Omalizumab is effective in the preseasonal treatment of seasonal allergic rhinitis

Abstract Background To date no study has evaluated the efficacy of preseasonal omalizumab therapy with cost effective dose and at appropriate time point compared with standard medication in seasonal allergic rhinitis (SAR) patients. Methods This was a prospective randomized controlled open‐label single‐centre trial. 32 SAR patients were randomized to receive a single injection of omalizumab 300‐mg approximately two weeks before start of the pollen period (PP) or medication therapy. All patients completed daily questionnaires; recording symptoms, medication use and quality of life (QoL) throughout the observation period. The primary efficacy parameter was the mean daily Combined Symptom and Medication Score (CSMS). Results Preseasonal omalizumab significantly reduced the changes of mean daily CSMS of nose during the PP (p < 0.001), peak pollen period (PPP) and PP after PPP (PPP‐PP) (p = 0.002) and Post‐PP (p = 0.009) compared to standard medication. The proportion of allergy symptoms‐relieving medication‐free days during PPP‐PP was also significantly higher in preseasonal omalizumab‐treated group (76.2(16.7‐98.8))% than in medication‐treated group (19.0(0‐71.4))% (p = 0.030). Omalizumab could achieve the same nasal symptom control during the entire pollen season and better eye symptoms relieving results in PP (p = 0.046) and PPP‐PP (p = 0.004) than medication treatment. Significantly greater improvement in QoL was also obtained with omalizumab‐pretreatment during the PP (p = 0.037) and PPP‐PP (p = 0.004). Conclusions Administration of a single injection of 300 mg omalizumab two weeks before start of the pollen season achieves better overall control of symptoms and QoL, with significantly reduced allergy symptoms‐relieving medication usage, compared with standard pharmacotherapy in SAR patients.


S C H L Ü S S E L W € OR T E R
Behandlung vor der Saison, Omalizumab, Saison der Pollen, Saisonale allergische Rhinitis

| INTRODUCTION
Allergic rhinitis (AR) is a chronic inflammatory disease caused when inhaled allergens contact the nasal mucosa and induce an immunoglobulin E (anti-immunoglobulin E(IgE))-mediated response; which results in the symptoms of nasal itching, rhinorrhea, sneezing, nasal obstruction, ocular pruritus, redness and/or lacrimation. Allergic rhinitis can be classified into seasonal AR (seasonal allergic rhinitis (SAR)) and perennial AR (PAR) and outdoor pollens are major causes for SAR. It has been demonstrated that sensitization to common pollens such as artemisia and ragweed tends to lead to persistent and moderate/severe AR 1 and the disease control is not satisfactory. 2 A recent study involving 6043 subjects from the grasslands of Northern China has demonstrated that 18.5% of these subjects had pollen-induced AR (PiAR) based on allergen tests, 3 indicating a large population of SAR patients. In patients who are allergic to pollen, the nasal mucosa priming phenomenon starts and the symptoms of AR present almost as soon as pollination begins; becoming more severe when pollen concentrations are highest until the end of the pollen season. 4 Extra attention needs to be directed towards management of SAR.
Selection of pharmacotherapy for patients with AR aims to control the disease and depends on many factors such as symptom severity and self-management strategies. 5 It has been pointed that guidelines recommended standard therapies are not sufficiently followed because they are not close enough to patients' needs and probably do not reflect real life. 5 Actually, an early study investigating AR patients in UK general practice has reported that only 27% of the patients used standard medication involving both oral antihistamines and intranasal corticosteroids (INS) regularly, and 62% of these subjects described their symptom control as partial or poor. 6 More recent evidence also suggests that adherence to treatment is fairly low in allergic diseases and asthma, 7,8 suggesting that novel treatments or treatment strategies may be needed to improve adherence and management of patients whose symptoms are inadequately controlled with standard medication care. In this regard, a recombinant humanized anti-immunoglobulin E (IgE) antibody (omalizumab), which mainly blocks the binding of IgE to high-affinity receptors (FceRI) on effector cells and thereby prevents the activation of the IgE-mediated disease, has been shown safe and effective in the treatment of patients with moderate-to-severe allergic asthma, 9 refractory chronic spontaneous urticaria, 10

| Ethics statement
The study (NCT04489121) was approved by the medical ethics committee of Beijing TongRen Hospital, and written informed consent was obtained from each patient before participation. comorbid asthma or atopic dermatitis; (4) treated with a systemic glucocorticoid within 4 weeks or oral antihistamine and intranasal corticosteroid within 2 weeks prior to recruitment; (5) treated with allergen specific immunotherapy for pollens within last 5 years; (6) any kind of surgery within 4 weeks prior to recruitment; (7) participation in any clinical study within the 3 months prior to recruitment;
Eligible patients were randomized in ratio of 1:1 to receive either omalizumab or the control standard medication according to a computer-generated randomization code. Omalizumab was administered about 2 weeks before the start of the autumn PP as a single 300-mg subcutaneous injection by a designated nurse with no other role in the trial, based on the findings of Casale and colleagues. 12 The following drugs were permitted as allergy symptoms-relieving medications according to the actual needs in both groups: Clarityne (tablet), Budesonide (nasal spray) and Patanol (eye drop), which were distributed free of charge to patients at visit 2 and visit 3.
Concomitant use of any other agent apart from the above mentioned an allergy symptoms-relieving medication was prohibited.
All patients included in the study completed daily questionnaires; Daily concentrations of pollen were also recorded over the course of the study.

