Laurie A. Lee

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma

BACKGROUND Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. METHODS We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. RESULTS Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). CONCLUSIONS In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

Fluticasone furoate nasal spray is more effective than fexofenadine for nighttime symptoms of seasonal allergy.

Nasal symptoms of allergic rhinitis are an important cause of sleep disturbance. Reduction of nasal symptoms, particularly nasal obstruction, has been linked to improvements in self-reported sleep quality. The enhanced-affinity intranasal corticosteroid fluticasone furoate and the oral antihistamine fexofenadine were compared with respect to nighttime symptoms of seasonal allergic rhinitis. In two randomized, double-blind, double-dummy, parallel-group studies, patients received fluticasone furoate nasal spray (FFNS),110 microg (study 1, n = 312; study 2, n = 224); fexofenadine, 180 mg (study 1, n = 311; study 2, n = 227); or placebo (study 1, n = 313; study 2, n = 229) once daily for 2 weeks. Fluticasone furoate was more effective (p < 0.001) than fexofenadine and placebo in both studies with respect to the mean changes from baseline over the treatment period in the nighttime symptoms score, nighttime reflective total nasal symptom score, predose instantaneous nasal symptom score, and morning peak nasal inspiratory flow. Fluticasone furoate was more effective than placebo (p <or= 0.001) in study 1 and more effective than both placebo and fexofenadine (p <or= 0.034) in study 2 with respect to the mean changes from baseline in the nighttime reflective total ocular symptom score and predose instantaneous total ocular symptom score. In these double-dummy studies, fexofenadine did not separate from placebo in comparisons of the nighttime symptoms score or the nighttime nasal or ocular symptom measures. The incidence of adverse events was similar among groups. FFNS once daily was more effective than fexofenadine and placebo with respect to nighttime sleep disturbance caused by seasonal allergy symptoms.

Ocular safety of fluticasone furoate nasal spray in patients with perennial allergic rhinitis: a 2-year study.

BACKGROUND This is the first study, to our knowledge, to evaluate the ocular effects of an intranasal corticosteroid during 2 years of treatment for perennial allergic rhinitis (PAR). OBJECTIVE To assess ocular safety in adult and adolescent patients 12 years and older with PAR after 2 years of continuous treatment with fluticasone furoate nasal spray (FFNS), 110 μg once daily, and placebo. METHODS This was a 2-year, randomized, double-blind, placebo-controlled study of once-daily FFNS, 110 ìg, and placebo in 548 patients 12 years and older with PAR. The primary ocular safety end points were time to first occurrence of an event for the Lens Opacities Classification System, Version III (LOCS III), posterior subcapsular opacity (PSO) and time to first occurrence of an event for intraocular pressure (IOP). RESULTS On the basis of survival analyses, the difference between the treatment groups for time to first occurrence of a LOCS III PSO and time to first occurrence of an IOP event was not statistically significant (P = .39 and P = .34, respectively). Changes from baseline in visual acuity, LOCS III PSO, cortical opacity, LOCS III nuclear opacity and nuclear color, IOP, and horizontal cup-to-disc similar between treatment groups. There were no ophthalmic-related adverse events of LOCS III PSO or IOP that led to early withdrawal. The most common drug-related adverse event was epistaxis (FFNS, 28%; placebo, 14%). CONCLUSION These data neither support nor negate current recommendations for regular ophthalmic monitoring in patients treated with intranasal corticosteroids. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00682643.

Fluticasone furoate nasal spray reduces symptoms of uncomplicated acute rhinosinusitis: a randomised placebo-controlled study.

BACKGROUND Uncomplicated acute rhinosinusitis (ARS) is usually a self-limiting inflammatory condition often treated with antibiotics. AIMS To assess the safety and efficacy of fluticasone furoate nasal spray (FFNS) compared with placebo for symptomatic relief of uncomplicated ARS. METHODS A randomised, double-blind, placebo-controlled, parallel-group, multicentre, 2-week treatment study of FFNS 110 μg once and twice daily was undertaken in adults/adolescents. RESULTS A statistically significant reduction was seen in the daily major symptoms score, a composite score of three individual symptoms (nasal congestion/stuffiness, sinus headache/pressure or facial pain/pressure, and postnasal drip on a 0-3 scale) by both FFNS doses compared with placebo (least square mean differences vs. placebo of -0.386 (p=0.008) and -0.357 (p=0.014) for once daily and twice daily FFNS, respectively). The differences in median times to symptom improvement were not statistically significant between each dose of FFNS (7 days) and placebo (8 days). There were no treatment differences in antibiotic use for possible fulminant bacterial rhinosinusitis (3% in each group). The safety profile of FFNS was similar to placebo. CONCLUSIONS FFNS reduces symptoms of uncomplicated ARS compared with placebo and is well tolerated, providing support for withholding antibiotics in selected patients.

No mucosal atrophy and reduced inflammatory cells: active-controlled trial with yearlong fluticasone furoate nasal spray.

