Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials).

Rationale: Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. Methods: These phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trials were conducted between September 2020 and December 2022 at 250 research centers and pulmonology practices in 17 countries. Patients aged 40-80 years with moderate to severe symptomatic COPD were enrolled. Measurements and Main Results: Totals of 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% receiving concomitant long-acting muscarinic antagonists or long-acting ß2-agonists, respectively. Post-bronchodilator FEV1 percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV1 area under the curve at 0-12 hours versus placebo (ENHANCE-1, 87 ml [95% confidence interval, 55, 119]; ENHANCE-2, 94 ml [65, 124]; both P < 0.001). Ensifentrine treatment significantly improved symptoms (Evaluating Respiratory Symptoms) and quality of life (St. George's Respiratory Questionnaire) versus placebo at Week 24 in ENHANCE-1 but not in ENHANCE-2. Ensifentrine treatment reduced the rate of moderate or severe exacerbations versus placebo over 24 weeks (ENHANCE-1, rate ratio, 0.64 [0.40, 1.00]; P = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87]; P = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97]; P = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87]; P = 0.009). Adverse event rates were similar to those for placebo. Conclusions: Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies. Clinical trial registered with www. CLINICALTRIALS: gov and EudraCT (ENHANCE-1, www. CLINICALTRIALS: gov identifier NCT04535986, EudraCT identifier 2020-002086-34; ENHANCE-2, www. CLINICALTRIALS: gov identifier NCT04542057, EudraCT identifier 2020-002069-32).

Measurement of FeNO with a portable, electrochemical analyzer using a 6-second exhalation time in 7-10-year-old children with asthma: comparison to a 10-second exhalation.

Objective: Fractional exhaled nitric oxide (FeNO) is a valuable tool for assessing Th2 inflammation in children with asthma. Exhalation times of 6 and 10 s meet the current recommendations for assessing FeNO. The 6-s exhalation provides an alternative for 7-10 year olds not able to complete the 10-s exhalation. Methods: We performed a sub-analysis on data from 7-10-year-old children who participated in a previous study which evaluated the agreement of the 6 and 10-s exhalation times in 6-10 year olds with asthma. Agreement between observed FeNO results obtained by both modes was assessed by weighted Deming regression analysis and Bland-Altman plots. Repeatability was also assessed. Results: Repeatability and agreement of the 6 and 10-s exhalations was demonstrated in 7-10 year olds with two measurements in each mode. Mean observed FeNO measurements were 33.59 ppb (SD = 25.804) for 6 s and 32.46 ppb (SD = 25.302) for 10-s exhalation. Paired differences were centered close to 0 ppb (median = 0.50). Conclusions: Children aged 7-10 years can successfully perform FeNO measurements using a portable, electrochemical FeNO analyzer. Measurements from the 6 and 10-s exhalations were repeatable and consistent with a high degree of agreement between one another. Thus, in young children successful FeNO measurements can be obtained in either the 6-s or 10-s mode, providing physicians valuable information on airway inflammation to aid in the diagnosis and treatment of asthma.

Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD.

Ensifentrine is a novel, potent, and selective dual inhibitor of phosphodiesterase (PDE)3 and PDE4 designed for delivery by inhalation that combines effects on airway inflammation, bronchodilation and ciliary function in bronchial epithelia. In Phase 2 studies in subjects with COPD, ensifentrine demonstrated clinically meaningful bronchodilation and improvements in symptoms and health-related quality of life when administered alone or in combination with current standard of care therapies. Ensifentrine is currently in late-stage clinical development for the maintenance treatment of patients with COPD. This review summarizes non-clinical data as well as Phase 1 and Phase 2 efficacy and safety results of nebulized ensifentrine relevant to the maintenance treatment of patients with COPD.

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy.

