From the genesis to the present: The evolution of sublingual immunotherapy for cedar pollinosis.

In 2004, we started the initial attempt to evaluate the efficacy of SLIT for Japanese cedar pollinosis (JCP) using Japanese cedar (JC) pollen extract solution through a multicenter, placebo-controlled, double-blind comparative study. Based on its success in demonstrating the substantial efficacy of SLIT, we next conducted a larger-scale study by administering JC pollen to all JCP patients recruited. It was because of aiming to ascertain the effectiveness and safety of SLIT and its underlying mechanisms by comparing high- and non-responder patients. Despite limitations posed by liquid medication, significant effectiveness and safety demonstrated by the 2-year treatment served as the foundation for launching the first SLIT medicine for JCP, in 2014. Furthermore, in addition to the clearer Th1/Th2-imbalanced property in the high-responders, the possible involvement of bitter taste receptors in CD4+ T cells, apoptosis pathways in CD4+ T cells and basophils, and inducing a mast cell degranulation inhibitory molecule in the effect of SLIT was demonstrated. To solve the limitations posed by liquid medication, clinical trials evaluating JC pollen sublingual tablets started in 2014. Due to the minimal side effects, ease of administration, and convenient storage, the sublingual tablet medicine was launched in 2018. Giving the ongoing rise in demand for SLIT and considering that more than 1% of JCP patients are currently undergoing SLIT, the practical use of this treatment for multiple allergens is becoming increasingly important.

House dust mite sublingual immunotherapy tablet safety in adolescents with allergic rhinoconjunctivitis: Worldwide clinical trial results.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet is a treatment option for allergic rhinitis with/without conjunctivitis (AR/C) approved in adults worldwide and in adolescents in some countries. OBJECTIVE: To supplement existing adolescent HDM SLIT-tablet safety data by conducting the MT-18 trial in adolescents. METHODS: MT-18 (EudraCT:2020-000446-34) was a phase 3, open-label, single-arm, 28-day safety trial of daily HDM SLIT-tablet (12 SQ-HDM dose) in European adolescents (12-17 years) with HDM AR/C, with or without asthma. The primary end point was at least 1 treatment-emergent adverse event (TEAE). MT-18 results were compared with 12 SQ-HDM adolescent subpopulation data from previously described 1-year phase 3 trials conducted in North America (P001; clinicaltrials.gov:NCT01700192) or Japan (TO-203-3-2; JapicCTI:121848). RESULTS: No treatment-related anaphylaxis, epinephrine administrations, severe local swellings, severe mouth or throat edema, or eosinophilic esophagitis occurred in the trials. For MT-18 (N = 253), P001 (N adolescents = 189), and TO-203-3-2 (N adolescents = 206), the percentage of adolescents treated with 12 SQ-HDM reporting any TEAE was 88%, 95%, and 93%, respectively, and the percentage reporting any treatment-related AE (TRAE) was 86%, 93%, and 66%, respectively. The most common TRAEs were local application site reactions. Most TRAEs were mild in intensity and were typically experienced the first 1 to 2 days of treatment. There were no asthma-related TEAEs with the HDM SLIT-tablet. The safety profile appears similar between adolescents with or without asthma at baseline. CONCLUSION: The HDM SLIT-tablet was well tolerated in European, North American, and Japanese adolescents with HDM AR/C, indicating safety of the HDM SLIT-tablet is insensitive to age or geographic region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: (P001: NCT01700192); EudraCT: (MT-18; 2020-000446-34); JapicCTI: (TO-203-3-2; 121848).

Executive summary: Japanese guidelines for allergic rhinitis 2020.

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today. The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described.

Adaptation and validation of the main concept analysis of spoken discourse by native Japanese adults.

