Real-world safety and efficacy of omalizumab in patients with severe allergic asthma: A long-term post-marketing study in Japan.

BACKGROUND: Omalizumab (anti-IgE monoclonal antibody) is an approved add-on therapy for Japanese patients with severe allergic asthma. As directed by the Ministry of Health, Labor and Welfare Japan, a post-marketing surveillance (PMS) study on omalizumab was conducted between 2009 and 2017. METHODS: The PMS observed safety and efficacy of omalizumab in patients treated with open-label omalizumab for 52 weeks (with optional 2-year extension period). Primary safety outcomes included incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs). Primary efficacy outcomes included physician-assessed global evaluation of treatment effectiveness (GETE). Asthma-exacerbation-related events including requirement for additional systemic steroid therapy, hospitalization, emergency room visits, unscheduled doctor visits, and absenteeism were also evaluated. RESULTS: Of 3893 patients registered, 3620 (age [mean ±â€¯SD] 59.3 ±â€¯16.11 years) were evaluated for 52 weeks; 44.12% were aged ≥65 years and 64.45% were women. Overall, 32.24% reported AEs and 15.30% reported serious AEs. ADRs were seen in 292 (8.07%) patients. GETE results showed that the majority of patients experienced clinical improvements (58.29% at 16 weeks and 62.40% at 52 weeks). Nearly half of all patients (47.96%) were free from asthma exacerbations after therapy. Omalizumab also reduced all events related to asthma exacerbations. No specific ADRs were observed in the elderly population. CONCLUSIONS: This post-marketing study confirmed the clinically meaningful benefits of omalizumab in a majority of patients from Japan, and showed safety and efficacy in a real-life clinical setting to be consistent with previous reports.

Transdermal tulobuterol patch, a long-actingß(2)-agonist.

Tulobuterol patch (HokunalinTM Tape), which contains a ß(2)-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. This drug delivery system ensures that the time at which the peak drug concentration in the blood is reached coincides with the morning dip in respiratory function. The use of the patch also prevents excessive increase in blood drug concentrations, thereby reducing the incidence of systemic adverse reactions. Since 1998, when it was first approved in Japan and worldwide, the tulobuterol patch has been used widely in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD), and evidence collected since it was approved has confirmed its clinical efficacy and safety. Because the patch is easy to use and requires only once-daily application, treatment adherence of patients using the patch is good. In this article, we discuss the rationale behind the development of the tulobuterol patch, evaluate data on its clinical efficacy and safety in the treatment of asthma and COPD, and examine the treatment adherence in individuals using the patch.

Time trend in the prevalence of adult asthma in Japan: findings from population-based surveys in Fujieda City in 1985, 1999, and 2006.

BACKGROUND: The burden of asthma is recognized as an important public health problem worldwide. In most countries, the prevalence of asthma has been reported to increase in the last few decades. However, more recent epidemiological studies have shown that the prevalence of asthma has been flat or even decreasing after the 1990 s in some developed countries. The recent time trend in the prevalence of adult asthma in Japan is unknown. METHODS: Population-based surveys were conducted three times in the same region, in 1985, 1999, and 2006, at Fujieda City, Shizuoka, Japan, and the results were reported previously. We compared the results of these surveys to reveal the time trend in the prevalence of adult asthma. Although the questionnaires used in these surveys were not exactly the same, the time trend was assessed by comparing the responses to relevant questions between questionnaires. RESULTS: The prevalences of wheeze following a common cold and dyspneal feeling at night increased significantly from 1985 to 1999 (4.2% to 7.6%, and 3.2% to 5.3%, respectively). The prevalences of lifetime asthma and current asthma also significantly increased from 1999 to 2006 (5.1% to 6.7%, and 1.5% to 3.4%, respectively). CONCLUSIONS: The prevalences of asthma among adults in Fujieda City consistently increased from 1985 to 2006. There was no evidence that the prevalences were in plateau or decreasing. These findings suggest that more efforts are required to stop the increase in the burden of this disease in Japan.