PURPOSE: Ensifentrine is an inhaled dual inhibitor of phosphodiesterase (PDE) 3 and 4 that has shown bronchodilatory effects and symptom improvement in clinical studies in patients with chronic obstructive pulmonary disease (COPD), and anti-inflammatory effects in healthy volunteers in a model of COPD-like inflammation. This manuscript reports on the results of the clinical study examining if ensifentrine provides meaningful improvements in lung function when added on to tiotropium over 4 weeks in patients with COPD who have impaired lung function and symptoms despite treatment with tiotropium. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with moderate-to-severe COPD. Patients were randomized to open-label tiotropium once daily (QD) plus (+) blinded escalating doses of ensifentrine or placebo twice daily (BID). Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks. RESULTS: A total of 416 COPD patients were randomized and 413 received at least one dose of blinded study medication + tiotropium. All ensifentrine doses produced a significant and dose-dependent increase in peak forced expiratory volume in 1 second (FEV1) from baseline to Week 4, with placebo-corrected differences of 77.5 mL when added to tiotropium (0.375 mg; 95% CI: 4.8, 150.1 mL; p=0.037) to 124.2 mL (3 mg; 95% CI: 51.0, 196.8 mL; p<0.001). A significant increase in average FEV1 (0-12h) was shown at Week 4 with the 3 mg dose (87.3 mL; 95% CI: 20.0, 154.5 mL; p=0.011). Clinically meaningful and statistically significant improvements in the St. George's Respiratory Questionnaire - COPD (SGRQ-C) additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses. Adverse events were similar in frequency between the ensifentrine and placebo arms. CONCLUSION: This clinical study demonstrated that nebulized ensifentrine added on to tiotropium produced clinically important improvements in lung function and QoL over 4 weeks in COPD patients receiving tiotropium who demonstrated symptoms and lung function impairment, with a safety profile similar to placebo.

Symptom Improvement Following Treatment with the Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine in Patients with Moderate to Severe COPD - A Detailed Analysis.

Introduction: Ensifentrine is an inhaled first-in-class dual inhibitor of phosphodiesterase (PDE) 3 and 4. In a four-week randomized, double-blind, placebo-controlled, parallel-group study in patients with chronic obstructive pulmonary disease (COPD), nebulized ensifentrine 0.75 to 6mg twice daily significantly improved bronchodilation and symptoms, with all doses being well tolerated. Here, we report data for a number of prespecified exploratory and post hoc endpoints from this study that help to further profile the effect of ensifentrine on symptoms. Methods: Eligible patients were males or females aged 40-75 years with COPD, post-bronchodilator forced expiratory volume in 1 second 40-80% predicted. Other than being clinically stable for at least four weeks prior to entry, there were no symptomatic inclusion or exclusion criteria. The outcome measures reported in this manuscript are the Evaluating Respiratory Symptoms [E-RS™:COPD] questionnaire total score and subscales (breathlessness, cough/sputum and chest symptoms) at Weeks 1-4, Transition Dyspnea Index (TDI) focal score at Weeks 2 and 4, and St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) total score and domain data (symptoms, activity and impacts) at Week 4. Results: There was a gradual improvement versus placebo with all ensifentrine doses for all three E-RS™:COPD subscales from Week 1 to Week 4, with the greatest ensifentrine effect on the breathlessness subscale, and all four doses superior to placebo from Week 2 onwards (p<0.05). For TDI focal score, all ensifentrine doses were superior to placebo at Weeks 2 and 4 (p<0.05). In the individual SGRQ-C domains at Week 4, ensifentrine had the greatest effect on the symptoms domain, with ensifentrine 6mg superior to placebo (p<0.05). Conclusion: In these analyses, ensifentrine demonstrated a notable early and meaningful effect on dyspnea, with this effect observed across two different assessment tools.

Efficacy and safety of low-dose fluticasone propionate compared with zafirlukast in patients with persistent asthma.

