A Clinical Study to Assess the Efficacy and Safety of MP-AzeFlu Nasal Spray in Comparison to Commercially Available Azelastine Hydrochloride and Fluticasone Propionate Nasal Sprays in Chinese Volunteers with Allergic Rhinitis

The study was a phase III clinical trial conducted between June 2018 and September 2019 in 28 study sites in China (NCT03599791). Patients were required to have at least a 2-year history of AR (seasonal and/or perennial) during the same time of year as the scheduled study time. This was a multicenter, randomized, double-blind, active controlled prospective clinical study in adult and adolescent patients with AR. The study consisted of a lead-in period for qualifying patients for the treatment period and obtaining baseline data. During the lead-in period, the patient self-administered the MP-AzeFlu vehicle without active ingredients (placebo). It was followed by a 14-day double-blind treatment period in which patients administered either MP-AzeFlu nasal spray or AZE nasal spray or FLU nasal spray (one spray per nostril twice daily) according to randomization (Fig. 1). Patients were requested to keep a patient diary of nasal and ocular symptoms throughout the study period. The patients were required to record their symptoms in a paper diary twice daily, right before using the nasal spray (similar to the four foreign clinical trials conducted earlier in the US). The symptom severity was scored on a four-point scale [0–3] where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms. For each patient, treatment duration was 17–23 days, including 3–7 days of placebo lead-in period and 14 (+ 2) days of treatment period. Patients were prohibited from using any investigational drug within 30 days prior to the screening visit. At least a 3-day lead-in period was required in this trial to obtain baseline for efficacy analyses. Furthermore, the lead-in period would provide study sites sufficient time to obtain data to confirm eligibility of the patients, e.g., to obtain results of specific IgE tests. The flexible duration of the lead-in period (from 3 to 7 days) would allow study sites to randomize a patient as soon as eligibility of the patient has been confirmed.

The study was approved by the China National Medical Products Administration (NMPA) prior to enrollment of the first patient (Approval Number by China Food and Drug Administration [CFDA] 2017L01096). The ethical number for the leading site (Beijing Tongren Hospital, Capital Medical University) is TREC2018-13. This study was conducted in accordance with the Declaration of Helsinki 1964, International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP) (ICH E6 (R2)), General Data Protection Regulation, local regulations as applicable and the Beijing Hospital Standard Operating Procedures. Prior to enrollment, written informed consent was obtained from each patient. A copy of the signed ICF was provided to each patient or legal representative (for pediatric patients) by the investigator, and the original was retained by the investigator.

Male and female patients ≥ 12 years of age and having moderate-to-severe rhinitis or rhino conjunctivitis with a minimum 2-year perennial allergic rhinitis (PAR) history were eligible for the study. The patients needed to have 12-h reflective total nasal symptom score (rTNSS) of at least 8, a congestion score of 2 or 3, a sneezing or nasal itching score of 2 or 3 during screening visit. Similar criteria should be fulfilled by the patients before randomization. Patients who had moderate-to-severe rhinitis or rhino conjunctivitis, defined as rhinitis/rhino conjunctivitis with one or more of the following, presented [8]: (i) Sleep disturbance; (ii) Impairment of daily activities, leisure and/or sport; (iii) Impairment of learning or work; (iv) Troublesome symptoms. Patients who had moderate-to-severe rhinitis or rhino conjunctivitis and monotherapy with either intranasal antihistamine or glucocorticoid were not considered sufficient at the discretion of the investigator and/or designee. Additionally, they should have immunoglobulin E (IgE)-mediated hypersensitivity to one or more aeroallergens present in the study environment, confirmed by a positive response to an established standard diagnostic test at the site within the last year. The main exclusion criteria were: (i) presence of any hypersensitivity to drugs similar to azelastine hydrochloride (HCl), fluticasone propionate, or to any of the excipients; (ii) clinically significant arrhythmia (or unstable despite medical treatment) or symptomatic cardiac conditions; (iii) patients with a diagnosis of glaucoma, cataract, or central serous chorioretinopathy; (iv) presence of nasal disease(s) likely to affect deposition of intranasal medication, such as sinusitis, rhinitis medicamentosa, clinically significant polyposis, or nasal structural abnormalities (e.g., nasal septum deviation) or nasal surgery within the last year; (v) received specific immunotherapy within 6 months prior to the screening visit. If the patient received immunotherapy, a 6-month washout period was required following the last dose of immunotherapy.

The results of adult RQLQ showed improvement of QoL in all treatment groups. The improvements in all domains already exceeded the minimum clinically significant difference of − 0.50 at day 8 and then maintained until day 15 (study end). The improvement of QoL was less pronounced in the AZE group compared to MP-AzeFlu and FLU groups.

The most frequent TEAEs (Supplementary Material Table 4) in ≥ 1% of patients in MP-AzeFlu group were: dysgeusia (4.3%), epistaxis (1.3%), nasal dryness (1.0%), and headache (1.0%). Except for dysgeusia (bitter taste) that was reported by more patients (13 [4.3%]) in the MP-AzeFlu group, the incidence of all other TEAEs in MP-AzeFlu group was comparable or even lower than in other treatment groups. The incidence of fatigue was comparable to FLU treatment group and lower than AZE treatment group. Somnolence was lower than AZE treatment group but slightly higher compared to FLU treatment group. Most patients in all three treatment groups had no severe findings on the focused nasal examination at the study end. Mucosal edema and nasal discharge were generally improved over time across all treatment groups. No study treatment-related severe (Grade 3) TEAE was reported in this study.

