Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study.

Omalizumab is a monoclonal anti-IgE antibody used to treat severe allergic asthma (SAA). The aim of the STELLAIR study was to determine the importance of pre-treatment blood eosinophil count as a predictive measure for response to omalizumab.This retrospective real-life study was conducted in France between December 2015 and September 2016 using medical records of SAA omalizumab-treated patients. Response to omalizumab was assessed by three criteria: physician evaluation, reduction of ≥40% in annual exacerbation rate and a combination of both. Response rate was calculated according to blood eosinophil count measured in the year prior to omalizumab initiation.872 SAA omalizumab-treated patients were included by 78 physicians (723 adults (age ≥18 years) and 149 minors (age 6-17 years)). Blood eosinophil count was ≥300 cells·µL-1 in 52.1% of adults and 73.8% of minors. By physician evaluation, 67.2% of adults and 77.2% of minors were responders and 71.1% adults and 78.5% minors had a ≥40% reduction in the exacerbation rate. In adults, the response rate for combined criteria was 58.4% (95% CI 53.2-63.4%) for blood eosinophils ≥300 cells·µL-1 (n=377) and 58.1% (95% CI 52.7-63.4%) for blood eosinophils <300 cells·µL-1 (n=346).This study shows that a large proportion of patients with SAA have a blood eosinophil count ≥300 cells·µL-1, and suggests that omalizumab effectiveness is similar in "high" and "low" eosinophil subgroups.

Efficacy and safety of indacaterol in patients with chronic obstructive pulmonary disease aged over 65 years: A pooled analysis.

BACKGROUND: Although the prevalence of chronic obstructive pulmonary disease (COPD) increases with age, no specific therapeutic approaches are available till date for the elderly population. AIM: To assess the efficacy and safety of once-daily indacaterol 150 and 300 µg in elderly patients with moderate to severe COPD. METHODS: Data were pooled from 11 randomized, double-blind, placebo- and active-controlled studies (8445 patients with COPD). The patient population was stratified into age groups: young (≥40-<65 years; 52.3%), elderly (≥65-<75 years; 36.4%), and very elderly (≥75 years; 11.4%). The efficacy outcomes included improvements in trough forced expiratory volume in 1 s (FEV1), transition dyspnea index (TDI), and health status (St. George's Respiratory Questionnaire [SGRQ]); safety was also assessed at 12 weeks. RESULTS: At Week 12, the mean improvement in FEV1 with indacaterol 150 µg versus placebo was comparable in the elderly (150 mL), very elderly (160 mL), and young (170 mL) groups (p < 0.001 for all comparisons). Similar improvement in FEV1 was observed with indacaterol 300 µg versus placebo in each group (p < 0.001). This improvement was also significantly higher with indacaterol than formoterol, salmeterol, and tiotropium in all groups (p < 0.01). Both TDI and SGRQ scores significantly improved with indacaterol versus placebo across age groups (p < 0.001) and were significantly higher than that for tiotropium (p < 0.001). Incidences of adverse events among indacaterol- or placebo-treated patients were similar, regardless of the age group. CONCLUSIONS: This pooled analysis suggests that the efficacy and safety of indacaterol treatment is similar between elderly and younger patients with COPD.

Immediate salbutamol responsiveness does not predict long-term benefits of indacaterol in patients with chronic obstructive pulmonary disease.