To compare the efficacy and safety of fluticasone propionate and zafirlukast in patients with relatively stable persistent asthma who were previously treated with inhaled corticosteroids and short-acting beta(2)-agonists.A total of 440 patients (> or =12 years of age) previously treated with inhaled corticosteroids (beclomethasone dipropionate or triamcinolone acetonide) and short-acting beta(2)-agonists were included in this randomized double-blind study. After an 8-day run-in period, patients were treated with fluticasone (88 microg) or zafirlukast (20 mg) twice daily for 6 weeks. Outcome measures included pulmonary function (forced expiratory volume in 1 second [FEV(1)], peak expiratory flow [peak flow]), albuterol use, asthma symptoms, withdrawals due to lack of efficacy, and asthma exacerbations. Patients treated with fluticasone (n = 224) experienced greater mean increases in FEV(1) (0.24 L vs. 0.08 L, P <0.001), morning peak flow (30 L/min vs. 6 L/min, P <0.001), and evening peak flow (23 L/min vs. 5 L/min, P <0.001) during the study than did those treated with zafirlukast (n = 216). Fluticasone-treated patients had significantly greater increases in the mean percentages of symptom-free days (22% vs. 8%, P <0.001), rescue-free days (23% vs. 10%, P = 0.002), nights with uninterrupted sleep (<1% vs. -5%, P = 0.006), and fewer asthma exacerbations (1% vs. 6%, P = 0.005). Fewer fluticasone-treated patients were withdrawn due to lack of efficacy (2% vs. 13%, P <0.001).Inhaled fluticasone was more effective than zafirlukast in maintaining or improving asthma control in patients with relatively stable asthma who were switched from low-dose inhaled corticosteroids.

Efficacy and safety of low-dose fluticasone propionate compared with montelukast for maintenance treatment of persistent asthma.

OBJECTIVE: To compare the long-term effects of an inhaled corticosteroid with those of a leukotriene modifier on measures of clinical efficacy, subject preference, and safety in patients with persistent asthma. PATIENTS AND METHODS: Between November 17, 1998, and May 26, 2000, we conducted a multicenter, randomized, double-blind, double-dummy, parallel-group study of patients aged 15 years or older with persistent asthma. The patients were symptomatic while taking short-acting beta2-agonists alone and were treated with fluticasone propionate (88 microg [2 puffs of 44 microg] twice daily) or montelukast (10 mg/d) for 24 weeks. Measures of pulmonary function, asthma symptoms, albuterol use, nighttime awakenings, physician assessments of efficacy, patient satisfaction, asthma-related quality of life, and safety were evaluated. RESULTS: A total of 522 patients were randomized to receive fluticasone or montelukast, and 395 patients completed the study. At end point, treatment with fluticasone significantly improved pulmonary function, asthma symptom scores, the percentage of symptom-free days, rescue albuterol use, and the number of nighttime awakenings due to asthma when compared with montelukast (P< or = .002, each comparison). Significantly more patients were satisfied with fluticasone therapy (83%) compared with montelukast therapy (66%) (P<.001), and fluticasone therapy was rated as effective by a significantly greater portion of physicians (67%) than was montelukast therapy (54%) (P<.001). Treatment with fluticasone significantly improved asthma-related quality-of-life measures compared with montelukast (P< or =.01). The incidence of asthma exacerbations was similar in the fluticasone (19 patients, 7%) and montelukast (21 patients, 8%) treatment groups, although slightly more patients in the montelukast group were withdrawn from the study because of asthma exacerbations (6% vs 4%, respectively). CONCLUSION: Long-term treatment with a low dose of inhaled fluticasone is more effective than oral montelukast as first-line maintenance therapy for the treatment of persistent asthma.

Cost-effectiveness comparison of salmeterol/fluticasone propionate versus montelukast in the treatment of adults with persistent asthma.