[Cost-effectiveness of salmeterol/fluticasone combination therapy vs. fluticasone propionate in Japanese asthmatic patients].

We commenced to estimate the economic impact of salmeterol/fluticasone combination (SFC) therapy compared to fluticasone propionate (FP) therapy for asthma control in Japanese patients. A Markov model with five health states, developed by Price in 2002, was used. 1-week transition probabilities among status of asthma management were obtained from literature and epidemiological data from public data base. Direct cost for treatment was estimated from Japan medical fee schedule. Cost and effectiveness were not discounted due to 12-week simulation by the model. Univariate sensitivity analyses were undertaken to examine the main variables affecting cost-effectiveness. Probabilistic analysis was also undertaken to discuss statistical argument and to provide information for decision-making. In this analysis, the model was run over a 12-week period of time using transition probabilities. The results showed that treatment with SFC resulted in a higher proportion of totally controlled weeks per patient than treatment with FP (65.0 vs. 49.5%; incremental effectiveness by 15.5%), and lower mean direct asthma management costs ( yen168 702 vs. yen227 820). Probabilistic sensitivity analysis, conducted to assess robustness of the above base case result, showed that in the 95% of cases SFC was dominant (more effective and less costly) to FP. It suggested that SFC will be the most cost-effective therapy for asthma control. It would, however, be required to further evaluate cost-effectiveness of SFC in long-term observation.

One year treatment with omalizumab is effective and well tolerated in Japanese Patients with moderate-to-severe persistent asthma.

BACKGROUND: We have previously demonstrated that addition of omalizumab to standard therapy improved asthma control by significantly improving lung function and reducing asthma exacerbations in Japanese patients with moderate-to-severe asthma. The aim of this study was to evaluate the effects of omalizumab on long-term disease control in Japanese patients with moderate-to-severe persistent asthma. METHODS: An open-label, 48-week study was conducted in 133 Japanese patients with moderate-to-severe persistent asthma. Omalizumab was administered subcutaneously every 2 or 4 weeks based on serum IgE level and body weight in each patient. RESULTS: Treatment with omalizumab significantly improved lung function. A subgroup of patients with inadequately controlled severe persistent asthma, despite high dose inhaled corticosteroids and other multiple controller therapies, which corresponds to the Japanese label (label population), showed greater improvements in morning PEF and FEV(1) than the whole study population (full Analysis Set). Serum free IgE levels decreased to below the target and were maintained during the treatment period in almost all patients. The majority of adverse events were mild-to-moderate in severity and there was no trend toward an increase in incidence of adverse events with increase in duration of omalizumab. In addition, the profile of adverse events in this study was similar to that in a 16-week, placebo-controlled study which the present authors had conducted previously in Japan. There were no anaphylactic reactions and no anti-omalizumab antibodies were detected. CONCLUSIONS: Long-term treatment with omalizumab is effective and well tolerated in Japanese patients with moderate-to-severe persistent asthma.

Efficacy, safety, and tolerability of mometasone furoate in adult Japanese patients with mild asthma: open-label clinical trial findings.

