-on effect of intranasal levocabastine with a mometasone furoate nasal spray (MFNS) for patients with JCP.

      2. Methods

      2.1 Subjects

      The inclusion and exclusion criteria for the JCP subjects enrolled in this study were identical to those of our previous reports [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ,
      • Haruna T
      • Kariya S
      • Higaki T
      • Makihara S
      • Kanai K
      • Komatsubara Y
      • et al.
      Determining an appropriate time to start prophylactic treatment with intranasal corticosteroids in Japanese cedar pollinosis.
      . In brief, male or female patients who were (a) between the ages of 16 and 65 years, (b) had a history of JCP of at least 2 years, (c) showed sensitization to Japanese cedar pollen as assessed by ImmunoCap (Uppsala, Sweden), and (d) had the ability to accurately fill in diary cards were included. Patients were excluded from the study if they (a) had a concomitant sinonasal disease that could potentially affect the outcome of the trial (e.g., nasal polyps, rhinosinusitis, or nasal septum deviation), (b) received concomitant treatment for allergic rhinitis caused by allergens other than Japanese cedar pollen, (c) had rhinitis medicamentosa and non-infectious, non-allergic rhinitis, (d) received cedar pollen-specific immunotherapy, (e) underwent sinonasal surgery, including laser vaporization of inferior turbinates, within the last year, (f) took anti-allergic drugs, including antihistamine, chromones, glucocorticoids, and decongestants, within 2 weeks of the study initiation, (g) showed hypersensitivity to mometasone furoate and/or levocabastine, (h) had a systemic infection, including mycosis, or (i) were pregnant and/or breastfeeding.

      2.2 Study design

      The study was a single-center, double-blinded, randomized, placebo-controlled, two-armed parallel group trial that was performed in 2017. Screening visits were performed in January, 2017. Prior to the study initiation, we estimated the sample size that would be required based on the mean and standard deviation values of the groups reported in our previous studies using INS [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ,
      • Haruna T
      • Kariya S
      • Higaki T
      • Makihara S
      • Kanai K
      • Komatsubara Y
      • et al.
      Determining an appropriate time to start prophylactic treatment with intranasal corticosteroids in Japanese cedar pollinosis.
      . To obtain a study power of 80% for the mean ± standard deviation values of the previous active and placebo groups (0.48 ± 0.87 and 1.24 ± 1.20, respectively), a total of 20 subjects were required for the primary endpoint of the symptom score (α = 0.05).
      Allocation concealment was done by the central registry and computer-generated block randomization. On March 1, 2017, all patients started to receive MFNS (MSD K.K., Tokyo, Japan; 100 μg per nostril once daily in the morning). They concomitantly received a levocabastine nasal spray (Nippon Shinyaku Co., Ltd., Kyoto, Japan; 50 μg per nostril four times a day in the morning, afternoon, evening, and at bedtime) or a placebo for 2 weeks. The inactive placebo consists of saline and 0.015% benzalkonium chloride to equalize a possibility of irritation with levocabastine. The levocabastine and placebo nasal sprays were provided in identical bottles. Patients were allowed to use a fexofenadine hydrochloride tablet (60 mg; Sanofi Aventis Japan, Tokyo, Japan) and olopatadine eye drops (Kyowa Hakko Kirin Co., Tokyo, Japan) as rescue medications on demand. This study was approved by the Institutional Review Board of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (m21001), and was registered in the UMIN database (UMIN000025508). Written informed consent was obtained from each patient.

      2.3 Endpoints

      The primary endpoint was the comparison of the total nasal symptom score (TNSS; the sum of the sneezing, rhinorrhea, and nasal congestion scores) from baseline between the two groups; the scores were obtained from diary cards that were filled out from February 28th (Day 0) to March 14th (Day 14), 2017 [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ,
      • Haruna T
      • Kariya S
      • Higaki T
      • Makihara S
      • Kanai K
      • Komatsubara Y
      • et al.
      Determining an appropriate time to start prophylactic treatment with intranasal corticosteroids in Japanese cedar pollinosis.
      . The secondary endpoints were the comparisons of the total ocular symptom score (TOSS; the sum of the scores for watery eyes and itchy eyes), total symptom score (TSS; the sum of three nasal and two ocular symptom scores), individual symptom scores, total medication score (TMS), total symptom-medication score (TSMS) from baseline, and safety. TMS was determined by the sum of rescue medication calculated as follows: 0, no rescue medication taken; 1, use of either a fexofenadine hydrochloride tablet or olopatadine hydrochloride eye drops; and 2, use of a levocetirizine tablet and olopatadine eye drops.