OBJECTIVE: To compare the relative cost effectiveness of salmeterol (50 microg)/ fluticasone propionate (100 microg) with that of oral montelukast (10mg) as initial maintenance therapy in patients with persistent asthma uncontrolled on short-acting beta2-agonist therapy alone. STUDY DESIGN: A cost-effectiveness analysis was performed based on effectiveness and resource utilisation data that was prospectively collected from a randomised, double-blind, double-dummy, 12-week trial. PATIENTS AND METHODS: Patients (>15 years of age) who had asthma for at least 6 months. Effectiveness measurements in this analysis included improvement in forced expiratory volume in 1 second (FEV(1)) and symptom-free days (SFDs). Cost of asthma drug treatment as well as costs related to an asthma exacerbation were used in the cost analysis. The study assumed a payer's perspective. All costs are in 2001 US dollars. RESULTS: Of the 423 patients eligible for the study, 211 were randomised to salmeterol/fluticasone propionate and 212 to montelukast. Treatment with salmeterol/fluticasone propionate resulted in a significantly higher proportion of patients who achieved a 12% increase in FEV(1) (successful treatment) [salmeterol/fluticasone propionate: 71% vs montelukast: 39%; p < 0.001] and percentage of SFDs (salmeterol/fluticasone propionate: 46.8% vs montelukast: 21.5%; p < 0.001) compared with montelukast. The mean daily costs per successfully treated patient were lower in the salmeterol/fluticasone propionate group (US dollars 5.03, 95% CI US dollars 4.61 to US dollars 5.50) compared with the montelukast group (US dollars 8.25, 95% CI US dollars 6.98 to US dollars 9.93). Furthermore, per patient mean daily cost per SFD was lower with salmeterol/fluticasone propionate (US dollars 7.63, 95% CI US dollars 6.90 to US dollars 8.50) compared with montelukast (US dollars 14.89, 95% CI US dollars 12.36 to US dollars 17.98). Incremental cost-effectiveness ratios (ICERs) showed that the additional costs to achieve these benefits with salmeterol/fluticasone propionate were minimal. With regards to improvement in lung function, the ICER was US dollars 1.33 (95% CI US dollars 0.80 to US dollars 2.02) and with regards to SFD, the ICER was US dollars 1.69 (95% CI US dollars 1.01 to US dollars 2.48). Sensitivity analysis demonstrated the stability of the results over a range of assumptions. CONCLUSIONS: From a third-party payer perspective, this analysis shows that based on increased efficacy and only a slight increase in cost, twice-daily treatment with salmeterol/fluticasone propionate is more cost effective than once-daily treatment with montelukast as initial maintenance therapy for persistent asthma. This finding complements the results of the clinical analyses indicating that treatment of both inflammation and bronchoconstriction with products such as salmeterol/ fluticasone propionate may be more cost effective as initial maintenance asthma therapy than the use of leukotriene modifiers such as montelukast.

Cost effectiveness of fluticasone propionate plus salmeterol versus fluticasone propionate plus montelukast in the treatment of persistent asthma.

BACKGROUND: Asthma is a chronic disease, the two main components of which are inflammation and bronchoconstriction. Fluticasone propionate (FP) and salmeterol, a strategy that treats both main components of asthma, has been recently compared with FP plus montelukast in a randomised clinical trial. The present study reports economic evaluation of these two strategies. OBJECTIVE: To determine the relative cost effectiveness when persistent asthma is treated with FP/salmeterol 100/50 microg twice daily administered via a single Diskus inhaler device versus treatment with FP 100 microg twice daily via a Diskus inhaler plus oral montelukast 10mg once daily. STUDY DESIGN: A cost-effectiveness analysis was performed by applying cost unit data to resource utilisation data collected prospectively during a US randomised, double-blind, 12-week trial of FP/salmeterol (n = 222) versus FP + montelukast (n = 225). Patients were > or =15 years of age and were symptomatic despite inhaled corticosteroid (ICS) therapy. PATIENTS AND METHODS: Efficacy measurements in this analysis included improvement in forced expiratory volume in 1 second (FEV(1)) and symptom-free days. Direct costs included those related to study drugs, emergency room department visits, unscheduled physician visits, treatment of drug-related adverse events (oral candidiasis), and rescue medication (salbutamol [albuterol]). The study assumed a US third-party payer's perspective with costs in 2001 US dollars. RESULTS: Treatment with FP/salmeterol resulted in a significantly higher proportion (p < 0.001) of patients who achieved a > or =12% increase in FEV(1) than treatment with FP + montelukast (54% [95% CI 47%, 61%] vs 32% [95% CI 26%, 38%]). Lower daily costs and greater efficacy of FP/salmeterol resulted in a cost-effectiveness ratio of US6.77 dollars (95% CI US5.99 dollars, US7.66 dollars) per successfully treated patient in the FP/salmeterol group compared with US14.59 dollars (95% CI US12.12 dollars, US17.77 dollars) for FP + montelukast. In addition, FP/salmeterol achieved similar efficacy in terms of symptom-free days compared with FP + montelukast (31% [95% CI 26%, 35%] vs 27% [95% CI 23%, 32%]), but at a significantly lower daily per-patient cost (US3.64 dollars [95% CI US3.60, US3.68 dollars] vs US4.64 dollars [95% CI US4.56 dollars, US4.73 dollars]). Sensitivity analyses demonstrated the stability of the results over a range of assumptions. CONCLUSION: From a US third-party payer's perspective, these findings suggest that treating the two main components of asthma (inflammation and bronchoconstriction) with FP/salmeterol may not only be a more cost-effective strategy but may actually lead to cost savings compared with the addition of montelukast to low-dose FP in patients with persistent asthma. The results were found to be robust over a range of assumptions.