The reduction of each symptom score (rTNSS, rTOSS, and rT7SS) each day was mostly greater in the MP-AzeFlu group than the other two treatment groups. This is similar to the results from previous global studies, as the combination of azelastine HCl and fluticasone propionate showed greater and quicker effects than the individual components [6]. For the primary efficacy endpoint, the MP-AzeFlu group consistently showed the greatest reduction of combined 12-h rTNSS from baseline. The LS mean change from baseline was statistically significantly larger in the MP-AzeFlu group than in the other two treatment groups. In a randomized multicenter study done in 149 patients with SAR in Russia, MP-AzeFlu significantly (p < 0.001) reduced the rTNSS (– 2.47), rTOSS (– 1.62), and rT7SS (– 4.34) values [13]. The reduction in 12-h rTNSS was greater (7.59 points) among Chinese patients compared to a previous study (MP4001) done with US patients (5.3 points) [14]. The benefit of MP-AzeFlu over AZE and FLU on ocular symptoms was more pronounced in Chinese patients. The differences in change from baseline of combined rTOSS were consistently statistically significant between the MP-AzeFlu group and the other two treatment groups (all p < 0.05) whether over the first week or over the entire 2-week treatment period.

The current study indicated that study medications provided full-day sustained effects on patients when administered twice daily. In addition, a greater symptom relief in MP-AzeFlu group compared to AZE and FLU groups were demonstrated for both AM and PM rTNSS. In general, the benefit of MP-AzeFlu on individual nasal and ocular symptoms was also more pronounced in Chinese patients when compared with data from previous studies. The previous double-blind studies done with MP-AzeFlu did not test its efficacy in PAR (perennial allergic rhinitis). Nasal and ocular symptoms (nasal congestion, nasal itching, watery eyes, itchy eyes) are some of the most bothersome symptoms of AR. However, subgroup analysis done for AR types in the present study showed that MP-AzeFlu was effective in reducing nasal and ocular symptoms of SAR and PAR and the effect was superior to that of FLU and AZE. Previous studies have shown that use of intranasal corticosteroids inhibits nasal ocular reflex, resulting in effective symptom relief from nasal and ocular symptoms [15, 16].

FLU is an anti-inflammatory corticosteroid with highly specific glucocorticoid receptor activity. AZE is a second-generation INAH approved for use in SAR. AZE is a non-sedating H1-antagonist with antihistaminic, anti-inflammatory, and mast cell stabilizing properties [17]. It affects eosinophil function and also downregulates intercellular adhesion molecule-1 (ICAM-1) expression [18]. MP-AzeFlu has a synergistic action in inhibition of inflammatory cell recruitment and desensitization of sensory neurons [19]. A recent in vitro study has shown that MP-AzeFlu downregulates the production of the inflammation markers IL-6, IL-8, and GM-CSF in cultured fibroblasts isolated from nasal mucosa (NM) and nasal polyp (NP) [20]. Recent studies with MP-AzeFlu have shown its effectiveness in providing complete symptom control of AR than first-line therapies [6, 14, 21]. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines recommend MP-AzeFlu for all patients with AR, independent of disease type or severity [11]. Use of MP-AzeFlu might improve adherence of the patients towards taking medication.

AR significantly affects the patient’s quality of life (QoL) and work productivity and performance. In addition, AR is often accompanied by co-morbidities such as asthma and atopic dermatitis [10]. Studies done in Chinese patients have shown that AR substantially reduces their QoL (e.g., sleep disturbances, emotional problems, impairment in activities of daily life or social functioning) [4, 22]. Improvements of QoL were seen in all treatment groups and in line with previous clinical experiences. In general, the improvement of QoL was less pronounced in the AZE group compared to the MP-AzeFlu and FLU groups. The improvements in all RQLQ domains exceeded the minimum clinically significant difference of - 0.50 in all treatment groups. In a recent multicenter, prospective, non-interventional, real-life study, MP-AzeFlu improved patient-reported QoL regardless of the AR type [23].

Overall, compliance with the study treatments was high in all three treatment groups (average overall compliance > 99.7% in each treatment group). In the current study, the incidence of TEAEs was similar in all three groups, although for some events the incidence was found to be higher in the AZE group than other treatment groups (Supplementary Material Table 4). There was no increase in frequency of dysgeusia under MP-AzeFlu treatment in Chinese patients compared with previous clinical experiences outside of China. In this study, it is notable that MP-AzeFlu did not inherit all the TEAEs commonly reported by AZE or FLU treatment. TEAEs was not always reported in a higher frequency in MP-AzeFlu-treated patients. Instead, frequency of common TEAEs reported by MP-AzeFlu was mostly lower than (or equal to) those in the other two treatment groups except dysgeusia. This indicated that MP-AzeFlu is generally safe and tolerable to Chinese patients. Somnolence and fatigue are two of the most associated side effects of antihistamine usage. The current study showed lesser incidence of somnolence and fatigue for MP-AzeFlu.