OBJECTIVE: To evaluate the clinical efficacy and safety of mometasone furoate administered via a dry powder inhaler (MF-DPI) in Japanese patients with intermittent or mild persistent asthma who were not previously receiving inhaled corticosteroids. RESEARCH DESIGN AND METHODS: This was an 8-week open-label study conducted in Japanese patients > or =16 years of age with intermittent or mild persistent asthma. All patients provided informed written consent before baseline and were treated with MF-DPI 200 microg/day, taken as 100 microg twice daily (BID). Inhaled steroids other than the study drug are not used, the drugs used previously are continued, dose of concomitant drug may be reduced if symptoms are improved and no new drugs were allowed during the trial. The primary efficacy variable was the change from baseline in morning peak expiratory flow (AM PEF). Secondary efficacy variables were evening (PM) PEF, spirometric measurements of lung function, and subjective symptoms. Descriptive statistics and standard errors were calculated for each efficacy evaluation. The safety of MF-DPI treatment was evaluated by measuring adverse events (AEs) and laboratory tests. RESULTS: Twenty patients received MF-DPI, and 19 patients (nine with intermittent asthma and 10 with mild persistent asthma) were included in the full analysis set (FAS). The mean AM PEF and PM PEF values increased by 9.1% (P < 0.0001) and 7.3% (P < 0.0001), respectively, in the FAS. Improvements in AM and PM PEF occurred as early as week 1 and were sustained throughout treatment. Improvements at week 8 in forced expiratory volume in 1 second and forced vital capacity were 11.0% and 8.2%, respectively. Notable decreases occurred for subjective symptom scores. The reported AEs were mild to moderate in severity. Study limitations include the small sample size and open-label treatment. This study was planned as the first study of MF-DPI in Japanese mild asthma patients without receiving other inhaled steroids. In addition, the cost:benefit ratio of MF-DPI in patients with intermittent asthma was not addressed. CONCLUSION: MF-DPI 100 microg BID is an effective treatment for Japanese patients with intermittent or mild persistent asthma.

Efficacy and safety of omalizumab in an Asian population with moderate-to-severe persistent asthma.

BACKGROUND AND OBJECTIVE: The efficacy and safety of the anti-IgE antibody, omalizumab, has been widely studied in patients with asthma. However to date, no large studies have been performed in Asian populations. The aim of this study was to compare the efficacy and safety of omalizumab with placebo, as add-on therapy in Asian patients with moderate-to-severe persistent asthma. METHODS: Japanese patients (20-75 years of age) with uncontrolled asthma, despite receiving high-dose inhaled corticosteroids and other standard therapies, were randomized to receive add-on treatment with omalizumab or placebo in a 16-week, double-blind, parallel-group, multicentre study. RESULTS: Altogether, 315 treated patients were included in the efficacy and safety analyses. The change from baseline in morning PEF was 15.45 L/min (least squares mean) with omalizumab versus 2.25 L/min with placebo, a statistically significant difference of 13.19 L/min (P = 0.0004). Clinically significant asthma exacerbations occurred in six patients (4.0%) treated with omalizumab and in 18 patients (11.0%) treated with placebo. The odds ratio for the risk of experiencing an asthma exacerbation was 0.32 in favour of omalizumab (P = 0.0192). Changes in asthma symptom scores, daily life activity scores, sleep scores and rescue medication use were in favour of omalizumab, but group differences did not reach statistical significance. Adverse event rates were similar between omalizumab and placebo, except for injection site reactions, which were more frequently observed in the omalizumab group. CONCLUSIONS: Add-on treatment with omalizumab improved asthma control without significant adverse events in Japanese patients with moderate-to-severe persistent asthma.

Efficacy and safety of once-daily inhaled ciclesonide in adults with mild to moderate asthma: a double-blind, placebo-controlled study.

BACKGROUND AND OBJECTIVE: Inhaled corticosteroids are recommended as first-line therapy for the management of asthma, although side-effects may limit their use. Ciclesonide, a novel pro-drug inhaled corticosteroid, exerts potent and prolonged local anti-inflammatory effects in the lungs, and is considered to have an improved safety and tolerability profile. The aim of this study was to evaluate the efficacy and safety of ciclesonide in adult patients with mild to moderate asthma. METHODS: A placebo-controlled, multicentre, randomized, double-blind, parallel-group study was conducted. During the 4-week baseline period, patients were given 400 microg/day of beclomethasone dipropionate in a chlorofluorocarbon formulation. After the baseline period, 311 patients were given once-daily 100, 200 or 400 microg of ciclesonide or placebo for an 8-week treatment period without the use of a spacer. The primary efficacy variable was morning PEF. RESULTS: Changes in the morning PEF (least squares mean) at the end of the study were 4.23 L/min (P < 0.001) in the 100 microg group, 3.75 L/min (P < 0.001) in the 200 microg group, -0.40 L/min (P < 0.001) in the 400 microg group, as compared with -24.95 L/min in the placebo group. In the ciclesonide groups, the PEF remained at the same level as the baseline period. No large differences were observed between the placebo group and the ciclesonide groups regarding safety. CONCLUSION: Once-daily administration of ciclesonide at doses of 100, 200 or 400 microg was shown to be effective in adult patients with mild to moderate asthma. Ciclesonide is considered to have favourable safety profiles and be well tolerated.