Many people with aphasia demonstrate problems of oral production at the discourse level. The Main Concept Analysis (MCA) for oral discourse production is a published evidence-based battery for quantifying the degree of presence, accuracy, completeness, and efficiency of targeted main concepts in oral discourse. In Japan, such a standardized tool specialized for assessing spoken discourse is currently lacking. The purpose of this study was to adapt the Japanese version of MCA for oral discourse production (the Japanese-MCA) and examine its validity and reliability. Stage 1 of the study involved the establishment of linguistically-specific main concepts (MCs) of the Japanese-MCA. Ten speech-language-hearing therapists and 60 healthy participants who were native monolingual Japanese speakers were recruited to determine MCs. Stage 2 examined the criterion validity and reliability of the Japanese-MCA. Language samples of 20 participants with aphasia, as verified by Standard Language Test of Aphasia (SLTA), and 20 healthy older participants were used. Results of Stage 1 of the study yielded normative data with a set of target MCs that were geographically and linguistically specific for use in Japan. The results also revealed the comparability of the Japanese-MCA and previously reported versions of other languages. Stage 2 findings indicated not only a high correlation of criterion validity, but also good reliability of the test. With established norms and specific scoring criteria of the Japanese-MCA, it is believed that this new tool will become a useful addition to clinical management and research of aphasia in Japan.

Long-term treatment of Japanese cedar pollinosis with Japanese cedar pollen SLIT drops and persistence of treatment effect: A post-marketing clinical trial.

BACKGROUND: There have been no reports of treatment effect persistence after long-term sublingual immunotherapy (SLIT) in patients with Japanese cedar (JC) pollinosis. Therefore, we conducted a post-marketing clinical trial to investigate the efficacy, safety, and effect persistence of JC pollen SLIT drops after approximately 3 years of treatment. METHODS: This was an open-label trial of 233 patients with JC pollinosis who were treated with JC pollen SLIT drops for approximately 3 years (2015-2017) and followed-up for an additional 2 years (2018-2019). Efficacy and effect persistence were evaluated using nasal and ocular symptom scores, daily use of rescue medication, and Japanese Rhinoconjunctivitis Quality of Life Questionnaire scores recorded during the JC pollen dispersal season of each year. Safety was evaluated by monitoring adverse events and adverse drug reactions. RESULTS: The mean combined total nasal symptom and medication score (range 0-18) during the peak symptom periods of 2015 through 2019 were 5.47 ± 3.38, 4.52 ± 3.13, 3.58 ± 2.63, 5.28 ± 4.01, and 6.83 ± 4.65, respectively. The percentage of patients who used no rescue medications during the same periods was 64.8%, 75.2%, 80.3%, 63.7%, and 50.3%, respectively. A total of 138 adverse drug reaction incidents were recorded in 73 of the 233 patients (31.3%), of which 134 incidents (97.1%) were mild in severity. CONCLUSIONS: JC pollen SLIT drops demonstrated treatment duration-dependent efficacy with effects that persisted for 2 years after cessation of treatment. The drug had a favorable safety profile over the 5-year study period.

Roles of omalizumab in various allergic diseases.

IgE and mast cells play a pivotal role in various allergic diseases, including asthma, allergic rhinitis, and urticaria. Treatment with omalizumab, a monoclonal anti-IgE antibody, has significantly improved control of these allergic diseases and introduced a new era for the management of severe allergic conditions. About 10 years of experience with omalizumab treatment for severe allergic asthma confirmed its effectiveness and safety, reducing symptoms, frequency of reliever use, and severe exacerbations in patients with intractable conditions. Omalizumab is particularly useful in childhood asthma, where atopic conditions often determine clinical courses of asthma. Recently, omalizumab is approved for the treatment of chronic spontaneous urticaria (CSU) with the fixed dose of 300 mg. Although the mechanisms underlying the actions of omalizumab in CSU are not fully clarified, nearly 90% of patients with CSU showed a complete or a partial response to omalizumab treatment. Furthermore, omalizumab is just approved for the treatment of severe Japanese cedar pollinosis (JC) based on the successful results of an add-on study of omalizumab for inadequately controlled severe pollinosis despite antihistamines and nasal corticosteroids. For proper use of omalizumab to treat severe JC, co-administration of antihistamines is necessary, while patients should meet the criteria including strong sensitization to Japanese cedar pollen (≥class 3) and poor control under standard treatment. In the management of severe allergic diseases using omalizumab, issues including cost and concerns about relapse after its discontinuation should be overcome. At the same time, possibilities for application to other intractable allergic diseases should be considered.

Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

Causal Relationships Among Pollen Counts, Tweet Numbers, and Patient Numbers for Seasonal Allergic Rhinitis Surveillance: Retrospective Analysis.

BACKGROUND: Health-related social media data are increasingly used in disease-surveillance studies, which have demonstrated moderately high correlations between the number of social media posts and the number of patients. However, there is a need to understand the causal relationship between the behavior of social media users and the actual number of patients in order to increase the credibility of disease surveillance based on social media data. OBJECTIVE: This study aimed to clarify the causal relationships among pollen count, the posting behavior of social media users, and the number of patients with seasonal allergic rhinitis in the real world. METHODS: This analysis was conducted using datasets of pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis from Kanagawa Prefecture, Japan. We examined daily pollen counts for Japanese cedar (the major cause of seasonal allergic rhinitis in Japan) and hinoki cypress (which commonly complicates seasonal allergic rhinitis) from February 1 to May 31, 2017. The daily numbers of tweets that included the keyword "kafunsho" (or seasonal allergic rhinitis) were calculated between January 1 and May 31, 2017. Daily numbers of patients with seasonal allergic rhinitis from January 1 to May 31, 2017, were obtained from three healthcare institutes that participated in the study. The Granger causality test was used to examine the causal relationships among pollen count, tweet numbers, and the number of patients with seasonal allergic rhinitis from February to May 2017. To determine if time-variant factors affect these causal relationships, we analyzed the main seasonal allergic rhinitis phase (February to April) when Japanese cedar trees actively produce and release pollen. RESULTS: Increases in pollen count were found to increase the number of tweets during the overall study period (P=.04), but not the main seasonal allergic rhinitis phase (P=.05). In contrast, increases in pollen count were found to increase patient numbers in both the study period (P=.04) and the main seasonal allergic rhinitis phase (P=.01). Increases in the number of tweets increased the patient numbers during the main seasonal allergic rhinitis phase (P=.02), but not the overall study period (P=.89). Patient numbers did not affect the number of tweets in both the overall study period (P=.24) and the main seasonal allergic rhinitis phase (P=.47). CONCLUSIONS: Understanding the causal relationships among pollen counts, tweet numbers, and numbers of patients with seasonal allergic rhinitis is an important step to increasing the credibility of surveillance systems that use social media data. Further in-depth studies are needed to identify the determinants of social media posts described in this exploratory analysis.

Antihistamines for Allergic Rhinitis Treatment from the Viewpoint of Nonsedative Properties.

Antihistamines targeting the histamine H1 receptor play an important role in improving and maintaining the quality of life of patients with allergic rhinitis. For more effective and safer use of second-generation drugs, which are recommended by various guidelines, a classification based on their detailed characteristics is necessary. Antihistamines for first-line therapy should not have central depressant/sedative activities. Sedative properties (drowsiness and impaired performance) are associated with the inhibition of central histamine neurons. Brain H1 receptor occupancy (H1RO) is a useful index shown to be correlated with indices based on clinical findings. Antihistamines are classified into non-sedating (<20%), less-sedating (20⁻50%), and sedating (≥50%) groups based on H1RO. Among the non-sedating group, fexofenadine and bilastine are classified into "non-brain-penetrating antihistamines" based on the H1RO. These two drugs have many common chemical properties. However, bilastine has more potent binding affinity to the H1 receptor, and its action tends to last longer. In well-controlled studies using objective indices, bilastine does not affect psychomotor or driving performance even at twice the usual dose (20 mg). Upon selecting antihistamines for allergic rhinitis, various situations should be taken into our consideration. This review summarizes that the non-brain-penetrating antihistamines should be chosen for the first-line therapy of mild allergic rhinitis.

Efficacy and safety of rupatadine in Japanese patients with seasonal allergic rhinitis: A double-blind, randomized, multicenter, placebo-controlled clinical trial.

