Tushar Shah

Inhaled salmeterol and fluticasone: a study comparing monotherapy and combination therapy in asthma.

BACKGROUND The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms. OBJECTIVE To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids. METHODS A total of 136 male and female patients at least 12 years of age with asthma [forced expiratory volume in 1 second (FEV) between 50% and 80% of predicted] were randomized to twice daily salmeterol 42 microg, fluticasone propionate 88 microg, fluticasone propionate 220 microg, salmeterol 42 microg plus fluticasone propionate 88 microg, salmeterol 42 microg plus fluticasone propionate 220 microg, or placebo for 4 weeks. RESULTS Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great (0.6 to 0.7 L) as improvements in patients treated with salmeterol (0.3 L) or fluticasone propionate alone (0.3 L) (P < .05). Patient-rated data (peak expiratory flow, asthma symptom scores, percent of days with no asthma symptoms) confirmed greater (P < .05) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone. No clinically significant differences were noted between treatment groups in any safety measurement. CONCLUSION Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone.

Fluticasone propionate powder: Oral corticosteroid–sparing effect and improved lung function and quality of life in patients with severe chronic asthma

BACKGROUND Many patients with severe asthma are dependent on oral corticosteroids for maintenance control of their disease. Treatments that allow patients to be weaned off oral corticosteroids may help to minimize the risk of side effects associated with their chronic use. OBJECTIVE This study evaluated whether inhaled fluticasone propionate powder could maintain pulmonary function while reducing the dose of oral prednisone in patients with chronic, severe asthma. METHODS Oral prednisone-dependent (5 to 40 mg/day) adolescents and adults with asthma (n = 111; mean FEV1 = 61% of predicted value) were randomized to placebo or twice daily fluticasone propionate 500 or 1000 microg administered by means of a multidose powder inhaler for 16 weeks in a double-blind, parallel-group study. Patients underwent controlled prednisone reduction on the basis of predetermined asthma stability criteria. RESULTS Oral prednisone was eliminated by 75% and 89% of patients in the twice daily 500 and 1000 microg fluticasone propionate groups, respectively, versus 9% of the placebo group (P <.001). FEV1, morning and evening peak expiratory flow, asthma symptoms, albuterol use, and nighttime awakenings improved with fluticasone propionate treatment, achieving statistical significance (P </=.009) primarily in the 1000 microg twice daily group. Hypothalamic-pituitary-adrenal axis suppression observed at baseline improved when patients were weaned off oral prednisone to fluticasone propionate. Adverse events ascribed to drug treatment were primarily topical effects of inhaled corticosteroids or those associated with prednisone withdrawal. Patient quality of life assessed by means of the Asthma Quality of Life Questionnaire was clinically and significantly improved after fluticasone propionate treatment (P </=.003). CONCLUSION Fluticasone propionate powder (500 or 1000 microg twice daily) effectively improved lung function, adrenal function, and asthma-specific quality of life in patients with severe chronic asthma previously treated with oral prednisone while allowing most patients to be weaned off oral corticosteroid therapy.

Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma.

BACKGROUND Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking. OBJECTIVE This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy. METHODS Fluticasone propionate powder, 500 microgram, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-group study. Primary safety variables were measured at baseline and every 6 months thereafter. Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals. RESULTS Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L1 to L4 ) bone density at week 104 was not significantly different between fluticasone propionate (-0.006 +/- 0.008 g/cm2) and placebo (-0.007 +/- 0.010 g/cm2). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations (P =.021) and 8-hour plasma cortisol area under the curve values (P =.020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment. CONCLUSION Fluticasone propionate powder, 500 microgram twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma.

Improved Ability to Perform Strenuous Activities After Treatment with Fluticasone Propionate/Salmeterol Combination in Patients with Persistent Asthma

Patients with asthma experience disruptions in usual activities that can impair their quality of life, and in patients whose daily routine involves an active lifestyle, these disruptions can be severe. We assessed the patient-perceived effect of treatment with fluticasone propionate/salmeterol combination (FSC), compared with fluticasone propionate (FP) or salmeterol (SAL) alone, on activity limitations, particularly strenuous physical activities. The Asthma Quality of Life Questionnaire (AQLQ) was administered in two 12-week, randomized, double-blind, placebo-controlled trials comparing FSC 100/50 or 250/50 µg twice daily vs. the individual components alone in 686 adults and adolescents with asthma. In one study, patients were stratified by prior treatment [low to medium doses of inhaled corticosteroids (ICS) or SAL], and in the other study, all patients were previously treated with medium to high doses of ICS. Patients prospectively identified five activities they performed regularly and were asked how these activities were limited by their asthma. The effect of randomized treatment on strenuous activities (e.g., aerobics, cycling, hiking, and basketball) was assessed. In both studies, treatment with FSC resulted in clinically meaningful improvements (i.e., change in AQLQ of ≥0.5) and was statistically significantly better than SAL in both studies and FP in one study. Treatment of the two main components of asthma—inflammation and bronchoconstriction—with FSC results in clinically meaningful improvements in the ability of patients with persistent asthma to perform not only their usual activities but also strenuous activities.

