Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough.

BACKGROUND: The purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3 versus P2X2/3. METHODS: In a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2-3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated. RESULTS: Of 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks of treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary end-point) and over 24 h (secondary end-point) were -31.6% (p=0.0546) and -30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration. CONCLUSIONS: Sivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.

Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial.

BACKGROUND: The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites. METHODS: SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits. RESULTS: In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks' treatment, while 163 received ≥ 104 weeks' treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor. CONCLUSIONS: In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517 .

Clinical benefit of two-times-per-day aclidinium bromide compared with once-a-day tiotropium bromide hydrate in COPD: a multicentre, open-label, randomised study.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is mainly treated pharmaceutically with bronchodilators. The purpose of this study was to evaluate the clinical benefits of two-times-per-day aclidinium bromide (Acli-BID) compared with once-a-day tiotropium bromide hydrate (Tio-QD) in patients with COPD. DESIGN: This study was a multicentre, open-label, randomised study. SETTING: Fourcentres in Kagawa prefecture, Japan. PARTICIPANT: Patients who were diagnosed to have COPD Grade 2-3 according to the Global Initiative for Chronic Obstructive Lung Disease 2015 criteria were enrolled. INTERVENTIONS: Patients were randomly assigned to receive Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. Acli-BID was administered in the morning and night, and Tio-QD was administered in the night. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was forced expiratory volume in one second area under the curve (FEV1AUC0-3), and secondary outcomes were pulmonary function, physical activity, St George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC), the 8-item Short-Form Health Survey (SF-8) and COPD exacerbations. Adverse events were evaluated during the study. RESULTS: 44 patients were included in this study. FEV1AUC0-3 at week 8 was 4.62±1.43 L·hour in Acli-BID and 4.73±1.60 L·hour in Tio-QD (mean difference (MD) -0.11 L·hour; 95% CI), -1.04 to 0.83). Significant improvement was observed in activity-related subscales of SGRQ (MD -7.78; 95% CI -14.61 to -0.94) and SF-8 (MD 4.01; 95% CI 0.37 to 7.65), mMRC (MD -0.66; 95% CI -1.19 to -0.13) and rate ratio (0.52, 95% CI 0.27 to 0.99) of exacerbations in the Acli-BID compared with the Tio-QD. Acli-BID and Tio-QD significantly improved sedentary behaviour (MD -35.20 min; 95% CI -67.41 to -2.94 and MD -55.40 min; 95% CI -98.15 to -12.77) within each group, but there was no significant difference between the two groups. CONCLUSION: Acli-BID as with Tio-QD could be one of the therapeutic options for patients with COPD to improve pulmonary function. Also, our results suggest that intervention with bronchodilators enhanced physical activity in patients with COPD. TRIAL REGISTRATION NUMBER: UMIN 000020020.

Asthma mortality based on death certificates: A demographic survey in Kagawa, Japan.

BACKGROUND: We aimed to determine the reasons for the high rate of asthma mortality in Kagawa Prefecture, Japan, by analyzing death certificates. METHODS: We analyzed the death certificates between 2009 and 2011 in a demographic survey. Of 1187 patients with documented disease names suggesting bronchial asthma, analysis was performed on 103 patients in whom the cause of death was classified as asthma based on ICD-10 Codes. The patients were then classified into the following 4 groups: asthma death, asthma-related death, non-asthma death, and indistinguishable death. Based on this classification, consistency between ICD-10-based asthma death and asthma/asthma-related deaths was examined for each age group as well as for the site of death. RESULTS: Of 103 asthma deaths based on the ICD-10 classification, 30 (29%) were classified as asthma death, 44 (43%) as asthma-related death, 16 (16%) as non-asthma death, and 13 (13%) as indistinguishable death. Asthma death based on our classification correlated with that of ICD-10-based classification as a cause of death in patients younger than the median age (87 years), but correlation was not observed in patients aged older than 87 years. Deaths occurred outside the hospital in 45% of patients, and many ICD-10-based deaths reported at nursing homes and geriatric health care facilities were classified as non-asthma deaths in this survey. CONCLUSION: Re-examination of the death certificate revealed that asthma deaths were reported incorrectly on the death certificates of elderly patients who died outside the hospital.

Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma.

BACKGROUND: In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial. METHODS: CALIMA was a randomised, controlled trial of 1306 patients (aged 12-75 years; registered at ClinicalTrials.gov: NCT01914757) with severe asthma uncontrolled by medium- to high-dosage inhaled corticosteroids and long-acting ß2-agonists (ICS/LABA). Patients received 56 weeks' benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), or placebo Q4W. The primary analysis population was patients receiving high-dosage ICS/LABA with blood eosinophils ≥300 cells/µL. This subgroup analysis covered Japanese patients from this group. RESULTS: Of 83 patients randomised in Japan, 46 were receiving high-dosage ICS/LABA and had blood eosinophils ≥300 cells/µL. Compared with placebo, benralizumab reduced the annual rate of asthma exacerbations by 66% (Q4W; rate ratio 0.34, 95% CI, 0.11-0.99) and 83% (Q8W; rate ratio 0.17, 95% CI, 0.05-0.60); increased prebronchodilator FEV1 by 0.334 L (Q4W; 95% CI, 0.020-0.647) and 0.198 L (Q8W; 95% CI, -0.118 to 0.514); and decreased total asthma symptom score by 0.17 (Q4W; 95% CI, -0.82 to 0.48) and 0.24 (Q8W; 95% CI, -0.87 to 0.40). Percentages of adverse events were consistent with the overall CALIMA group. CONCLUSIONS: Benralizumab reduced annual asthma exacerbations and symptoms, increased lung function, and was well-tolerated by Japanese patients with severe, uncontrolled eosinophilic asthma.

Ongoing allergic rhinitis impairs asthma control by enhancing the lower airway inflammation.

BACKGROUND: The relationship between allergic rhinitis and asthma is well accepted; however, little is known about the mechanism that underlies the interactions between the upper and lower airways. OBJECTIVE: To investigate the symptomatic and inflammatory linkages between allergic rhinitis and asthma in patients with atopy. METHODS: We enrolled 520 patients with asthma who were taking inhaled corticosteroids, and examined them by using the Asthma Control Questionnaire, spirometry, exhaled nitric oxide fraction (FENO), visual analog scale for nasal symptoms, allergic rhinitis questionnaire, and serum specific IgE (study 1). The symptomatic and inflammatory marker responses to nasal corticosteroids in patients with incompletely controlled asthma (Asthma Control Questionnaire > 0.75) and moderate-to-severe persistent allergic rhinitis were also observed (study 2). RESULTS: A total of 348 patients (66.9%) had atopy and allergic rhinitis. There was a striking difference in the proportion of patients with incomplete asthma control, depending on the presence as well as the activity of rhinitis (no rhinitis, 11.0%; mild intermittent, 20.4%; moderate-to-severe intermittent, 44.6%; mild persistent, 53.1%; moderate-to-severe persistent, 65.7%). The FENO levels were increased with the activity of rhinitis, and the nasal visual analog scale was positively correlated with the FENO levels (r = 0.31; P < .0001). The additive treatment with nasal corticosteroids improved the nasal visual analog scale, Asthma Control Questionnaire, and FENO levels, and the changes in these variables were correlated with each other in all parameters (all P < .001). CONCLUSION: This observational study of patients with atopy indicates that the ongoing allergic rhinitis is related to worsening of asthma by enhancing the lower airway inflammation.

Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial.

