Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of Azelastine Hydrochloride in Children with Perennial Allergic Rhinitis

Allergic rhinitis (AR) affects up to 40% of the pediatric population [1]. Treatment options for AR in children include oral or intranasal antihistamines (INAH), intranasal corticosteroids (INCSs), and leukotriene receptor antagonists [2]. Pediatric AR guidelines published by the European Academy of Allergy and Clinical Immunology (EAACI) recommend oral and INAH and INCS as first-line therapy [3]. The US practice parameter recommends the use of INAH or INCS as first-line therapy for the treatment of AR [4]. Although not directly targeted to children, the recent US practice parameters proposed INAH as first-line therapy [4] whereas the ARIA guidelines did not [5].

Azelastine hydrochloride (AZE) is a phthalazine derivative which is a selective, non-sedating H1 antagonist along with anti-inflammatory and mast cell-stabilizing properties [6‒8]. AZE nasal spray has a superior efficacy compared to other oral antihistamines and also exhibits an excellent safety profile [9]. Earlier studies with 0.10% AZE have shown its superior efficacy and safety in treating symptoms of seasonal allergic rhinitis (SAR) in adults and children ≥5 years of age [9]. A newer formulation of higher dose AZE (0.15%) has also shown a greater dose-dependent efficacy in controlling SAR compared to 0.10% AZE while maintaining safety and tolerability [10‒12]. A recent study in perennial allergic rhinitis (PAR) patients with higher dose AZE showed that it was safe and effective in relieving PAR symptoms [13]. However, randomized controlled trials with AZE 0.15% in children are lacking. A randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of 0.15% AZE and 0.10% AZE compared with placebo at a dosage of 1 spray per nostril twice daily in school-aged children of 6 to <12 years with PAR.

This was a randomized, double-blind, parallel-group study (NCT01018862) which compared AZE 0.10% and 0.15% to placebo (Fig. 1) of one spray per nostril twice daily in pediatric subjects with moderate-to-severe symptomatic PAR. The allocation ratio was 1:1:1. The study began with a washout period from prohibited medications if needed. The washout period was followed by a 7-day, single-blind, placebo lead-in period and a 28-day double-blind treatment period. The primary endpoint of the study was the change from baseline in 12-h reflective combined AM+PM total nasal symptom score (TNSS, comprising of 4 nasal symptoms) for the entire 4-week study period compared with placebo. The secondary endpoint was change from baseline in 12-h combined AM+PM reflective total ocular symptom score (TOSS). Safety was assessed based on reported adverse experiences, nasal examinations, and assessment of vital signs.

The study was conducted outside the seasonal allergy season for each subject at each site to reduce the possibility of symptoms due to seasonal pollens. A total of 39 sites in the USA participated in this study, and each site was expected to randomize approximately 15 to 24 subjects.

Children 6 to <12 years with moderate-to-severe symptomatic PAR were included in the study. Subjects needed to have positive skin tests at visit 1 to dust mite, cockroach, mold, cat dander, or dog dander. A positive response was defined as an average cross-sectional wheal diameter of ≥5 mm larger than the negative control for the skin prick test. Histamine control also needed to be positive with an average cross-sectional wheal diameter ≥5 mm larger than the control. The other main inclusion criteria were (i) 12-h reflective TNSS ≥6 and a congestion score of ≥2 or a rhinorrhea score of ≥2 during screening visit, (ii) 12-h reflective TNSS ≥6 and 12-h reflective congestion score of ≥2 or a rhinorrhea score of ≥2 during randomization, (iii) 12-h reflective TNSS ≥42 and 12-h reflective congestion score of ≥14 or a rhinorrhea score of ≥14 during lead-in period, (iv) subjects needed to have taken at least 10 doses of study medication during the placebo lead-in period, and (v) subjects receiving immunotherapy injections needed to have been on a stable maintenance regimen for at least 30 days before the first study visit (adjustments to regimen following a brief period of missed injections did not preclude participation) [14].

The main exclusion criteria were subjects with (i) superficial nasal mucosal erosion, moderate nasal mucosal erosion, nasal mucosal ulceration, nasal septum perforation; (ii) other nasal disease(s) likely to affect the deposition of intranasal medication, such as acute sinusitis, rhinitis medicamentosa or clinically significant polyposis or nasal structural abnormalities; (iii) nasal surgery or sinus surgery within the previous year; (iv) chronic sinusitis; (v) use of any investigational drug within 30 days prior to visit 1; (vi) sensitivity to drugs similar to azelastine and to either sorbitol or sucralose; as well as (vii) subjects receiving sublingual immunotherapy (SLIT). A 6-month washout period was required following the last dose of SLIT.

Informed consent forms, assent forms, and other study-related information provided to caregivers were approved by the New England Institutional Review Board of Wellesley, MA, Institutional Review Board (ID 3330). A dated consent form was signed by the caregiver of the child. This study was conducted in compliance with the study protocol in accordance with good clinical practices, International Committee on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practices 1996, US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR including parts 50 and 56 concerning informed consent and Institutional Review Board regulations), and the Declaration of Helsinki, concerning medical research in humans.