      2.4 Measurement of pollen dispersion

      Daily Japanese cedar pollen counts were performed using Durham samplers that were installed on the rooftops of Okayama University Hospital buildings from January 7th, 2017 to the end of April.

      2.5 Statistical analysis

      Values are expressed as the mean of each subject group. The t-test, two-way analysis of variance (ANOVA) followed by the post-hoc Sidak test, and chi-squared test were used to compare the data between groups. Statistical analyses were performed using GraphPad Prism (GraphPad Software, Inc., La Jolla, CA, USA) version 8, and P values <0.05 were considered to indicate statistical significance.

      3. Results

      3.1 Patient population

      In total, 40 patients were screened, and they all fulfilled the inclusion criteria. After enrollment, patients were randomly allocated into the levocabastine group (MFNS plus levocabastine nasal spray) or placebo group (MFNS plus placebo nasal spray). None of the patients dropped out. The demographic characteristics of the levocabastine and placebo groups were comparable: the mean age was 40.8 ± 6.9 and 42.4 ± 9.2 years, respectively (P = 0.627 by the t-test), and there were 8 males and 12 females in both groups. The baseline symptoms were similar between the levocabastine and placebo groups, except for watery eyes, for which the levocabastine group showed a significantly higher score than the placebo group (0.50 ± 0.76 vs. 0.10 ± 0.31, respectively; P = 0.036; Fig. 1).
      Fig. 1
      Fig. 1Baseline symptoms between the placebo and levocabastine groups. A: Sneezing. B: Rhinorrhea. C: Congestion. D: Eye itching. E: Watery eyes. The P values were determined by the t-test.

      3.2 Fluctuations in cedar pollen dispersion

      During 2017, the continuous dispersion of Japanese cedar pollen started on February 17th. The highest cedar pollen dispersion was seen on March 2nd at 183 grains/cm2/day. The total cedar pollen count during the study period was 620 grains/cm2 (Fig. 2).
      Fig. 2
      Fig. 2Fluctuations in cedar pollen dispersion.

      3.3 Primary endpoint efficacy

      Changes in the TNSS from baseline were set as the primary endpoint. Two-way ANOVA revealed that the average of changes in the TNSS of 14 days were significantly different between the placebo and levocabastine groups (P < 0.01). The post-hoc Sidak test showed that no significant change in the TNSS was seen in the placebo group. In contrast, a significant improvement in the TNSS was seen in the levocabastine group on days 9, 10, 11, and 14 (P < 0.05). In addition, the TNSS was significantly lower in the levocabastine group than in the placebo group on day 14 (P < 0.05; Fig. 3A).
      Fig. 3
      Fig. 3Comparison of scores between the placebo (open circle) and levocabastine (closed circle) groups. A: Total nasal symptom score. B: Total ocular symptom score. C: Total symptom score. D: Total medication score. E: Total symptom and medication score. *: P < 0.05 from baseline. **: P < 0.01 from baseline. †: P < 0.05 from the placebo group. ‡: P < 0.01 from the placebo group.

      3.4 Secondary endpoint efficacy

      Two-way ANOVA revealed that the average of changes in the TOSS of 14 days were also significantly different between the two groups (P < 0.01). The TOSS was significant higher in the placebo group on day 9 when compared to the baseline (P < 0.05). In contrast, the TOSS was significantly lower in the levocabastine group on days 9 and 10 when compared to the baseline (P < 0.05). In addition, the TOSS was significantly lower in the levocabastine group than in the placebo group on days 3, 5, and 8 to 14 (P < 0.05; Fig. 3B).
      Similar results were seen for the TSS (P < 0.01 by two-way ANOVA). No significant changes in the TSS were seen in the placebo group, while a significant decrease in the TSS was seen in the levocabastine group on days 9 (P < 0.05) and 10 (P < 0.01). In addition, the TSS was significantly lower in the levocabastine group than in the placebo group from day 8 until the end of the trial (P < 0.05; Fig. 3C).
      During the study period, significantly more patients in the placebo group (12 of the 20 patients) used the rescue medications than in the levocabastine group (5 of the 20 patients; P = 0.01 by the chi-squared test). Significant use of the rescue medications was seen in the placebo group on days 5, 9, and 11 to 14 (P < 0.05, and P < 0.01 on day 13). In contrast, no significant use of the rescue medications was seen in the levocabastine group. The TMS was significantly higher in the placebo group than in the levocabastine group on day 5 (P < 0.05; Fig. 3D).
      The TSMS, which is the sum of the TSS and TMS, was significantly higher in the placebo group on days 13 and 14 when compared to the baseline (P < 0.05). In contrast, the TSMS was significantly lower in the levocabastine group on days 9 and 10 when compared to the baseline (P < 0.05). In addition, the TSMS was significantly lower in the levocabastine group than in the placebo group on days 5, 8, and 12 (P < 0.05) as well as days 9 to 11, 13, and 14 (P < 0.01; Fig. 3E).