PURPOSE: Amrubicin is a novel 9-aminoanthracycline. This multicenter phase II study was conducted to evaluate the efficacy and safety of amrubicin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-one previously untreated patients with stage III or IV NSCLC were entered this study. The patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Amrubicin was administered by daily intravenous injection at 45 mg/m2/day for 3 consecutive days every 3 weeks. At least 3 cycles of treatment were administered to each patient. RESULTS: All 61 patients registered in this trial were eligible and assessable for efficacy and toxicity. Of them, 17 patients achieved objective responses, consisting of one complete response and 16 partial responses, and the overall response rate was 27.9% (95% confidence interval [CI], 17.1% to 40.8%). The median survival time was 9.8 months (95% CI, 7.7 months to 14.9 months). The major toxicity was myelosuppression. The incidences of grade 3 or 4 toxicity were 72.1% for neutropenia, 52.5% for leukopenia, 23.0% for anemia, and 14.8% for thrombocytopenia. As noticeable toxic events, grade 3 hypotention and alkaline phosphatase elevation were transiently observed in one patient each. In addition, three patients who had had asymptomatic interstitial pneumonitis, identified by diagnostic imaging before treatment, aggravated after amrubicin treatment; two of them died. Other non-hematologic toxicities were relatively mild. CONCLUSION: Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.

[Measurement of peak inspiratory flow with asthma: effect of inhaled beta2-stimulant].

This study was designed to evaluate peak inspiratory flow (PIF) and peak expiratory flow (PEF) in 24 patients with mild asthma. After inhalation of a beta2-stimulant (beta2), PIF significantly increased from 173.0 +/- 67.0 (range 70-300 L/min) to 194.0 +/- 66.7 after 1 minute, and to 199.3 +/- 63.0 after 15 minutes (p < 0.0025, and p < 0.008, respectively). PEF also significantly increased. The previous inhalation of beta2 improved the efficacy of inhalation of dry powder. This evidence should be considered in performing patient education for effective methods of inhalation.

[Effect of oral beta2-stimulant on pulmonary function in asthma patients treated with multiple medications].

This study was designed to evaluate the effect of discontinuing oral beta2-stimulant in patients with asthma who were being treated with multiple medications. Thirty-two asthmatics controlled under multiple medications who had a stable PEF were entered. Patient symptoms, PEF, FEV10, V75,V50, and V25 were evaluated before and after discontinuing beta2-stimulant. Results showed that after discontinuing beta2-stimulant, there was little change in symptoms, PEF, or FEV10, and only two patients had to be re-medicated with oral beta2-stimulant. However, deterioration of V50 and V25 were clearly observed, suggesting that oral beta2-stimulant had an affect on dilatation of the small airway. Based on our data, we should regard that when discontinuing oral beta2-stimulant from combined use, the lung function reflecting the small airway decreases even if no change of symptoms is observed.

[Acute effect of inhaled beta(2)-agonists with different type of intrinsic activity on airway resistance in healthy volunteers].

Inhaled beta(2)-agonists (long-acting as well as short acting) are used world-wide for the relief of asthma symptoms. However, there are few reports which have evaluated the additive effect of short-acting beta(2)-agonists to long-acting beta(2)-agonists on airway resistance measured by a plethysmography. This study was designed to evaluate the additive effect of inhaled short-acting beta(2)-agonists (protecarol) to long-acting beta(2)-agonists (salmeterol) on airway resistance in normal healthy volunteers (S+P group). In addition, to compare the effects of beta(2)-agonists which have different types of intrinsic activities, acute effect of inhaled procaterol adding to procaterol was also evaluated (P+P group). Seven healthy volunteers (all male and all non-smokers) were entered in this study. Pulmonary function was measured by a body plethysmography. Forced expiratory volume per 1 second (FEV1), the maximum flow rate at 25% (V(.) 25), the maximum flow rate at 50% of forced vital capacity (V(.) 50), and airway resistance were measured before and after inhalation of salmeterol (1 dry powder, 50 microg) or procaterol (2 puffs, 20 microg). Sixty minutes after inhalation of salmeterol, or 15 minutes after inhalation of procaterol, inhalation of procaterol (2 puffs, 20 microg) was added, and then pulmonary function was monitored. FEV1, V(.) 25, and V(.) 50 were significantly increased after inhalation of salmeterol as well as procaterol. In addition, airway resistance decreased significantly after inhalation of salmeterol as well as procaterol. In the S+P group, additional decrease of airway resistance after inhalation of procaterol was relatively small compared with the P+P group. In conclusion, although additional bronchodilatoric effects were observed in the S+P and P+P group, the effects seemed to be different based on the intrinsic activity of each beta(2)-agonist.

