Long-term safety and efficacy studies of epinephrine HFA metered-dose inhaler (Primatene® Mist): a two-stage randomized controlled trial.

Objective: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI.Method: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline.Results: The primary efficacy endpoint (AUC0-6hrs of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant.Conclusion: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.

Forced Expiratory Flow (FEF25-75%) as a Clinical Endpoint in Children and Adolescents with Symptomatic Asthma Receiving Tiotropium: A Post Hoc Analysis.

INTRODUCTION: In pediatric patients with asthma, measurements of forced expiratory volume in 1 s (FEV1) may be normal or may not correlate with symptom severity. Forced expiratory flow at 25-75% of the vital capacity (FEF25-75%) is a potentially more sensitive parameter for assessing peripheral airway function. This post hoc analysis compared FEF25-75% with FEV1 as an endpoint to assess bronchodilator responsiveness in children with asthma. METHODS: Change from baseline in trough FEF25-75% and trough FEV1 following treatment with either tiotropium (5 µg or 2.5 µg) or placebo Respimat® was analyzed in four phase III trials in children (aged 6-11 years) and adolescents (aged 12-17 years) with symptomatic moderate (VivaTinA-asthma® and PensieTinA-asthma®) and mild (CanoTinA-asthma® and RubaTinA-asthma®) asthma. Data from all treatment arms were pooled and correlations between FEF25-75% and FEV1 were calculated and analyzed. RESULTS: A total of 1590 patients were included in the analysis. Tiotropium Respimat® consistently improved FEF25-75% and FEV1 versus placebo, although in adolescents with severe asthma, the observed improvements were not statistically significant. Improvements in FEF25-75% response with tiotropium versus placebo were largely more pronounced than improvements in FEV1. Statistical assessment of the correlation of FEV1 and FEF25-75% showed moderate-to-high correlations (Pearson's correlation coefficients 0.73-0.80). CONCLUSIONS: In pediatric patients, FEF25-75% may be a more sensitive measure to detect treatment response, certainly to tiotropium, than FEV1 and should be evaluated as an additional lung function measurement.

A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene® MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma.

Background: Two sequential single-dose crossover dose-ranging studies were performed to evaluate the clinical efficacy and safety profile of epinephrine hydrofluroalkane (HFA) metered-dose inhaler (MDI) formulation at various doses in subjects with asthma. Methods: In these multicenter, multiarm, double-blinded, or evaluator-blinded studies, subjects were randomized to receive the epinephrine HFA (Primatene® MIST HFA) MDI medication at doses ranging from 90 to 440 µg/dose, as well as to a placebo (PLA) control and an active control of epinephrine CFC (chlorofluorocarbon) MDI (Primatene® MIST CFC) at 220 µg/inhalation. Results: Spirometry testing for FEV1 (Forced Expiratory Volume in one second) demonstrated statistically significant improvements over PLA for epinephrine HFA MDI at all doses above 125 µg, as the amount out of the actuator (i.e., mouthpiece). The efficacy results for epinephrine HFA MDI in the dose range of 125-250 µg were also comparable to epinephrine CFC MDI (220 µg/inh). Safety assessments demonstrated minimal safety concerns for all treatment groups. No notable safety differences were observed between the studied doses of epinephrine HFA MDI and the active control formulation of epinephrine CFC MDI. Conclusion: The findings indicate that epinephrine HFA MDI provided clinically significant bronchodilator efficacy with minimal safety concerns in a dose range of 125-250 µg. These findings confirmed the optimal treatment doses of 125-250 µg that were appropriate for use in longer term 12 and 26 week chronic dosing studies of epinephrine HFA MDI for patients with intermittent or mild to moderate persistent asthma. Clinical trials registration number: NCT01025648.

Bronchodilation with mometasone furoate/formoterol fumarate administered by metered-dose inhaler with and without a spacer in children with persistent asthma.

BACKGROUND: The bronchodilatory effect of mometasone furoate/formoterol fumarate (MF/F) administered by metered-dose inhaler (MDI) with or without a spacer has not been evaluated previously in children aged 5-11 years. METHODS: This was a randomized, multicenter, placebo-controlled, single-dose, four-period crossover study. Children with persistent asthma aged 5-11 years participated in this study. Subjects used inhaled corticosteroids with/without long-acting beta-2 agonists for 12 weeks before enrollment and at screening had forced expiratory volume in 1 sec (FEV1 ) ≥70% predicted. Subjects received MF/F MDI 100/10 µg with/without spacer (AeroChamber Plus® with Flow-Vu® Anti-Static Valved Holding Chamber), F-Dry Powder Inhaler (F-DPI) 10 µg, and placebo MDI with/without spacer in separate treatment periods. The primary endpoint was FEV1 area under the curve from 0 to 12 hr (AUC0-12hr ) for the comparison of MF/F with spacer versus placebo. Secondary measurements included MF/F without spacer versus placebo, as well as MF/F with spacer versus MF/F without spacer, and F-DPI versus placebo. Analysis was performed with an analysis of covariance model for a crossover study. RESULTS: Data from 87 subjects were analyzed. MF/F with spacer demonstrated a larger change in mean FEV1 AUC0-12hr versus placebo (115 vs. -9 mL), with a treatment difference of 124 mL (95% CI 94-154, P < 0.001). Similarly, MF/F without spacer versus placebo resulted in a 102 mL difference in mean-adjusted FEV1 AUC0-12hr (95% CI 73-131, P < 0.001), whereas the difference between MF/F with spacer versus MF/F without spacer was 22 mL (95% CI -8 to 52, P = 0.144). The difference between F-DPI versus placebo was 106 mL (95% CI 77-135, P < 0.001). No unexpected adverse events were observed. CONCLUSIONS: In this trial, MF/F MDI 100/10 µg demonstrated significant bronchodilation in children aged 5-11 years regardless of the use of a spacer. No difference in bronchodilation was observed between MF/F MDI and F-DPI.