Characterization of airway inflammation in patients with COPD using fractional exhaled nitric oxide levels: a pilot study.

OBJECTIVE: To characterize fractional exhaled nitric oxide (FeNO) levels that may be indicative of Th2-mediated airway inflammation in patients with chronic obstructive pulmonary disease (COPD). METHODS: This single-visit, outpatient study was conducted in 200 patients aged 40 years and older with COPD. All patients underwent spirometry and FeNO testing. COPD severity was classified according to the Global initiative for chronic Obstructive Lung Disease (GOLD) 2010 guidelines. RESULTS: Patients who participated in the study had a mean age of 63.9 ± 11.3 years and a mean smoking history of 46 ± 29 pack years. Patients had a mean forced expiratory volume in 1 second % predicted of 53.9% ± 22.1%. The percentage of patients classified with COPD severity Stage I, II, III, and IV was 13%, 40%, 39%, and 8%, respectively. In addition, according to current procedural terminology codes, 32% of patients were classified as mixed COPD/asthma, 26% as COPD/emphysema, and 42% as all other codes. The mean FeNO level for all patients was 15.3 ± 17.2 parts per billion (ppb). Overall, 89% of patients had a FeNO <25 ppb, 8% had a FeNO 25-50 ppb, and 3% had a FeNO >50 ppb. The percentages of patients with FeNO in the intermediate or high ranges of FeNO were greatest among patients with mixed COPD/asthma (intermediate, 11.5%; high, 6.6%) compared with COPD/emphysema (intermediate, 8%; high, 0) and all other codes (intermediate, 6.3%; high, 1.3%). CONCLUSION: Increases in FeNO were identified in a subset of patients with COPD, particularly in those previously diagnosed with both COPD and asthma. Since FeNO is useful for identifying patients with airway inflammation who will have a beneficial response to treatment with an inhaled corticosteroid, these data may have important implications for the management of COPD patients.

Determining economic feasibility of fluticasone propionate-salmeterol vs montelukast in the treatment of persistent asthma using a net benefit approach and cost-effectiveness acceptability curves.

BACKGROUND: The choice of treatment can have a major impact on the total costs associated with asthma care. OBJECTIVE: To determine the relative cost-effectiveness of twice-daily treatment with inhaled fluticasone propionate-salmeterol via Diskus, 100/50 microg, with that of once-daily treatment with oral montelukast as initial maintenance therapy in patients with persistent asthma uncontrolled with a short-acting beta2-agonist alone. METHODS: Data from a randomized, double-blind, double-dummy, 12-week clinical trial were analyzed. Efficacy end points included (1) symptom-free days (SFDs) during the 12-week period and (2) a 12% or greater increase in forced expiratory volume in 1 second (FEV1) from baseline. The economic analysis was performed from a payer's perspective, and hence only direct costs were included in the analysis. The incremental cost-effectiveness ratio (ICER), which is the mean difference in average costs divided by the mean difference in average effectiveness, was calculated for both effectiveness outcomes (SFDs and FEV1). RESULTS: For the SFDs end point, the ICER for fluticasone propionate-salmeterol vs montelukast was $2.87 (95% confidence interval, -$1.08 to $6.65), indicating that it costs, on average, an extra $2.87 per day for an additional SFD with fluticasone propionate-salmeterol than with montelukast. With regard to FEV1, the ICER was $1.79 (95% confidence interval, -$0.72 to $3.86), indicating that it costs, on average, an extra $1.79 per day to achieve a lung function improvement of 12% or greater from baseline with fluticasone propionate-salmeterol than with montelukast. At a widely acceptable ceiling ratio of $9.95 per day, the probability of fluticasone propionate-salmeterol being more cost-effective than montelukast was 99.8% for SFDs and was almost 100% for an FEV1 improvement of 12% of greater. CONCLUSIONS: Treating 2 main components of asthma, inflammation and smooth muscle dysfunction, using fluticasone propionate-salmeterol is more cost-effective than using a single mediator antagonist alone, such as montelukast, as initial maintenance therapy for persistent asthma in patients treated with a short-acting beta2-agonist only.