Individual symptoms/signs of the TNSS and TOSS were scored on a 4-point scale where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms for the 4 nasal symptoms (rhinorrhea, obstruction, pruritus, and sneezing). The maximum combined AM and PM TNSS was 24. Throughout the 4-week, double-blind treatment phase, subjects and/or caregivers continued to record 12-h (AM and PM) reflective TNSS in the diary. The symptoms were evaluated before taking the study medicine in the morning (as soon as the patient woke up) and about 12 h later. At visit 3, the subjects went back to the clinic for a follow-up assessment. The 4-week double-blind treatment period ended, and on visit 4, the subjects went back to the clinic for a final assessment of the study.

Subjects were stratified so that equal numbers in the age ranges 6 to <9 years and 9 to <12 years were randomized. TNSS and TOSS baseline values were not considered for randomization. An interactive voice recognition system was utilized for this study to ensure proper stratification. Randomization data were kept confidential. The study’s blinding was maintained at the study locations until all participants had finished it and the database had been locked (except from subject-specific information when there was a grave safety risk).

A sample size of roughly 158 subjects per treatment group would be needed to demonstrate (i) efficacy with 1 spray per nostril twice daily compared with placebo in the 0.10% AZE group and (ii) an observable dose-response difference between 0.10% AZE and 0.15% AZE groups, considering a reduction of 1.5 units in AM and PM combined rTNSS with standard deviation of 4.1. The sample size of 180 patients per group (allowing for a 12.5% dropout rate) should be sufficient to meet the primary objective which is to show a statistically significant reduction for overall change from baseline in rTNSS at the 0.05 level of significance with 90% power, since the effect size with 1 spray per nostril twice a day of 0.15% AZE should be somewhat bigger than with 0.10% AZE.

No imputation methods were applied to demographic, baseline characteristics and safety data.

For continuous variables, descriptive statistics included the number of subjects reflected in the calculation (n), mean, and standard deviation. All statistical conclusions were based on a 0.05 level of significance, and all statistical tests were 2-sided. Analyses were performed using repeated measures mixed model with no imputation values on the intent-to-treat population. To adjust for multiplicity, a gate-keeping strategy was employed for the primary endpoints. The 0.15% AZE-placebo comparison was first tested at the 0.05 significance level. If it was significant, the 0.10% AZE-placebo comparison was also done at the 0.05 level. If the 0.15% AZE-placebo comparison was not significant at the 0.05 level, no comparison of the low dose to placebo was to be made [13].

Subject demographics and baseline characteristics for all intent-to-treat subjects (n = 486) are presented in Table 1. Figure 2 shows the patient disposition. The three treatment groups were comparable with regard to demographic and baseline clinical characteristics. The subjects ranged in age from 6 to 12 years with a mean age of approximately 8.8. The average duration of AR history ranged from 1 to 11 years. The mean baseline rTNSS score was 16.7 in the 0.15% AZE group, 16.5 in the 0.10% AZE group, and 16.3 in the placebo group. All the subjects were PAR positive. Out of the 486 subjects, 252 were both SAR and PAR positive.

The change from baseline was statistically significant for 0.15% AZE (p = 0.005) and 0.10% AZE (p = 0.015) versus placebo. Here, 0.15% AZE showed an LS mean change of −3.45 (20.2%) over the 28-day treatment period from a baseline value of 16.60 in rTNSS (Fig. 3a, b) and 0.10% AZE showed an LS mean change of −3.37 (20.5%) over the 28-day treatment period from a baseline value of 16.35 in rTNSS. The LS mean change in placebo group over the 28-day treatment period was −2.48 (15%) from a baseline value of 16.09.

The change from baseline in rTOSS was statistically significant (p < 0.05) after day 2 in the 0.15% AZE group compared to placebo. The LS mean change from baseline at day 3 was −1.16 (2.83) for 0.15% AZE (p = 0.032), −0.98 (2.98) for 0.10% AZE (p = 0.122), and −0.48 (2.85) for placebo (p = 0.549). The overall change in TOSS at the end of treatment (day 28) was −1.57 (2.71) for 0.15% AZE (p = 0.249), −1.67 (3.124) for 0.10% AZE (p = 0.157), and −1.32 (3.01) for placebo (p = 0.677).

The number of treatment-emergent AEs and the number and percentage of subjects with treatment-emergent AEs were similar in the three treatment groups (Table 2). There were no deaths and no serious AEs in any of the three groups. The percentage of subjects with treatment-emergent AEs leading to discontinuation was higher in the placebo group (3.7%) than in the 0.15% AZE group (1.2%). Somnolence was reported by 1 patient in the 0.1% group and 1 placebo patient (both of mild severity and unlikely to be related to treatment). None of the patients reported fatigue.

It is essential to perform studies in school children (6–11 years). However, for INAH, few studies exist in SAR, and, to our knowledge, there are no studies in PAR. This study shows for the first time that the higher dose of AZE is safe and effective in school children with PAR.