BACKGROUND: Rupatadine is a novel non-sedating second-generation H1-antihistamine with antiplatelet-activating factor activity, first marketed in Spain in 2003. It is used for treating allergic rhinitis in more than 80 countries. This study investigated its efficacy and safety in Japanese patients with seasonal allergic rhinitis (SAR). METHODS: This was a randomized, placebo-controlled, double-blind study conducted at 4 medical institutions in Japan (JapicCTI-152785). Adolescent and adult SAR outpatients aged 12-64 years entered a 1-week placebo run-in period. After eligibility was confirmed, patients orally received placebo, rupatadine 10 mg, or 20 mg once daily for 2 weeks. The primary endpoint was a change from baseline to second week of treatment in total 4 nasal symptom score (T4NSS). RESULTS: Nine hundred patients were randomly assigned to placebo, rupatadine 10 mg, or rupatadine 20 mg (302, 298, and 300 patients, respectively). The least squares mean difference in the primary endpoint between rupatadine and placebo was -1.085 for 10 mg, and -1.415 for 20 mg (analysis of covariance, both P < 0.001). The rates of adverse events were 6.6%, 14.1%, and 15.0% for placebo, rupatadine 10 mg, and rupatadine 20 mg, respectively. Somnolence was most frequently reported: 7.0% for rupatadine 10 mg and 7.3% for rupatadine 20 mg. No serious adverse drug reactions were observed, and no adverse events resulted in premature discontinuation. CONCLUSIONS: Rupatadine 10 and 20 mg were significantly superior to placebo in improving nasal and ocular symptoms of SAR, and were well tolerated.

Treatment duration-dependent efficacy of Japanese cedar pollen sublingual immunotherapy: Evaluation of a phase II/III trial over three pollen dispersal seasons.

BACKGROUND: We conducted a randomized, placebo-controlled, double-blind clinical trial to investigate the optimal dose and long-term efficacy and safety of Japanese cedar (JC) pollen tablets for SLIT (JapicCTI-142579). Here, we report details of the effects of the JC pollen SLIT tablet on rhinitis and conjunctivitis symptoms over three pollen dispersal seasons. METHODS: A total of 1042 JC pollinosis patients (aged 5-64 years) were randomized to receive tablets containing placebo (P), 2000, 5000, or 10,000 Japanese allergy units (JAU) of JC pollen for 15 months to identify an optimal dose. Patients receiving P (n = 240) and the optimal dose (5000 JAU; A, n = 236) were then randomized to receive P or A for an additional 18 months (AA, AP, PA, and PP groups, allocation ratio 2:1:1:2). Nasal and ocular symptoms, rescue medication use, and quality of life (QOL) were assessed on quantitative scales. RESULTS: In the second and third seasons, the AA, AP, and PA groups exhibited significantly better improvements in nasal, ocular, and medication scores compared with the PP group in the order AA > AP > PA > PP during the second season and AA > PA > AP > PP during the third season. Rescue medication use and QOL scores were also significantly better in the AA, AP, and PA groups compared with the PP group. CONCLUSIONS: The JC pollen SLIT tablet relieved nasal and ocular symptoms and medication use and improved QOL in a treatment duration-dependent manner. Continuous dosing regimens appear to enhance the efficacy of the drug.

Efficacy and safety of SQ house dust mite sublingual immunotherapy-tablet in Japanese children.

BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (TO-203, Torii, Japan/ALK, Denmark) treatment has been effective against respiratory allergic diseases in patients aged ≥12 years during European, Japanese, and North American trials. This trial was conducted to investigate the efficacy and safety of this treatment in Japanese children (5-17 years) with moderate-to-severe HDM allergic rhinitis (AR). METHODS: In this randomized, double-blind, placebo-controlled trial, 458 Japanese children were randomly assigned to a daily SQ HDM SLIT-tablet [10 000 Japanese Allergy Unit (JAU), equivalent to 6 SQ-HDM in Europe and the US] or placebo (1:1) treatment for 1 year. Inclusion required an AR symptom score of ≥7 on at least 7 days during a 14-day run-in period while symptomatic treatment was withdrawn. The primary endpoint was the total combined rhinitis score (TCRS) comprising AR symptom and medication scores during the last 8 weeks of the treatment period. RESULTS: The analysis of primary endpoint demonstrated statistically significant absolute reduction in TCRS of 1.22 with a relative difference of 23% (95% confidence interval, 14% to 31%) in the 10 000 JAU compared with placebo. Predefined stratified analyses revealed the same degree of efficacy of 1.11 (P = 0.002), 21% (8% to 32%) and 1.36 (P = 0.001), 26% (11% to 38%), respectively, in pediatric (5-11 years) and adolescent subjects (12-17 years). The treatment was well tolerated by both pediatric and adolescent subjects. CONCLUSION: This trial, for the first time, demonstrated the efficacy and safety of the HDM SLIT-tablet in pediatric patients with moderate-to-severe HDM AR (JapicCTI-152953).