Loss of response to treatment with leukotriene receptor antagonists but not inhaled corticosteroids in patients over 50 years of age.

BACKGROUND: There are limited published data describing the relative efficacy of available treatment options in younger versus older patients with persistent asthma. OBJECTIVE: To compare the efficacy of fluticasone propionate (FP) and zafirlukast (Z) in younger (12 to 49 years of age) versus older (50 years and older) patients with asthma. METHODS: A retrospective analysis of five randomized, double-blind, double-dummy studies 4 to 12 weeks in duration of 1,742 patients <50 years of age and 243 patients aged 50 years or older. Interventions were inhaled fluticasone propionate (FP) 88 microg, oral Z 20 mg, or placebo twice daily. RESULTS: Treatment with FP resulted in significantly greater improvements than Z in all efficacy measurements (except for nighttime awakenings) regardless of age. In older patients, treatment with FP significantly increased pulmonary function compared with Z: FEV (FP= +0.19 L; placebo = -0.34 L; Z = -0.06 L); AM peak expiratory flow rate [PEFR] (FP = +25 L/minute; placebo = -18 L/minute; Z = +4 L/minute); PM PEFR (FP = +24 L/minute; placebo = -24 L/minute; Z = +5 L/minute; P < or = 0.023; for all comparisons). Compared with Z, treatment with FP in older patients also resulted in significantly greater increases in the percentage of symptom-free days (25% vs 13%) and rescue-free days (35% vs 17%); and significantly greater reductions in albuterol use (-1.6 vs -0.3 puffs/day) and the percentage of patients with exacerbations (2.7% vs 14.3%; P < or = 0.031). CONCLUSIONS: Regardless of age, treatment with FP in patients with asthma significantly improved pulmonary function and overall asthma control. In contrast, treatment with Z in older patients with asthma resulted in small improvements in asthma symptoms, whereas lung function improved minimally or not at all, and exacerbations increased. These data suggest that FP effectively controls inflammation in older patients, whereas Z may mask inflammation and may not provide the level of bronchodilatory or anti-inflammatory activity needed for effective asthma control in older patients.

The efficacy of intranasal fluticasone propionate in the relief of ocular symptoms associated with seasonal allergic rhinitis.

Intranasal corticosteroids have been shown to decrease ocular symptoms associated with allergic rhinitis as well as nasal symptoms. The primary objective of this retrospective analysis was to evaluate the efficacy of fluticasone propionate (FP) aqueous nasal spray in the treatment of ocular symptoms in patients with seasonal allergic rhinitis (SAR). We pooled efficacy data from seven multicenter, randomized, double-blind, placebo-controlled studies of similar design. Each study evaluated the efficacy of intranasal FP, 200 micrograms, given once daily in the treatment of nasal and ocular symptoms associated with SAR. At baseline and after 7 and 14 days of treatment, clinicians rated the severity of four individual ocular symptoms (itching, tearing, redness, and puffiness) via visual analog scales of 0-100, where 0 = no symptoms and 100 = worst symptoms. The four ratings were added to form the total ocular symptom score (TOSS). Patients rated the overall severity of their ocular symptoms (all symptoms evaluated with a single score) daily on diary cards in a similar fashion. The primary outcome was the mean change from baseline in the clinician-rated TOSS. A between-group difference of 25 points in the mean change from baseline TOSS by day 14 was considered clinically relevant. The FP group had greater mean changes from baseline in the TOSS and in all four individual symptom scores compared with placebo at days 7 and 14. At day 7, mean decreases from baseline in the TOSS were 76.0 points for the FP group and 50.9 points for the placebo group (p < 0.001), a difference between groups of 25.1. At day 14, mean decreases from baseline in the TOSS were 91.8 points for the FP group and 60.2 points for the placebo group (p < 0.001), a difference between groups of 31.6. Consistent with the clinician-rated data, patient-rated data showed a significantly greater reduction in the overall ocular symptom score for the FP group compared with placebo for both weeks 1 and 2 (p < 0.001). Intranasal FP provides safe and effective relief of ocular symptoms associated with SAR. Patients with allergic rhinitis who also have ocular symptoms as a component of their disease may benefit from intranasal FP monotherapy without the addition of topical ophthalmologic agents or oral antihistamines. Such an approach may have advantages regarding compliance and cost-effectiveness of treatment.