      3.5 Changes in individual symptoms

      Two-way ANOVA revealed that the average of changes in all of the individual symptoms of 14 days were significantly different between the placebo and levocabastine groups (P < 0.05 for sneezing, and P < 0.01 for rhinorrhea, congestion, eye itching, and watery eyes). The post-hoc Sidak test showed significant differences between the two groups for rhinorrhea on day 8 (P < 0.01), eye itching on days 9, 10, 11, and 13 (P < 0.05), and watery eyes on days 7, 8, 11, 12, and 14 (P < 0.05) as well as days 9 and 10 (P < 0.01; Fig. 4).
      Fig. 4
      Fig. 4Comparison of individual symptom scores between the placebo (open circle) and levocabastine (closed circle) groups. A: Sneezing. B: Rhinorrhea. C: Congestion. D: Eye itching. E: Watery eyes. *: P < 0.05 from baseline. †: P < 0.05 from the placebo group. ‡: P < 0.01 from the placebo group.

      3.6 Safety

      Both treatments were well-tolerated and had a similar safety profile. All of the adverse events encountered were mild, and none of the events caused any of the patients to drop out of the study (Table 1).
      Table 1Adverse events of MFNS plus levocabastine or MFNS plus the placebo.
      Adverse eventPatients (n=20/group)
      MFNS + placeboMFNS +l evocabastine
      Cough2
      Headache1
      Sore throat11
      Body itching1
      Dry mouth1
      Epistaxis1
      Nose discomfort1
      Sleepiness1