| Definition of pollen phase
Data of daily total pollen concentration; expressed as grains per to the first day when the total daily pollen count was <80 total pollen/1000 mm 2 . Similarly, the PPP was defined as the period between the first and last three consecutive days with ≥300 total pollen/1000 mm 2 each day. 11,16 The date of about two weeks before the start of the autumn PP for 2020, and thus the date for initiation of treatment, was estimated based on data of daily pollen concentrations in Beijing in recent years. 16 For the purpose of the present study, it was estimated that the date for the start of the autumn PP in Beijing would fall between mid to late August, and thus the initiation of treatment was arranged in early August (August 3-4). Once data provided by Meteorological Bureau demonstrated the total autumn pollen count was <80 total pollen/1000 mm 2 each day for three days, this suggested that the PP had ended and the study was concluded 1 week later (defined as Post-PP in this study). Based on daily pollen data as shown in

| Efficacy and safety assessments
The primary efficacy parameter was the mean daily Combined The routine daily questionnaires mainly involved three aspects of the effect of treatment on symptoms, medication usage and QoL using the mini RQLQ. 18 The subjective assessment of AR symptoms was generally based on the patient scores for four nasal symptoms (sneezing, rhinorrhea, nasal itching and nasal obstruction), and two ocular symptoms (ocular itching/grittiness/redness and ocular tearing); scored range of 0 (not at all) to 3 (severe). Total nasal symptom score and TESS were assessed as the sum of the scores for the four nasal symptoms and the two eye symptoms, respectively. The daily CSMS was calculated as follows: (total symptom scores ranging from 0 to 12 for nose or 0 to 6 for eye)/number of symptoms + MS. CSMSs concerning nose as well as eye were assessed.
Mini RQLQ, which contains 14 questions scored between 0 and 6 for activities, sleep, practical problems, nose symptoms, eye symptoms and emotional function, 19 was used to assess the QoL.
Patient Global Impression of Change was evaluated according to a five-point scale of 0-4; with 0 = symptoms were aggravated; 1 = no control over symptoms; 2 = minor control over symptoms; 3 = substantial control over symptoms; and 4 = total control over symptoms. 20

| Statistical analysis
The patients were assigned to the omalizumab group or to the control standard medication group at a 1: 1 ratio. The sample size in this study was calculated according to two aspects of data using PASS11 (NCSS Corp) before the start of the study. Firstly, we referred to studies investigating the treatment efficacy of omalizumab in Japanese cedar pollen-induced SAR, 11,21 which used the method of non-inferiority test to evaluate the efficacy of omalizumab and control group, and  Figure S1).

| Efficacy
The primary efficacy parameter was CSMS-nose. Omalizumab pre-   induced SAR patients. 11 The common treatment strategy employed in the studies in SAR 11,12 was that different doses of omalizumab (ranging from 50 to 375 mg) or placebo was administered 3 or 6 times to patients over the course of the entire 12-week pollen season. One study investigating the effect of preseasonal treatment of omalizumab on preventing fall asthma exacerbations in school children proposed intervention treatments from 4 to 6 weeks before the school start date to 90 days after the school start date, that is, over a period of about 4 months. 26 In comparison, the current study has   17 Although TNSS has often been chosen as the primary endpoint in the majority of the published placebocontrolled studies of omalizumab in the treatment of AR, the use of concomitant medication has also been considered as an important efficacy parameter in many studies. 11,12 As allergy symptomsrelieving medications are allowed to be used throughout the study, any improvement in patient's symptoms by the medication itself should also be taken into account. In this sense, the validated system for a "weighted" CSMS balances out these problems well.
Moreover, the principle of CSMS has been found to be associated with a large effect size, thereby leading to a high power to show treatment efficacy. 27 Treatment with omalizumab in the current study was also initiated before the onset of the autumn season to assess whether blocking IgE binding before the pollen season could reduce SAR symptoms during the entire pollen season. Indeed, an early study by Pipkorn et al. 28 hypothesized that beginning treatment before symptoms develop might prevent the priming effect of allergic inflammation in the nasal mucosa that lead to increased reactivity to allergen challenge when the seasonal pollen progresses. The theoretical basis of pre-seasonal treatment approach might also be attributable to dampening of "minimal persistent inflammation (minimal persistent inflammation (MPI))", which has been shown to be constantly detectable in asymptomatic mite-sensitized patients continuously exposed to low levels of allergen and elicits a state of heightened sensitivity to subsequent allergen exposure in these patients. 29 There is evidence that MPI is also present in the nasal passages of asymptomatic subjects with SAR and this is exacerbated by high pollen exposure during the pollen season. 30,31 Further studies are required to address the specific mechanism/s underlying the effects of omalizumab in the nasal mucosa of patients with SAR during pollen exposure.
Last but not least, the present study is limited in some aspects. In particular, no objective and/or laboratory test was investigated as an outcome, and as this was not a placebo-controlled study and involved small size of study population, the true benefit of a single dose of preseasonal omalizumab in the management of the symptoms of SAR during the pollen season cannot be evaluated fully. Consequently, this is also likely to reduce the level of evidence of this study.
Although the findings from the present study that an effective preventative strategy for autumn SAR can be achieved with targeted preseasonal omalizumab treatment suggest a paradigm shift for how to manage SAR patients, further confirmation is needed from multicentre, randomised, double-blinded, placebo-controlled studies involving larger well-characterised study populations with multiple sensitization profiles, with respect to both phenotypes and endotypes of SAR patients, who are most likely to benefit from such a novel approach. Moreover, the effects of omalizumab need to be investigated over a wider dose range for optimal effects. Similarly, the optimal period for pretreatment with omalizumab prior to the start of the pollen season needs to be addressed.