BACKGROUND: The purpose of this study was to evaluate the correlation between immediate responsiveness with the short-acting ß2-agonist salbutamol and effects of treatment with the ultra-long-acting ß2-agonist indacaterol in patients with chronic obstructive pulmonary disease (COPD). METHODS: The REVERBREZ study was a phase IV, multicentre, open-label study in which patients with moderate-to-severe COPD received indacaterol 150 µg once-daily for 5 months. The primary endpoint was the correlation between immediate response of forced expiratory volume in 1 s (FEV1) post-inhalation of salbutamol (400 µg) at study entry and the change from baseline in trough FEV1 after 1 month of indacaterol. Secondary endpoints included dyspnoea measured by the modified Medical Research Council (mMRC) grade and health-related quality of life measured by the clinical COPD questionnaire (CCQ). RESULTS: Of the 602 patients enrolled from 177 centres in France, 543 patients received at least one indacaterol dose, 512 patients completed 1 month of indacaterol treatment (primary endpoint), and 400 patients completed 5 months of treatment. At study entry, mean FEV1 values before and after salbutamol inhalation were 1.54 ± 0.50 L and 1.65 ± 0.53 L, respectively. Based on the magnitude of an immediate response of FEV1 after salbutamol inhalation at study entry, patients were classified into reversible (Rv, ≥12% and ≥200 mL from pre-salbutamol value; n = 106) and non-reversible (NRv, <12% or <200 mL from pre-salbutamol value; n = 431) groups. After 1 month of indacaterol treatment, mean absolute and relative difference in trough FEV1 were 100 mL and 9%, respectively. No significant correlation was found between the immediate FEV1 response to salbutamol at study entry and change from baseline in trough FEV1 after 1 month of indacaterol treatment (correlation coefficient = 0.056 [95% CI;-0.032, 0.144] for absolute response and 0.028 [95% CI;-0.06, 0.116] for relative response). At all subsequent visits, mMRC and CCQ scores, and FEV1 improved from baseline with no significant difference between the Rv and NRv groups. CONCLUSIONS: Immediate FEV1 response to salbutamol did not predict the long-term benefits observed with indacaterol treatment in patients with COPD. Patients considered reversible or non-reversible to salbutamol showed comparable improvements in lung function, dyspnoea and health-related quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272362 . Date: January 5, 2011.

A proof-of-concept, randomized, controlled trial of omalizumab in patients with severe, difficult-to-control, nonatopic asthma.

BACKGROUND: While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS: Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS: Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS: Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

Insights into severe asthma control as assessed by guidelines, pulmonologist, patient, and partner.

INTRODUCTION: The most recent guidelines on asthma management advocate a treatment strategy based on control of the disease rather than severity, a switch based on reported evidence. AIMS: This observational, questionnaire-based study set out to investigate how control of the disease is assessed by the physician as well as the patient and his/her live-in partner and to compare these assessments with an assessment made according to the guidelines. METHODS: In 169 patients with severe, persistent asthma on at least a high-dose inhaled corticosteroid plus an inhaled long-acting ß2-agonist, control of the disease was assessed by the pulmonologist, the patient, and the patient's live-in partner. These assessments were compared with an assessment based on the guidelines. Results. Both patients and partners tended to judge disease control as better than their pulmonologists who, in turn, estimated control as acceptable in 58% of their patients in whom the guidelines would advocate more aggressive treatment. The most common guidelines criteria defining inadequate control in the "uncontrolled" 87.4% of this population were "limitation of physical activity" (72.3%) and "FEV1" ≤ 85% of personal best" (63.3%). CONCLUSIONS: To assess control in severe asthma, the patient's opinion is of limited value, as is that of their partners. Although a guidelines-based strategy has been shown to be effective in clinical trials conducted on large-scale populations in which mild or moderate disease is predominant, more aggressive treatment to achieve definitive control may not be appropriate in the 10% of asthma sufferers with severe disease; in everyday practice, lung specialists appear to implement such a strategy.

Omalizumab-induced decrease of FcξRI expression in patients with severe allergic asthma.