Identification of biomarker sets for predicting the efficacy of sublingual immunotherapy against pollen-induced allergic rhinitis.

Sublingual immunotherapy (SLIT) is effective against allergic rhinitis, although a substantial proportion of individuals is refractory. Herein, we describe a predictive modality to reliably identify SLIT non-responders (NRs). We conducted a 2-year clinical study in 193 adult patients with Japanese cedar pollinosis, with biweekly administration of 2000 Japanese allergy units of cedar pollen extract as the maintenance dose. After identifying high-responder (HR) patients with improved severity scores and NR patients with unchanged or exacerbated symptoms, differences in 33 HR and 34 NR patients were evaluated in terms of peripheral blood cellular profiles by flow cytometry and serum factors by ELISA and cytokine bead array, both pre- and post-SLIT. Improved clinical responses were seen in 72% of the treated patients. Pre-therapy IL-12p70 and post-therapy IgG1 serum levels were significantly different between HR and NR patients, although these parameters alone failed to distinguish NR from HR patients. However, the analysis of serum parameters in the pre-therapy samples with the Adaptive Boosting (AdaBoost) algorithm distinguished NR patients with high probability within the training data set. Cluster analysis revealed a positive correlation between serum Th1/Th2 cytokines and other cytokines/chemokines in HR patients after SLIT. Thus, processing of pre-therapy serum parameters with AdaBoost and cluster analysis can be reliably used to develop a prediction method for HR/NR patients.

Efficacy and safety of the SQ house dust mite sublingual immunotherapy tablet in Japanese adults and adolescents with house dust mite-induced allergic rhinitis.

BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet has been approved in 11 European countries and Japan for patients with HDM-induced respiratory allergic disease. OBJECTIVE: This trial was conducted to confirm the efficacy and safety of the SQ HDM SLIT tablet in Japanese patients with moderate-to-severe HDM-induced allergic rhinitis (AR). METHODS: The trial was a randomized, double-blind, placebo-controlled trial including 946 Japanese adults and adolescents (12-64 years). Subjects were randomly assigned to daily treatment with the SQ HDM SLIT tablet at a dose of 10,000 Japanese allergy units (JAU) or 20,000 JAU or to placebo (1:1:1). The primary end point was the total combined rhinitis score (TCRS), which is composed of AR symptom and medication scores during the efficacy evaluation period. Symptom and medication scores of AR and conjunctivitis, rhinitis quality of life, and symptom-free and symptom-severe days were evaluated as secondary end points. RESULTS: Analysis of the primary end point demonstrated statistically significant reductions in TCRSs of 1.15 (22%, P < .001) in the 10,000-JAU group and 0.99 (19%, P < .001) in the 20,000-JAU group compared with the placebo group. The statistically significant treatment effect was evident from 12 weeks of treatment onward. All secondary end points, except AR medication score, were statistically significant in favor of active treatment compared with placebo. Post hoc analysis of TCRSs in adolescents showed the same efficacy as in adults (P < .05). The treatment was well tolerated by both adults and adolescents. CONCLUSION: The trial confirmed the efficacy and safety profile of the SQ HDM SLIT tablet in Japanese adult and adolescent patients with moderate-to-severe HDM-induced AR. These data support the robust efficacy and safety profile of previously reported European data.

An analysis of factors related to the effect of sublingual immunotherapy on Japanese cedar pollen induced allergic rhinitis.