[Beta 2-adrenoceptor polymorphism and effects of inhaled beta 2-stimulant (procaterol) and an anti-cholinergic drug (oxitropium) on the airway resistance].

It has been suggested that the Arg 16/Gly 16 allele at codon 16 of beta 2-adrenoceptor polymorphism plays a role in down-regulating the stimulus of bronchodilatation caused by beta 2-agonists. This study was designed to evaluate the difference of bronchodilator responsiveness to beta 2-agonist (procaterol) and anti-cholinergic drug (oxitropium) between those who have Arg 16/Gly 16 allele (hetero type) and those who have Gly 16/Gly 16 allele (variant type) at codon 16 of in healthy women. Airway resistance and other pulmonary function tests were measured by a body plethysmography before and 5, 10, 15, 20, and 30 minutes after inhalation of procaterol or inhalation of procaterol and oxitropium. In healthy women inhaled procaterol, percent changes of respiratory airway resistance compared with values before inhalation were -2.8 after 5 minutes, -7.5 after 10 minutes, -11.2 after 15 minutes, -15.4 after 20 minutes, and -12.6 after 30 minutes. In healthy women inhaled porcaterol and oxitropium, percent changes of respiratory airway resistance compared with values before inhalation were -14.5 after 5 minutes, -18.9 after 10 minutes, -17.0 after 15 minutes, -20.8 after 20 minutes, and -20.4 after 30 minutes. Patterns of decrease of respiratory airway resistance differed between women who have Arg 16/Gly 16 allele (hetero type) and those who have Gly 16/Gly 16 allele (variant type). In women who have Gly 16/Gly 16 allele (variant type), although acute decrease of respiratory airway resistance was observed, the duration of bronchodilator effect by inhaled procaterol and oxitropium was shorter than those observed in Arg 16/Gly 16 allele (hetero type). The present study showed inhalation of procaterol and oxitropium had a differential bronchodilator effect in healthy women, depending on their genotype of beta 2-adrenoceptor polymorphism at codon 16.

[Low-dose multi-slice CT (LMCT) assessment of pulmonary emphysema in public-school teachers].

Although rates of emphysematous change in smokers have been reported previously, the precise effects of smoking on emphysematous change have not been established because the study subjects of previous reports were heterogeneous. This study was designed to determine the incidence of emphysematous change identified by LMCT imaging in public-school teachers. We reviewed 1776 consecutive subjects (ages from 31 to 61 years) who had undergone LMCT scanning during health care examinations. In addition, their replies to questionnaires about smoking were obtained. Emphysematous change was found by LMCT imaging in 22 male smokers. In these 22 smokers, the scores of emphysematous change according to Goddard's method was well correlated with smoking history. According to the questionnaires, the smoking rates of male and female teachers were 56.7% and 4%, respectively. Eighty-five percent of the teachers worked in offices separated from smokers. Most smokers wished to quit smoking and most teachers knew the risk of nicotine as well as the rate of smoking among high school students. However, knowledge of the relationships between smoking and lung cancer, myocardial infarction, and subarachnoid hemorrhage were not adequate. Our present study clearly demonstrated the incidence of emphysematous change in school teachers. In addition, early exposure to information about the risks of smoking is believed to be important for students, but school teachers did not have enough of such information.

[beta 2-adrenoceptor polymorphism and effect of inhaled beta 2-stimulant (procaterol) on airway resistance measured by body plethysmography in healthy volunteers].

This study was designed to evaluate, in healthy volunteers, differences of bronchodilator responsiveness to a beta 2-agonist between those with the Arg 16/Gly 16 allele and those with the Gly 16/Gly 16 allele at codon 16 of beta 2 adrenoceptor polymorphism. Peak flow and pulmonary functions were measured by body plethysmography after the inhalation of procaterol. In the Arg 16/Gly 16 group, the resulting acute increase of V 25 and acute decrease of airway resistance were greater, and the bronchodilator effect of a single inhaled beta 2-agonist was longer, than those observed in the Gly 16/Gly 16 group. The present study showed that a single inhalation of procaterol has a varying bronchodilator effect on healthy adults, depending on the genotype of beta 2 adrenoceptor polymorphism at codon 16.