Efficacy and safety of inhaled ciclesonide compared with chlorofluorocarbon beclomethasone dipropionate in adults with moderate to severe persistent asthma.

BACKGROUND AND OBJECTIVE: Inhaled corticosteroids are recognized as first-line therapy in the management of asthma; however, their use may be limited by systemic and local side-effects. Ciclesonide, a novel pro-drug inhaled corticosteroid, is activated in the lungs and is expected to have less systemic and local side-effects. This study evaluated the efficacy and safety of ciclesonide in hydrofluoroalkane (HFA) compared with beclomethasone dipropionate (BDP) in a chlorofluorocarbon (CFC) formulation in adult patients with moderate to severe asthma. METHODS: This was a multicentre, randomized, open-label, parallel-group comparative study. The patients were given 800 microg/day of CFC-BDP in the four-week baseline period. After the baseline period, 319 patients were randomly allocated into three groups which, respectively, received HFA-ciclesonide 400 microg/day (without a spacer), HFA-ciclesonide 800 microg/day (without spacer) and CFC-BDP 800 microg/day (with spacer) for the eight-week treatment period. The primary efficacy variable was morning PEF. RESULTS: The morning PEF increased by 16.02 L/min in the 400 microg HFA-ciclesonide group, 23.98 L/min in the 800 microg HFA-ciclesonide group and 5.91 L/min in the 800 microg CFC-BDP group. Better outcomes were achieved by the use of 800 microg/day of HFA-ciclesonide compared with 800 microg/day of CFC-BDP (P = 0.001). There was no difference in adverse events between the groups. CONCLUSION: In adult patients with moderate to severe asthma, 800 microg/day of HFA-ciclesonide was significantly more effective than 800 microg/day of CFC-BDP. Ciclesonide at doses of 400 microg/day and 800 microg/day was safe and well tolerated.

A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD.

BACKGROUND: Theophylline is a useful drug for the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) recommend use of sustained-release theophylline products as controllers and of injectable aminophylline products as relievers. The Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention, the NHLB/WHP Workshop Report 1995 (GINA, 1995) and guidelines in Western countries recommend sustained-release theophylline, but not as positively as in the JGL. The aim of this survey was to determine the occurrence of serious adverse reactions. METHODS: The survey was conducted in 66 institutions staffed by physicians certified by the Japanese Society of Allergology (JSA). The target diseases were asthma and COPD including chronic bronchitis and pulmonary emphysema, which are indications for use of sustained-release theophylline products in Japan. RESULTS: 3,921 patients were included in the safety evaluation. No serious adverse reactions were observed among the patients in this survey, although 54 patients (1.38%) exhibited non-serious adverse reactions. The incidence of adverse reactions was found to be high in patients who had begun use of sustained-release theophylline products at the time of registration in this survey, and in patients who were concomitantly taking macrolide antibiotics. CONCLUSIONS: The present survey demonstrates that sustained-release theophylline is safe, as long as used appropriately, although adverse reactions tend to develop early after initiation of administration.

Prospective survey on safety evaluation of injectable methylxanthines in Japan.