BACKGROUND: It is documented that omalizumab treatment reduces the cell surface expression of immunoglobulin E high-affinity receptor (FcɛRI) on several cell types. This has not been investigated in patients with uncontrolled severe persistent allergic asthma. METHODS: In a double-blind, randomized, placebo-controlled study, patients with severe allergic asthma uncontrolled by high dose inhaled corticosteroids and long-acting ß(2)-agonist received either omalizumab (n = 20) or placebo (n = 11) over 16 weeks at appropriate doses and frequencies. Baseline and end of study (week 16) FcɛRI expression on basophils and plasmacytoid dendritic cells was determined by flow cytometry for the primary endpoint. Secondary efficacy endpoints included asthma control and lung function as part of an initial investigation into the use of FcɛRI expression as a marker of response. RESULTS: In the omalizumab group, and with respect to placebo, FcɛRI expression was significantly reduced at end of study on basophils (-82.6%, p < 0.01) and plasmacytoid dendritic cells (-44.2%, p = 0.029). FcɛRI expression reduction was not found to be correlated with clinical response. CONCLUSIONS: Long-term omalizumab treatment induced reduction of FcɛRI expression on circulating basophils and plasmacytoid dendritic cells. These changes were not associated with those of clinical features related to severe asthma, which does not support further investigation into its use as a predictive marker of response. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT00454051) and the European Clinical Trials Database, EudraCT (identifier: 2006-003591-35).

Prevalence and associated factors of oropharyngeal side effects in users of inhaled corticosteroids in a real-life setting.

BACKGROUND: Inhaled corticosteroids (ICS) are extensively used to treat asthma, and more recently, chronic obstructive pulmonary disease (COPD). Oropharyngeal disorders represent the most frequent side effect of these drugs, which may have a negative impact on adherence. OBJECTIVES: To evaluate the prevalence of oropharyngeal disorders in users of ICS in a real-life setting and investigate the factors associated with their occurrence. METHODS: For this observational cross-sectional study, general practitioners and pulmonologists were contacted and asked to include patients suffering from asthma or COPD treated by ICS. Physicians collected data during a medical examination. A multivariate regression model for the occurrence of oropharyngeal disorders was constructed. RESULTS: A total of 1778 physicians included 6740 patients. The mean (SD) age was 51.3 (18.5) years, 44.0% had no smoking history, and the ICS indication was asthma in 63.9% of subjects. Of the study subjects, 52.3% used beclometasone (43.4% without a long-acting ss(2)-agonist, LABA); 22.1% used budesonide (18.8% with a LABA), and 25.6% used fluticasone (19.3% with a LABA in a single inhaler). One-third (34.7%) of subjects suffered from at least one oropharyngeal disorder; the most frequently reported were hoarseness, tingling, mouth irritation, and reddening. Multivariate regression analysis found that the factors positively associated with oropharyngeal disorders were COPD indication [odds ratio (OR) 1.600; 95% confidence intervals (95% CI) 1.391, 1.839], nominal daily dose (OR = 1.388; 95% CI 1.227, 1.569), decreased adherence (OR = 1.318; 95% CI 1.104, 1.574) and the use of fluticasone (OR = 1.176; 95% CI 1.008, 1.372), whereas those negatively associated were the absence of smoking history (OR = 0.837; 95% CI 0.742, 0.945), increased adherence (OR = 0.663; 95% CI 0.581, 0.755), and beclometasone use (OR = 0.630; 95% CI 0.543, 0.732). CONCLUSIONS: The high prevalence of oropharyngeal disorders and the association of adherence with these must be taken into account by prescribers, especially in patients suffering from COPD, a relatively new group of ICS users.

Impact of patient-related factors on asthma control.