Clinical trials in the pediatric population are challenging since the trials are based on the guidelines prescribed by the regulatory agencies for adults. In pediatric trials, there is difficulty in recruiting a symptomatic study population due to children reporting less severe or briefer symptoms compared to adolescents and adult [15]. Allergic sensitization and disease do not fully establish before adolescence, leading to increased variation and reduced study sensitivity [15]. The endpoints specified are either rated by the children or caregiver which often results in lower treatment effect due to confounded caregiver assessment [16‒18]. Ensuring compliance with treatment regimens and study protocols can be challenging in pediatric populations, affecting the accuracy and reliability of data. Furthermore, clinicians saw the subjects only at study visits 2 and 4 weeks after treatment but AR symptoms should be evaluated every day. Due to these variabilities, ensuring the generalizability of study results across different age groups within the pediatric population and aligning findings with other age categories is challenging. Compared to the SAR study, it is more challenging to demonstrate efficacy in PAR. Since the average severity of PAR symptoms is lower than that of SAR symptoms, patients with PAR symptoms are less likely to exhibit treatment sensitivity. The endpoints of the study were designed for adolescent/adult populations (i.e., by rTNSS), in line with regulatory requirements which could be rated by either the children or caregiver [9]. A lower treatment effect was observed as being similar to other studies in the pediatric population, possibly due to confounded caregiver assessment [7, 8, 11]. Patients receiving SLIT were excluded. A 6-month washout period was required after the last dose of SLIT.

The primary objective was successfully met. Here, 0.15% AZE showed significant (p = 0.005) improvement in rTNSS compared to placebo from day 2 to 28, whereas the improvement in 0.10% AZE did not reach statistical significance during the first week of treatment. Also, 0.15% AZE showed a numerically higher LS mean change from baseline compared to 0.10% AZE (−3.45 vs. −3.37), showing a dose-dependent response. Although TOSS was the secondary endpoint, many subjects had no or mild eye symptoms at baseline, resulting in a low baseline TOSS value. This could be attributed to the lack of statistical significance at the end of the treatment period. Despite this, significant improvement in TOSS (p < 0.05) was observed at the end of day 2 for the 0.15% AZE group, showing its efficacy in treating ocular symptoms. Since the study was powered to test the significance of 0.15% AZE versus placebo, no significance was observed when compared to 0.10% AZE. The AEs occurring in the 0.10% AZE and 0.15% AZE groups were comparable, indicating that there was no dose-dependent increase in adverse effects. Hence, 0.15% AZE was well tolerated in the pediatric population. Somnolence and fatigue were not experienced by any of the subjects receiving 0.15% AZE and, therefore, were not reported.

A similar study in the adult population with PAR showed an improvement of 4.10 (4.26) units for 0.15% AZE and 3.81 (3.99) for 0.10% AZE from baseline in the AM and PM combined rTNSS [13]. Meta-analyses have shown that INCS are generally safe to use in the pediatric population [19]. However, one study has reported that there could be a reduction in growth velocity with once-daily fluticasone furoate nasal spray in prepubescent children with PAR [20]. Finally, 0.15% AZE could be a safe alternative for children with PAR.

Here, 0.15% AZE significantly improved the overall rTNSS compared with placebo over the 28-day study period and 0.15% AZE was well tolerated in this study. There were no unusual, unexpected, or serious adverse events that would preclude the use of 0.15% AZE in children 6 to <12 years of age. Hence, 0.15% AZE was effective and safe at a dosage of one spray per nostril twice daily. In addition, the comparison of the results of the present study in children to the previous study in adults with PAR supports a recommended dosage of 0.15% AZE of 1 spray per nostril twice daily in children 6 to <12 years of age.

The authors thank Arghya Bhattacharya, PhD, and Aswin Kumar Allupati, MBBS, from Viatris, for medical writing and editorial support.

This study was conducted in compliance with the study protocol in accordance with good clinical practices (GCP), the International Committee on Harmonization (ICH) Harmonized Tripartite Guidelines for GCP 1996, the US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR including parts 50 and 56 concerning informed consent and IRB regulations), and the Declaration of Helsinki, concerning medical research in humans. This study protocol was reviewed and approved by The New England Institutional Review Board of Wellesley, Massachusetts, Approval No. 3330. Written, informed consent was taken for all study participants prior to study. For children under 18 years of age, written, informed consent was provided by the parent(s) or legal guardian of these study subjects for study participation.

D.T.N., H.-C.K. and R.K.R. are employees of Viatris and were involved in the study design, conduct, and interpretation of data. W.E.B. is employed by Allergy and Asthma Solutions, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

This study and medical writing support were funded by Meda Pharmaceuticals, Somerset, NJ, USA (now Viatris).

Jean Bousquet, Ludger Klimek, G. Walter Canonica, and Rajesh Kumar Ramalingam were involved in the conceptualization, preparation, and critical review of the manuscript. Duc Tung Nguyen was involved in the planning, clinical oversight, and reporting of the study. Hans-Christian Kuhl was involved in the statistical planning and statistical oversight of the analysis of the study. William E. Berger was involved in patient recruitment, patient care, data collection, and result review. Jean Bousquet wrote the manuscript.

Edited by: H.-U. Simon, Bern.

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.