BACKGROUND: Injectable methylxanthines are useful drugs in the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) that are followed in Japan recommend the use of sustained-release theophylline to control the disease and use of injectable methylxanthines to alleviate symptoms. In contrast, the guidelines followed in the west do not promote theophylline use due to safety concerns, and the use of injectable methylxanthines in particular are not recommended. We thus conducted a study on adult patients with bronchial asthma or chronic obstructive pulmonary disease treated with theophylline and injectable methylxanthines in Japan in order to assess the safety of these drugs. METHODS: 876 patients were surveyed at 55 medical institutions by the Committee on the Safety of Sustained-Release Theophylline and Injectable Methylxanthines (CST) of the Committee for Asthma Prevention and Management Guidelines of the Japanese Society of Allergology (JSA). 682 of the patients were evaluated for safety. RESULTS: Adverse reactions including facial flushing, palpitations, headache, tinnitus, diaphoresis, nausea, vomiting and tachycardia were reported by only 2 (0.29%) of the 682 patients, but none of these were serious. CONCLUSIONS: The results confirm that injectable methylxanthines are safe, when used in accordance with the JGL.

[Cost-effectiveness of fluticasone propionate for asthma episodes in Japanese patients with asthma--Fluticasone Investigation of Asthma Episode (FINE) study].

BACKGROUND: To discuss and estimate the economic benefits gained by fluticasone propionate (FP) for patients with asthma over hospitalization, emergency room visit, unscheduled visit, and absence (representative by asthma-related episode). METHOD: Asthma-related episodes in pre and post 6 months of FP use were derived from a survey of FP on asthma-related episodes (FINE study). Medical cost was evaluated by macro-cost estimate and productivity loss by human capital approach. RESULTS: Discussion of asthma-related episodes in-between before and after the use of FP in eight hundred ninety-eight valuable subjects revealed that FP use significantly reduced asthma-related episodic costs of approximately 120,000 yen (p<0.001), whereas total drug acquisition costs for being newly consumed FP, leukotriene receptor antagonists, inhaled short-acting beta2 agonists, etc were significantly increased by approximately 16,000 yen. Moreover, while significantly avoiding productivity loss of approximately about 35,000 yen it totally provided cost-savings of about 70,000 yen at the patients' viewpoint. When sensitivity analyses were performed by adjusting the confounding factors using analysis of covariance, the aforementioned base case results might be persistent. For safety of FP, some adverse events related to the use of FP were identified of about 2.0%, and there were not any serious ones at all. CONCLUSION: The economic evaluation of FP demonstrated that it is sufficient, whereas an acquisition cost was increased. Use of FP economically impacts on Japanese society and patients.

Effects of nebulized sodium cromoglycate on adult patients with severe refractory asthma.

Many patients with severe refractory asthma, which is insufficiently controlled by additional high-dose of inhaled corticosteroids, require oral corticosteroids and/or immunosuppressant. Clinicians should seek for suitable medications, for its' chronic use may induce high risk of side effects. The purpose of this study was to evaluate the efficacy and safety of nebulized sodium cromoglycate (3-4 times/day) in adult severe asthmatic patients with poorly controlled asthmatic symptoms, despite treatments with high-dose inhaled corticosteroids. Adult patients with severe asthma (n=251) were enrolled in a randomized clinical trial at 30 medical centers in Japan. Isotonic saline was used as placebo. The study was conducted for 10 weeks; with initial 2 weeks of observation followed by 8 weeks of treatments. Efficacy was primarily evaluated based on improvements in morning peak expiratory flow after treatment. All patients who applied inhalation of nebulized sodium cromoglycate (SCG group) or saline (Controls) were treated with high-dose of inhaled corticosteroids (median of beclomethasone dipropionate equivalent dose: 1600 microg/days) and second-line control therapy including oral corticosteroids. There was no significant difference in morning peak expiratory flow between SCG group and controls. However, when patients were stratified into atopic and non-atopic groups, morning peak expiratory flow had significantly improved in the atopic SCG group compared to atopic Controls. Additional inhalation of nebulized sodium cromoglycate with inhaled corticosteroids is effective even in patients with severe atopic asthma. This finding shows that nebulized sodium cromoglycate is expected to be new second-line therapeutic option in severe asthma.