BACKGROUND: Patient-related factors are a significant component in the serious public health problem of poor asthma control, yet they have not been extensively studied. AIMS: To gauge the impact of baseline patient characteristics, compliance and inhaler device manipulation on Asthma Control Score (ACS). METHODS: ACS (between 0 and 9) was calculated from data recorded in a routine consultation in 4,362 patients with persistent asthma using a maintenance treatment with only inhaled corticosteroid and correlated with patient characteristics, compliance (using 2 methods) and critical errors in inhaler handling. RESULTS: Mean ASC was 2.95 (95%CI: 2.88-3.02) and asthma control was unsatisfactory (i.e., ACS > or = 4) in 41.1% of subjects, with higher proportions in smokers, non-compliant patients, and those misusing their device. Mean ACS tended to rise with age, and was higher in smokers than in non-smokers (+0.83 point) and ex-smokers (+0.49 point). More than 20% of all subjects were using their inhaler device incorrectly (Turbuhaler 37.1%; Metered-dose inhaler 28.1%; Diskus 21.3%; Aerolizer 7.4%) and this was associated with a 0.84-point increase in ACS. Mean ACS was lower in the most compliant patients (-0.74 points in the 13.4% with a perfect score on a compliance questionnaire) and much lower than in the least compliant (-1.84 points in the 6.6% who reported missing 4 or more doses per week). CONCLUSION: Patient-related factors including smoking, poor compliance and critical errors in device manipulation, have significant negative impact on asthma control. This could be addressed by patient education.

Effectiveness of omalizumab (Xolair) in the first patients treated in real-life practice in France.

OBJECTIVE: To describe omalizumab (Xolair) effectiveness in the first patients treated on compassionate grounds before its commercialisation in France. METHODS: In a historic-prospective study, data were obtained by questionnaire from the physicians whose patients had received a nominative temporary use authorisation (ATU) for omalizumab from July 2003 to January 2006. Anonymised patient data regarding demographics, asthma-related treatments and events in the year previous to the start of omalizumab treatment as well as the details of omalizumab treatment itself were obtained at inclusion. Follow-up data at more than 3 months following inclusion were also obtained and regarded asthma-related treatment (including omalizumab), events and undesirable effects suspected to be linked to omalizumab treatment. RESULTS: Data were obtained for 147 of the 154 patients treated via ATU. 31.3% received inappropriate monthly doses of omalizumab. Of the 28 patients (19%) who discontinued for unsatisfactory therapeutic effect, 7 were treated for less than the 16 weeks recommended to evaluate efficacy and 9 who were treated for a longer period of time were underdosed. During the treatment period and compared to the previous year, patients with follow-up data at 5 months or more had experienced 62% fewer exacerbations requiring oral corticosteroids, 65% fewer emergency department visits and 29% fewer hospitalisations per year. The nature of adverse effects reported was similar to that reported in omalizumab clinical trials. CONCLUSION: Results strongly suggest that omalizumab in the first patients treated in real-life setting provided a similar benefit to that observed in clinical trials. Underdosing of patients may limit this therapeutic effect.

Underdiagnosis of nocturnal symptoms in asthma in general practice.

OBJECTIVE: To evaluate the prevalence of nocturnal symptoms in a large sample of asthmatic patients, and to assess the agreement between patients' complaints and general practitioners' (GPs') reports in primary care. DESIGN: Cross-sectional survey involved 3,526 GPs and 751 specialists (pulmonologists and allergists) and included 13,493 patients with persistent asthma. Symptoms, treatment, and social and medical data were collected in real time by the patients and their GPs. SETTING: France. RESULTS: Prevalence of nocturnal symptoms was 60%. A total of 7,989 patients with nocturnal symptoms had complete data for both patients and GPs; 3,849 (48.1%) had perfect agreement between GP and their complaints for nocturnal symptoms (agreement group; [kappa = 1]); 3,376(42.2%) declared having no symptoms during the night, but these were detected by the GP during the visit (underestimated by patients and detected by GPs); 773(9.6%) declared having nocturnal symptoms, but these were not detected by GPs. Patients with a good agreement with their GP's opinion were significantly more frequently followed-up by a specialist than other patients (p = 0.002). CONCLUSIONS: Nocturnal symptoms appear to be underdeclared by patients. GPs should therefore systematically ask their patients about nocturnal symptoms to increase control of asthma and to adequately manage its treatment.

Total reversibility testing as indicator of the clinical efficacy of formoterol in COPD.