Effect of fluticasone propionate and salmeterol in a single device, fluticasone propionate, and montelukast on overall asthma control, exacerbations, and costs.

BACKGROUND: Inhaled corticosteroids are the most effective class of anti-inflammatory agents and are recommended for patients with persistent asthma. OBJECTIVE: To compare the effectiveness of (1) fluticasone propionate, 100 microg, and salmeterol, 50 microg; (2) fluticasone propionate, 100 microg; and (3) montelukast, 10 mg, as first-line maintenance treatment for persistent asthma. METHODS: Combined analysis of 4 clinical trials, 2 that compared fluticasone propionate-salmeterol with montelukast and 2 that compared fluticasone propionate with montelukast as initial asthma therapy. RESULTS: The 4 studies had a total of 1,910 patients 15 years or older with symptomatic asthma previously treated with inhaled short-acting beta2-agonists alone. At the end point, there were significantly greater increases in forced expiratory volume in 1 second with fluticasone propionate-salmeterol (0.57 L; P < or = .004) vs fluticasone propionate (0.48 L) and montelukast (0.31 L) and significantly greater increases in morning peak expiratory flow rate (84.9 L/min; P < .001) vs fluticasone propionate (56.0 L/min) and montelukast (36.1 L/min). Fluticasone propionate-salmeterol significantly increased the percentage of symptom- and rescue-free days and significantly reduced albuterol use vs fluticasone propionate and montelukast (P < or = .04 for both). Patients treated with fluticasone propionate and montelukast had 2.6 and 3.6 greater risk, respectively, of having an asthma-related exacerbation vs fluticasone propionate-salmeterol users. In addition, mean daily exacerbation costs per treated patient were dollars 0.41 for fluticasone propionate-salmeterol, dollars 4.60 for fluticasone propionate, and dollars 7.57 for montelukast, whereas mean daily costs per patient exacerbation for fluticasone propionate-salmeterol, fluticasone propionate, and montelukast were dollars 29, dollars 128, and dollars 154, respectively. CONCLUSIONS: Patients with symptomatic asthma previously treated with short-acting beta2-agonists only who require maintenance therapy are likely to have greater clinical benefits, lower risk of an asthma exacerbation, and reduced exacerbation-related costs when initiating therapy with fluticasone propionate-salmeterol vs fluticasone propionate or montelukast.

Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia.

BACKGROUND: Although response to intranasal corticosteroid therapy has been reported in patients with nonallergic rhinitis with eosinophilic syndrome (NARES), efficacy specifically in non-NARES patients has not been fully characterized. OBJECTIVE: To evaluate the efficacy of intranasal fluticasone propionate (FP) in the treatment of patients with perennial nonallergic rhinitis, with and without nasal eosinophilia. METHODS: Data from 983 patients in three randomized, double-blind, placebo-controlled PNAR trials were integrated. Patients received a total daily dose of FP 200 microg (n = 332), FP 400 microg (n = 325), or placebo (n = 326) for 28 days. Patients were > or =12 years of age with perennial rhinitis and negative skin tests to all allergens relevant to the geographic region. Nasal eosinophils were evaluated using a five-point scale. Patients were classified as non-NARES with a point score of 0 (n = 674; 69%); patients with a point score between I and 4 were classified as NARES (n = 309; 31%). Efficacy of FP was evaluated by the mean change in total nasal symptom score (TNSS), a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. RESULTS: Patients with either NARES or non-NARES had similar statistically significant improvement with FP 200 microg or 400 microg compared with placebo; thus, the total group comprising both varieties of rhinitis responded to FP. In the total population, both FP treatment groups showed significantly greater improvement in TNSS compared with placebo during each week of treatment (P < or = 0.002), with mean changes in TNSS for day 22 to day 28 ranging from -84 and -85 in the FP 200 microg and FP 400 microg groups, respectively, to -64 in the placebo group. The three study treatment groups had similar proportions of non-NARES (68 to 69%) and NARES (31 to 32%) patients at baseline. In the non-NARES subgroup, mean changes in TNSS for each treatment group were similar to changes seen in the total population. In the NARES subgroup, mean changes in TNSS for the FP 200 microg and placebo groups were similar to changes seen in the total population; mean change in TNSS for the FP 400 microg group was somewhat greater than changes seen in the total population. CONCLUSIONS: Intranasal FP is an effective treatment for perennial nonallergic rhinitis with or without nasal eosinophilia (NARES or non-NARES).