Dose-Ranging Efficacy and Safety Study of Albuterol Multidose Dry Powder Inhaler (MDPI) vs Albuterol Hydrofluoroalkane (HFA) and Placebo MDPI in Children With Asthma

Background: To evaluate the efficacy and safety of albuterol delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI) that does not require patient coordination of device actuation with inhalation and albuterol hydrofluoroalkane (HFA) at 2 dose levels relative to placebo in children with persistent asthma. Methods: A phase 2, multicenter, double-blind, doubledummy, single-dose, 5-period, crossover study (ABS-AS-202; NCT01899144) randomized pediatric patients (aged 4 11 years) with persistent asthma and prestudy forced expiratory volume in 1 second (FEV1) of 60% 90% of predicted normal to 1 of 10 treatment sequences containing albuterol MDPI (90 and 180 mcg), albuterol HFA (90 and 180 mcg), and placebo MDPI+placebo HFA. Spirometry was the primary measurement to evaluate study end points. Serial FEV1 measurements were obtained at designated time points over 6 hours after the completion of study drug administration at each treatment visit. Safety was evaluated by adverse events. Results: The full analysis set included 61 patients. Baseline-adjusted percent-predicted FEV1-time curve over 6 hours postdose (PPFEV1 AUC0-6) was significantly greater in all active treatment groups compared with placebo (P Table). PPFEV1 AUC0-6 was similar in the albuterol MDPI 90 mcg and 180 mcg groups (Table); however, the albuterol HFA 180 mcg group had significantly greater PPFEV1 AUC0-6 than the albuterol HFA 90 mcg group (P=0.0226; Table). All doses of albuterol were generally well tolerated. Conclusions: Albuterol MDPI significantly improved pulmonary function versus placebo in children with asthma. Improvements for albuterol MDPI 90 and 180 mcg were similar; a dose-response effect was observed with albuterol HFA. Results suggest that relief of asthma symptoms in children may be managed adequately with albuterol MDPI (1 2 inhalations). No new safety concerns were noted with albuterol MDPI, and its safety profile is consistent with that of albuterol HFA.

Efficacy and Safety of Albuterol Multidose Dry Powder Inhaler (MDPI) Versus Placebo in Children With Asthma

Background: To evaluate the chronic-dose efficacy and safety of albuterol delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI) that does not require patient coordination of device actuation with inhalation relative to placebo in pediatric patients with asthma. Methods: This phase 3, doubleblind, parallel-group, multicenter, 3-week study (ABS-AS-303; NCT02126839) included children (aged 4─11 years) with asthma and prestudy FEV1 of 50%– 95% of predicted. After a 14-day run-in period during which patients continued their current asthma therapy and received single-blind placebo MDPI, patients were randomized to albuterol MDPI 90 mcg/inhalation, 2 inhalations 4 times daily (total daily dose, 720 mcg), or placebo for 3 weeks. Serial FEV1 measurements were obtained at designated time points over 6 hours after baseline FEV1 assessment and completion of study drug administration on treatment day 1 (TD1) and 22 (TD22). Safety was evaluated by adverse events. Results: The full analysis set included 184 patients. Albuterol MDPI–treated patients experienced significantly (P<0.0001) greater improvements in area under the baselineadjusted percent-predicted FEV1-time curve over 6 hours postdose (PPFEV1 AUC0-6) over the 3-week study versus placebo patients (least squares mean difference of 25%•h in favor of albuterol). On TD1 and TD22, baseline-adjusted PPFEV1 AUC0-6 for albuterol MDPI–treated patients was similar and greater than patients receiving placebo MDPI (P<0.0001). The benefit of albuterol (mean change in PPFEV1) was evident 5 minutes after dosing and lasted several hours; maximal effect was noted 1–2 hours postdose. Albuterol MDPI was well tolerated. Conclusions: Albuterol MDPI, administered chronically for 3 weeks, improved pulmonary function in pediatric patients significantly better than placebo with similar improvements noted on TD1 and TD22. Clinical effects were evident within 5 minutes and maintained for >2 hours. Four-times-daily administration was generally well tolerated in pediatric patients.