      4. Discussion

      The present study demonstrated that treatment with MFNS plus levocabastine significantly improved the TNSS, which was set as the primary endpoint, when compared to not only the baseline, but also to treatment with MFNS plus the placebo. This result is consistent with those of previous reports that used an INAH, such as azelastine and olopatadine, with INS, and demonstrated the add-on effect of INAH with INS on nasal symptoms in SAR [
      • Prenner BM.
      A review of the clinical efficacy and safety of MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate, in clinical studies conducted during different allergy seasons in the US.
      ,
      • Seresirikachorn K
      • Chitsuthipakorn W
      • Kanjanawasee D
      • Khattiyawittayakun L
      • Snidvongs K.
      Effects of H1 antihistamine addition to intranasal corticosteroid for allergic rhinitis: a systemic review and meta-analysis.
      ,
      • Hampel FC
      • Pedinoff AJ
      • Jacobs RL
      • Caracta CF
      • Tantry SK.
      Olapatadine-mometasone combination nasal spray: evaluation of efficacy and safety in patients with seasonal allergic rhinitis.
      ].
      In addition, a significant effect on ocular symptoms was seen in the levocabastine group when compared to the placebo group. It is known that INS is effective not only for nasal symptoms, but also for ocular symptoms [
      • Bielory L
      • Chun Y
      • Bielory BP
      • Canonica GW.
      Impact of mometasone furoate nasal spray on individual ocular symptoms of allergic rhinitis: a meta-analysis.
      ]. However, we have previously reported that although prophylactic treatment with mometasone furoate is effective for suppressing ocular symptoms, post-onset treatment with mometasone furoate had no significant effect on ocular symptoms in JCP [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ]. This may be due to the huge amount of Japanese cedar pollen that is dispersed in Japan [
      • Yamada T
      • Saito H
      • Fujieda S.
      Present state of Japanese cedar pollinosis: the national affliction.
      ]. Thus, a levocabastine nasal spray as an add-on treatment may be effective for such INS-resistant ocular symptoms as it can suppress the nasal-ocular reflex, in which a nasal allergic reaction leads to an afferent reflex response, the efferent limb of which results in eye symptoms [
      • Baroody FM
      • Naclerio RM.
      Nasal-ocular reflexes and their role in the management of allergic rhinoconjunctivitis with intranasal steroids.
      ].
      Significant differences were seen between the levocabastine and placebo groups in the changes of all five individual symptoms (sneezing, rhinorrhea, congestion, eye itching, and watery eyes). We previously calculated the minimal clinically important difference of symptom scores to be 0.3 per item [
      • Higaki T
      • Okano M
      • Kariya S
      • Fujiwara T
      • Haruna T
      • Hirai H
      • et al.
      Determining minimal clinically important differences in Japanese cedar/cypress pollinosis.
      ]. On day 14 after the start of treatment, the difference in the scores between the levocabastine and placebo groups was 0.55, 0.65, 0.45, 0.75, and 0.81 for sneezing, rhinorrhea, congestion, eye itching, and watery eyes, respectively, suggesting that the add-on effect of the levocabastine nasal spray to MFNS was clinically meaningful for each symptom.
      A significant reduction from baseline in the TNSS was seen on day 9 after the start of treatment in the levocabastine group; in contrast, no significant reduction in the TNSS was seen in the placebo group during the 14-day study period. This result is consisntent with our previous report that post-onset treatment with MFNS did not significantly improve TNSS but it did inhibit the exacerbation of TNSS [
      • Higaki T
      • Okano M
      • Makihara S
      • Fujiwara T
      • Haruna T
      • Noda Y
      • et al.
      Early interventional treatment with intranasal corticosteroids compared with postonset treatment in pollinonsis.
      ]. Again, this may be due to the huge amount of Japanese cedar pollen dispersal in Japan [
      • Yamada T
      • Saito H
      • Fujieda S.
      Present state of Japanese cedar pollinosis: the national affliction.
      ]. JCP patients may feel an effectiveness when their nasal symptoms did not exacerbate after the use of INS. In addition, this result suggests that as a post-onset treatment, the combined treatment had a more rapid effect (by more than 6 days) on the TNSS than INS monotherapy. This is consistent with a previous report showing that the effect of a combined treatment with an azelastine and fluticasone nasal spray on the TNSS could be seen up to 5 days earlier than treatment with fluticasone alone [
      • Carr W
      • Bernstein J
      • Lieberman P
      • Meltzer E
      • Bacehrt C
      • Price D
      • et al.
      A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis.
      ]. In fact, although not significant, probably due to the relatively small number of patients, our result showed that the reduction of the TNSS in the levocabastine group on day 4 (0.95) exceeded the minimal clinically important difference of 0.9, suggesting that the combined treatment had a rapid effect.
      The encountered adverse events, including sleepiness, were similar in both groups, and no patients from either group dropped out of the study. The results of a meta-analysis study showed no significant difference in the adverse events from INAH added to INS [
      • Bielory L
      • Chun Y
      • Bielory BP
      • Canonica GW.
      Impact of mometasone furoate nasal spray on individual ocular symptoms of allergic rhinitis: a meta-analysis.
      ]. The present study confirmed the safety of INAH added to INS, which may lead to better compliance.
      We think that the placebo spray was indistinguishable from the levocabastine spray in appearance, smell and irritation for two reasons. First, we used identical bottles for both active and placebo. We bought levocabastine nasal sprays. Because the spray bottles were easy to be dismantled, we stripped the labels off and exchanged the substance in the bottles from levocabastine solution into saline, so the placebo bottles were identical to active levocabastine bottles in appearance. Second, all the subjects had no history to use levocabastine nasal spray before the study. One report showed that nasal irritation was seen in 3% of patients using levocabastine nasal spray [
      • Howarth PH.
      A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management.
      ]. In the present study, only one out of 20 patients in active levocabastine group showed nose discomfort whereas no smell disturbance or nasal irritation were seen in both active and placebo groups (Table 1).
      One of the problems with using nasal sprays is poor adherence. Especially levocabastine should be used four times a day. We interviewed the subjects about adherence after the intervention for 2 weeks. We confirmed that four thirds of subjects achieved the adherence more than 75%, and there were no subjects showing adherence less than 50%. The high adherence may be due to the characteristics of subjects who accepted a participation in this clinical trial.
      In conclusion, the present study showed that INAH added to INS provided additional effects not only on nasal symptoms, but also on other s secondary endpoints such as ocular symptoms and the need for rescue medications. The results presented herein may provide a basis for the development of an intranasal formulation of INAH and INS for JCP.

      Disclosure Statement

      MO received lecture fees from Kyorin Pharmaceuticals Co. Ltd., Taiho Pharmaceuticals Co. Ltd., Mitsubishi Tanebe Pharma Corporation, Sanofi KK, Novartis Pharma KK, and Sanofi K.K.

      Acknowledgements

      This work was supported in part by grants from the Japan Agency for Medical Research and Development (AMED) under Grant Number 21ek0410089h0001.

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