Linear growth and bone maturation are unaffected by 1 year of therapy with inhaled flunisolide hydrofluoroalkane in prepubescent children with mild persistent asthma: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Inhaled corticosteroids (ICS) are the preferred long-term therapy for subjects with persistent asthma. However, concerns remain about potential effects of long-term ICS use on growth in children. OBJECTIVE: To determine the effect of 1 year of inhalation therapy with flunisolide hydrofluoroalkane (HFA) on growth velocity and bone maturation in children with mild persistent asthma. METHODS: In this double-blind, placebo-controlled study, 218 prepubescent (Tanner Stage 1) children with mild persistent asthma ranging in age from 4 to 10 years were evaluated. After a 2-week run-in period, subjects were randomized (1:1) to 2 puffs flunisolide HFA twice daily (85 µg/puff) or placebo for 52 weeks. Height was assessed by stadiometry at each visit. Growth velocity (cm/52 weeks) was estimated by the slope of the linear regression of height over time. An independent assessor scored hand and wrist radiographs for bone development pretreatment and at week 52. Analysis of covariance was used for all efficacy endpoints. RESULTS: The 2 treatment groups were similar at baseline for sex, race, age, weight, and height. At the end of double-blind treatment, mean growth velocity was 6.01 ± 1.84 cm/52 weeks for flunisolide HFA (n = 106) and 6.19 ± 1.30 cm/52 weeks for placebo (n = 112) (P = .425). Mean advancement in bone age during the 1-year study was similar for the 2 groups: 0.93 ± 0.46 years for flunisolide HFA (n = 70) and 1.01 ± 0.41 years for placebo (n = 75) (P = .128). CONCLUSIONS: In this study, flunisolide HFA did not suppress growth or bone maturation at the highest approved dose for children with persistent asthma.

Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood.

BACKGROUND: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. METHODOLOGY/PRINCIPAL FINDINGS: Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. CONCLUSIONS/SIGNIFICANCE: This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Once-daily evening administration of mometasone furoate in asthma treatment initiation.

BACKGROUND: In a previous study, a 200-microg once-daily evening dose of mometasone furoate dry powder inhaler (DPI) was effective in patients with asthma previously taking inhaled corticosteroids. No studies have been conducted to test the effect of a once-daily evening dose in patients previously using only short-acting beta2-adrenergic agonists (SABAs) for symptom relief. OBJECTIVE: To evaluate the effectiveness of mometasone furoate DPI administered once daily in the evening as initial controller therapy in patients previously using SABAs alone for asthma. METHODS: Patients with mild-to-moderate persistent asthma from 18 US centers participated in a 12-week, randomized, double-blind, placebo-controlled study. Patients received either mometasone furoate DPI, 200 microg, or placebo once daily in the evening. The primary efficacy variable was the change in forced expiratory volume in 1 second from baseline to the end point (last evaluable visit). Other measurements included forced vital capacity, forced expiratory flow between 25% and 75%, morning and evening peak expiratory flow, asthma symptoms, use of albuterol, nocturnal awakenings, physicians' evaluation of response to therapy, and time to asthma worsening. RESULTS: At the end point, the mean increase in forced expiratory volume in 1 second relative to baseline for the mometasone furoate DPI group of 0.43 L (16.8%) was significantly greater than that for the placebo group of 0.16 L (6.0%) (P < .01). Morning peak expiratory flow, forced vital capacity, and forced expiratory flow between 25% and 75% also significantly improved with mometasone furoate DPI treatment relative to placebo (P < .01). Once-daily dosing with mometasone furoate DPI was well tolerated. CONCLUSION: Mometasone furoate DPI (200 microg) administered once daily in the evening significantly improves pulmonary function in patients previously using SABAs alone for asthma control.

Comparison of patient preference and ease of teaching inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers.

A multicenter, randomized, open-label, crossover study with two 4-week evaluation periods compared patient preference and ease of teaching correct inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers (pMDIs). Patients 18 to 65 years of age with stable, mild to moderate asthma, who required or were eligible for inhaled corticosteroid therapy, were randomized to treatment sequences consisting of 4-week evaluation periods with Pulmicort Turbuhaler (budesonide inhalation powder) two puffs (400 microg) bid and one of three inhaled corticosteroids via pMDI: Aerobid-M (flunisolide) four puffs (1 mg) bid, Flovent (fluticasone propionate) two puffs (440 microg) bid, or Vanceril Double Strength (beclomethasone dipropionate) five puffs (420 microg) bid. Patients indicated device preference at study end and completed the Patient Device Experience Assessment (PDEA) questionnaire after each evaluation period. Ease of teaching, time required to master use of the device, percentage of patients demonstrating mastery on the first attempt, and the number of attempts required to demonstrate mastery were assessed. Despite previous use of pMDIs by most patients, Pulmicort Turbuhaler was significantly preferred (p < 0.001) and required significantly less time to master than pMDIs (p < 0.001). Median times to device mastery were 3.67 min for Pulmicort Turbuhaler versus 5.33 min for pMDIs. Patients rated Pulmicort Turbuhaler significantly better than pMDIs on PDEA ease of use (p = 0.0005) and overall satisfaction (p < 0.0001) single-item scales and all four multi-item scales (pharyngeal symptoms, oral sensation, operational use, and inhaler attributes; p < 0.05). Overall, patients preferred Pulmicort Turbuhaler over pMDIs and required less time to be taught how to correctly use Turbuhaler trade mark.