Background Fluticasone furoate nasal spray (FFNS) and mometasone furoate nasal spray (MFNS) are well tolerated and more effective than placebo at relieving the symptoms of seasonal and perennial allergic rhinitis. Effects of FFNS on the nasal histology have not been previously reported. This study examines the effects of FFNS and MFNS, administered daily for 1 year, on the nasal mucosa in subjects with perennial allergic rhinitis. Methods Subjects with perennial allergic rhinitis were randomized 1:1 to q.d., open-label treatment with FFNS, 110 μg, or MFNS, 200 μg, for 1 year. These groups and a healthy control group that did not receive study medication underwent nasal biopsies at baseline and 12 months. Results The nasal biopsy population comprised 96 participants (37 using FFNS, 42 using MFNS, and 17 healthy controls). Epithelial thickness did not change appreciably from baseline to week 52 in any of the groups and mean change from baseline did not differ between FFNS and MFNS (least square mean difference, -0.001 mm, 95% confidence interval, -0.007, 0.006). Although not tested for significance, improvements over baseline were observed in epithelial histology in the FFNS group with more epithelium including intact columnar and ciliated epithelial cells. No appreciable change in the percentage of goblet cells was established. FFNS and MFNS were associated with decreases in epithelial and subepithelial nasal mucosal eosinophils and basophils from baseline to week 52. The percentage of subjects with no inflammatory cells at week 52 was 49 and 33% for eosinophils and 46 and 24% for basophils, for FFNS and MFNS, respectively. Conclusion Yearlong therapy with either FFNS or MFNS showed no changes in epithelial thickness or the percentage of goblet cells as well as a reduction in inflammatory cell infiltrate. FFNS was associated with improvements in epithelial histology. These data support the long-term safety of FFNS in subjects with perennial allergic rhinitis.

OCULAR SYMPTOM EFFICACY AND INTRANASAL CORTICOSTEROIDS

To the Editor: In their July 2009 letter, Bielory et al1 suggest that intranasal triamcinolone is efficacious for the ocular symptoms of seasonal allergic rhinitis (SAR) and that this is perhaps a class effect of all intranasal corticosteroids (INSs). However, 4 of the 5 studies cited as support lacked placebo controls. Without a placebo arm, positive ocular results are uninterpretable because the ocular symptoms could have disappeared as the seasons waned.2 The use of an “active comparator” in 3 of these 4 studies fails to compensate for the lack of a placebo arm because the active comparators have not been proved to be effective for ocular symptoms of SAR. Most remarkably, one well-controlled study3 of intranasal triamcinolone that evaluated ocular symptoms and demonstrated no difference from placebo was completely omitted from consideration. The authors of a review4 on the hazards of therapeutic substitution propose the following minimum criteria to define a class effect: (1) a clearly defined biological target or pathway, (2) comparable efficacy demonstrated for multiple agents in the class (with multiple randomized controlled clinical trials for each), and (3) the absence of convincing evidence that a member of the class lacks clinical benefit comparable with that of other agents in the class. The INSs meet only this first criterion: they all target the glucocorticoid receptor. Criteria 2 and 3 have, as yet, not been demonstrated. In fact, the evidence to date more firmly suggests that other INSs, including mometasone furoate and fluticasone propionate, lack ocular benefit based on their failure to consistently reduce ocular symptoms in well-controlled SAR studies.5 The authors did not acknowledge the one INS consistently demonstrated to be effective for ocular symptoms. Fluticasone furoate nasal spray reduced ocular symptoms in patients with SAR for 12 years or more in 6 of 6 randomized, prospective, placebo-controlled trials using rigorous regulatory standards.5 As the only INS proved to be effective for the ocular symptoms of SAR, fluticasone furoate nasal spray is the only active comparator currently available to evaluate this effect. Evidence-based medicine requires that the clinical evidence for a particular treatment be evaluated for its quality and weight relative to the scientific question. Generalizing results from clinical trials that lack substantive clinical weight to suggest that a treatment is efficacious for a symptom experienced by 71% of patients with allergic rhinitis5 is a disservice to the patient and the prescribing physician. A single positive randomized controlled study combined with less definitive sources of data does not support a class effect.

Use of clinical characteristics to predict spirometric classification of obstructive lung disease

Background There is no consensus on how to define patients with symptoms of asthma and chronic obstructive pulmonary disease (COPD). A diagnosis of asthma–COPD overlap (ACO) syndrome has been proposed, but its value is debated. This study (GSK Study 201703 [NCT02302417]) investigated the ability of statistical modeling approaches to define distinct disease groups in patients with obstructive lung disease (OLD) using medical history and spirometric data. Methods Patients aged ≥18 years with diagnoses of asthma and/or COPD were categorized into three groups: 1) asthma (nonobstructive; reversible), 2) ACO (obstructive; reversible), and 3) COPD (obstructive; nonreversible). Obstruction was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7, and reversibility as a post-albuterol increase in FEV1 ≥200 mL and ≥12%. A primary model (PM), based on patients’ responses to a health care practitioner-administered questionnaire, was developed using multinomial logistic regression modeling. Other multivariate statistical analysis models for identifying asthma and COPD as distinct entities were developed and assessed using receiver operating characteristic (ROC) analysis. Partial least squares discriminant analysis (PLS-DA) assessed the degree of overlap between groups. Results The PM predicted spirometric classifications with modest sensitivity. Other analysis models performed with high discrimination (area under the ROC curve: asthma model, 0.94; COPD model, 0.87). PLS-DA identified distinct phenotypic groups corresponding to asthma and COPD. Conclusion Within the OLD spectrum, patients with asthma or COPD can be identified as two distinct groups with a high degree of precision. Patients outside these classifications do not constitute a homogeneous group.

Efficacy and safety of fluticasone furoate nasal spray in adult and adolescent subjects with uncomplicated acute rhinosinusitis

Methods This randomized, double-blind, placebo-controlled, parallel-group, multicenter, 2-week treatment study evaluated FFNS 110 mcg once daily, twice daily vs. placebo in adults/ adolescents with uncomplicated ARS. Eligibility criteria reflected a clinical diagnosis and eliminated confounding conditions like common cold, symptomatic allergic rhinitis (AR), and other sinonasal conditions. Subjects with daily major symptom score (MSS; a composite score of 3 symptoms [nasal congestion/stuffiness, sinus headache/pressure or facial pain/pressure, and postnasal drip on a 0-3 scale]) >4.5 at baseline were randomized.