Fluticasone propionate aqueous nasal spray provided significantly greater improvement in daytime and nighttime nasal symptoms of seasonal allergic rhinitis compared with montelukast.

BACKGROUND: The safety and efficacy of intranasal corticosteroids for the treatment of allergic rhinitis is well documented in the literature. Additionally, an expert panel has concluded that intranasal corticosteroids are the first line of therapy when obstruction is a major component of rhinitis. Montelukast is a leukotriene receptor antagonist recently approved for the treatment of seasonal allergic rhinitis (SAR). OBJECTIVE: This randomized, double-blind, double-dummy, parallel-group study was conducted to compare the effectiveness of a 15-day course of intranasal fluticasone propionate 200 microg, once daily (FP200QD), to oral montelukast 10 mg, once daily (MON10QD), in relieving daytime and nighttime nasal symptoms associated with SAR. METHODS: The intent-to-treat (ITT) analysis population consisted of 705 eligible males and females (> or = 15 years) with SAR randomized to either FP200QD (N = 353) or MON10QD (N = 352). The primary efficacy endpoint was the mean change from baseline in subject-rated daytime total nasal symptom scores (the sum of four individual scores: nasal congestion, itching, rhinorrhea, and sneezing), evaluated via visual analog scales, and averaged over weeks 1 to 2. Secondary endpoints included the four daytime individual nasal symptom scores, the nighttime total, and individual nasal symptom scores (each evaluated on a four-point scale from 0 to 3). RESULTS: Statistically significant differences favoring FP200QD over MON10QD were observed for the mean change from baseline in daytime total nasal symptom scores (P < 0.001), daytime individual nasal symptom scores (P < 0.001), nighttime total (P < 0.001), and all individual nasal symptom scores (P < or = 0.002) over the 15-day treatment period. FP200QD and MON10QD were both well tolerated. CONCLUSIONS: The results of this well controlled study demonstrated that FP200QD was consistently superior to MON10QD with regard to every efficacy endpoint evaluated, including daytime and nighttime nasal congestion, in subjects with SAR.

Concurrent use of intranasal and orally inhaled fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function.

Two double-blind, randomized, placebo-controlled, parallel group safety and efficacy studies included evaluation of the hypothalamic-pituitary-adrenal (HPA)-axis effects of concurrent treatment with intranasal and orally inhaled fluticasone propionate (FP). In the first study, patients with asthma who were > or =12 years of age were assigned randomly to receive twice-daily doses (either 88 or 220 microg) of orally inhaled FP delivered from a metered-dose inhaler (MDI). In the second study, patients were assigned randomly to receive either orally inhaled FP 250 microg or orally inhaled FP 250 microg/salmeterol 50 microg delivered via the Diskus device. In both studies, patients with rhinitis were allowed to continue the use of intranasal FP at their usual dosing. Treatment periods were 26 weeks and 12 weeks for the MDI and Diskus studies, respectively. HPA-axis effects were assessed using response to short cosyntropin stimulation testing. The number and percentage of patients with an abnormal cortisol response, defined as a morning plasma cortisol of <5 microg/dL, a poststimulation peak of <18 microg/dL, or a poststimulation rise of <7 microg/dL, were summarized in two subgroups: patients who used intranasal FP and those who did not. The concurrent administration of intranasal FP and orally inhaled FP via an MDI or Diskus or via Diskus with salmeterol was not associated with HPA-axis effects compared with orally inhaled FP alone. The results of these two studies suggest that concurrent use of intranasal FP with orally inhaled FP administered via MDI or Diskus for treatment of comorbid rhinitis and asthma does not increase the risk of HPA-axis abnormalities.