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend bronchodilator reversibility testing to guide treatment decisions. This study evaluated the relationship between the change in forced expiratory volume in 1 s (FEV1) with salbutamol or formoterol and the clinical effects of a 4-week formoterol (Foradil) treatment. METHODS: At Visit 1, patients (n = 448) with stable chronic obstructive pulmonary disease took an FEV1 reversibility test using 200 microg salbutamol via a metered dose inhaler. At Visit 2 (Day 0), an FEV1 reversibility test was performed using formoterol via a dry-powder inhaler (Aerolizer). Patients then received formoterol 12 microg twice daily until Visit 3 (Day 21-30), when a further formoterol FEV1 reversibility test was performed. Clinical parameters included FEV1, symptom questionnaires and rescue medication use. RESULTS: There was no significant relationship between the immediate change in FEV1 with salbutamol and the absolute change from baseline in FEV1, symptom scores or rescue medication use after a 4-week formoterol treatment. Relative immediate change in FEV1 with formoterol was correlated with change in rescue medication use (P = 0.02) and FEV1 at Visit 3 (P < 0.001). Total reversibility in FEV1 with formoterol (post-dose Visit 3-pre-dose Visit 2) was correlated with all treatment efficacy variables (P<0.01). CONCLUSIONS: Immediate salbutamol reversibility testing, as performed under these study conditions, failed to predict the clinical efficacy of formoterol. Total reversibility after 4 weeks of formoterol treatment may be a better predictor of clinical benefits of long-term bronchodilator therapy.

Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV(1) reversibility.

BACKGROUND: Recent studies suggest that inspiratory capacity (IC) measured at rest can be used to predict improvements in dyspnea and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. In this study we compared the effect of formoterol (Foradil, Aerolizer) and salmeterol (Serevent, Diskus) in terms of IC in patients with COPD. METHODS: This was a multicentre, randomized, placebo-controlled, single-dose, double-dummy, crossover study conducted in five secondary care centres in four European countries. A total of 47 patients with Stage II and III COPD, as defined by ATS criteria, with an increase in forced expiratory volume in 1s (FEV(1)) of

Formoterol 12 microg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: a multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. OBJECTIVE: The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. METHODS: This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age >/=18 years) with suboptimally controlled asthma (mean salbutamol use, >/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control. RESULTS: A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P < 0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P < 0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol. CONCLUSION: In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.

Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study.

OBJECTIVES: To compare the onset and magnitude of bronchodilation after dry powder inhalations of formoterol fumarate (Foradil Aerolizer) versus salmeterol xinofoate (Serevent Diskus) with respect to normalized (*) forced expiratory volume in 1 s area under the curve 0 to 1 h after inhalation (FEV1 AUC*0-1 h). DESIGN: A double-blind, double-dummy, multicentre, randomized, placebo controlled, single-dose, five-period crossover study. SETTING: Five centres in four countries - one centre each in France, Greece and Italy, and two centres in the Netherlands. PATIENTS: Forty-seven patients aged 42 to 80 years (mean age 63.5 years) with chronic obstructive pulmonary disease (COPD) stage II and III, and mean baseline FEV1 1.17 L (range 0.56 to 1.77 L). INTERVENTIONS: Patients inhaled single doses of formoterol dry powder (12 and 24 mg), single doses of salmeterol (50 and 100 mg) and matching placebo on five separate days. MAIN RESULTS: The estimates of treatment difference in absolute terms (0.086 L) and percentage change from predose baseline (7.8%) for the primary end point, FEV1 AUC*0-1 h, showed that formoterol 12 mg was statistically significantly superior to salmeterol 50 mg (P=0.0044 and P=0.0021, respectively). In addition, both doses of formoterol were statistically superior to placebo for both absolute improvement and percentage change (P=0.0001). The analysis of secondary variables also confirmed the superiority of formoterol over salmeterol. CONCLUSIONS: Formoterol is associated with a faster onset of bronchodilation than salmeterol in patients with COPD.