BACKGROUND: Sublingual immunotherapy (SLIT) can improve the symptoms of allergic rhinitis and modify its natural history; however, its efficacy varies among patients. This study aimed to determine which factors modify the effect of SLIT through post hoc analysis of a previous phase 3 trial of standardized Japanese cedar (JC) pollen extract (CEDARTOLEN®). METHODS: The study included 482 patients who had previously completed a phase 3 trial during two seasons. The SLIT and placebo groups each contained 241 subjects. Because pollen dispersal differed in the two seasons, we identified good and poor responders from the SLIT group in the 2nd season. We compared patient baseline characteristics, changes in serum immunoglobulin, and severity of symptoms in the 1st season between good and poor responders, as well as between SLIT and placebo groups. RESULTS: When we compared the baseline characteristics of good and poor responders, a significant difference was observed in body mass index (BMI) such that the patients with BMI ≥25 presented with lower treatment efficacy. No significant difference was observed in correlation with any other factors or treatment-induced alterations of serum immunoglobulin levels. We found that 75.3% of the patients with moderate symptoms and 50.9% of the patients with severe or very severe symptoms in the 1st season met our criteria for good responders in the 2nd season. CONCLUSIONS: BMI might modify the effect of SLIT; however, other factors were not related clearly. The severity of symptoms in the 1st season of treatment does not predict that in the 2nd season.

Efficacy and safety of the emedastine patch, a novel transdermal drug delivery system for allergic rhinitis: Phase III, multicenter, randomized, double-blinded, placebo-controlled, parallel-group comparative study in patients with seasonal allergic rhinitis.

BACKGROUND: The emedastine patch was developed in Japan as the first transdermal drug delivery system of emedastine difumarate for allergic rhinitis. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison was conducted in patients with seasonal allergic rhinitis. Patients were administered Emedastine patches (4 or 8 mg), placebo, or levocetirizine hydrochloride (5 mg tablet) once daily for 2 weeks (double-dummy technique). The primary objective was superiority to placebo by the change of the total nasal symptom score (sneezing, rhinorrhea, and nasal congestion) in Week 2. Levocetirizine was a reference drug and not a comparator in this study. RESULTS: A total of 1276 patients were randomized to receive the 4 mg emedastine patch (n = 384), 8 mg emedastine patch (n = 382), placebo (n = 384), or levocetirizine (n = 126). The least squares mean (LSM) of the change from baseline of the total nasal symptom score (TNSS) in Week 2 was significantly larger in both emedastine patch groups than in the placebo group (adjusted p < 0.0001). In secondary analysis, LSM of the change in the TNSS was -1.20, -1.49, -0.44, and -1.32 in the 4 mg emedastine patch, 8 mg patch, placebo, and levocetirizine, respectively. Reductions in the number of episodes and scores of individual nasal symptoms were all significantly larger throughout the day in the emedastine patch groups than the placebo group (all p < 0.05). No clinically significant safety problems occurred. CONCLUSIONS: The emedastine patch (4 and 8 mg) effectively and safely controlled symptoms of seasonal allergic rhinitis with sustained action throughout the day. STUDY REGISTRATION: JapicCTI-153092.

Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial.

BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

[INVESTIGATION OF TREATMENT GOAL IN ALLERGEN IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS].

BACKGROUND/OBJECTIVE: As few reports are available on treatment goal for Japanese cedar pollinosis treated with allergen immunotherapy, therapeutic effect has to be assessed based on subjective symptoms in clinical practice. This research was conducted to investigate the informative treatment goal in clinical practice by using the results of TO-194SL phase III clinical trial. METHODS: In this investigation, correlation between total nasal symptom medication score (TNSMS), which was predefined as the primary endpoint, and secondary endpoints evaluated by severe symptom day, quality of life (QOL) score, and overall evaluation by subject, was firstly investigated. Based on the results, stratified analyses of the secondary endpoints to confirm relationships on the stratified results, TNSMS, and cedar season were performed. RESULTS: Correlation between TNSMS and evaluations which were severe symptom day, QOL score, and overall evaluation by subject was reasonably observed. TNSMS generally showed 3 or below (classified as mild) throughout the entire pollen season when these evaluations reached each threshold. CONCLUSIONS: The results of this investigation suggest that a few evaluation items would help patients to realize the therapeutic effects of allergen immunotherapy if they could be the treatment goal in clinical practice.