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.

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6-<12 years).

BACKGROUND: The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old. OBJECTIVE: To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma. METHODS: This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting ß2-agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 µg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 µg (160/9 µg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 µg (160/4.5 µg) BID (n = 95), or budesonide pMDI 80 µg (160 µg) BID (n = 92) for 12 weeks. RESULTS: Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 µg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 µg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments. CONCLUSION: Budesonide/formoterol pMDI 160/9 µg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 µg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02091986.

Efficacy and safety of budesonide administered by pressurized metered-dose inhaler in children with asthma.

BACKGROUND: Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been determined. OBJECTIVE: To examine the efficacy and safety of 160 µg twice daily of budesonide through a pMDI vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids. METHODS: A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized 304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 µg (80 µg × 2 inhalations) twice daily of budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efficacy end point was change from baseline in morning peak expiratory flow (PEF); safety end points included adverse events, vital signs, and discontinuations. RESULTS: Budesonide treatment significantly improved morning PEF vs placebo; mean treatment effect (budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed significant improvements vs placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory flow at 25% to 75% of pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than in the placebo group. No serious adverse events were reported. CONCLUSION: Budesonide at 160 µg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

Novel albuterol multidose dry powder inhaler in patients with exercise-induced bronchoconstriction: A single-dose, double-blind, randomized, 2-way crossover study.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) was developed that eliminates the need to coordinate device actuation with inhalation as is required with conventional metered-dose inhalers. OBJECTIVE: To evaluate albuterol MDPI efficacy and safety in patients with exercise-induced bronchoconstriction (EIB). METHODS: This single-dose, double-blind, 2-way crossover study randomized adolescents and adults with EIB (≥20% fall from pre-exercise challenge FEV(1)) to treatment sequences of albuterol MDPI (180 µg [2 inhalations of 90 µg each])/placebo MDPI (n = 19) or the reverse sequence (n = 19). FEV(1) was measured 30 and 5 min predose, 30 min postdose (ie, 5 min before treadmill exercise challenge; baseline) and 5, 10, 15, 30, and 60 min after exercise challenge. The primary efficacy endpoint was maximum percentage fall from baseline in FEV(1) up to 60 min post-exercise challenge. RESULTS: Mean maximum percentage fall in FEV(1) within 60 min post-exercise challenge was 6.2 ± 1.4% for albuterol MDPI versus 22.4 ± 1.4% for placebo MDPI (between-treatment difference: -16.2%; 95% CI: -20.2% to -12.1%; P < 0.0001). A significantly higher percentage of albuterol MDPI-treated patients were protected against EIB (<10% maximum FEV(1) fall post-exercise challenge) versus placebo MDPI (84.2% vs 15.8%; P < 0.0001). Protection with albuterol MDPI was evident within 5 min and maintained through 30 min; recovery was complete for both groups at 60 min. Treatment with a single dose of albuterol MDPI was generally well tolerated. CONCLUSIONS: Albuterol MDPI provides clinically significant protection from EIB in adolescents and adults with EIB; no new safety issues were observed with short-term albuterol MDPI use. ClinicalTrials.gov identifier NCT01791972.

The effect of GSK2190915, a 5-lipoxygenase-activating protein inhibitor, on exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.

Fluticasone/Formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma.

OBJECTIVES: This study investigated the efficacy and tolerability of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol)*, administered twice daily (BID) via a single aerosol inhaler, compared with fluticasone propionate (fluticasone) or formoterol fumarate (formoterol) administered alone, in patients with mild to moderate asthma. METHODS: Patients aged ≥12 years were evenly randomized to 12 weeks of treatment with fluticasone/formoterol (100/10 µg BID), fluticasone (100 µg BID), or formoterol (10 µg BID), in this multicenter, double-blind, parallel-group, study. The 2 coprimary end points were: (1) change in forced expiratory volume in 1 second (FEV(1)) from morning predose at baseline to predose at week 12 for the comparison of the combination product with formoterol alone; and (2) change in FEV(1) from morning predose at baseline to 2 hours postdose at week 12 for the comparison of the combination product with fluticasone alone. The secondary objective was to demonstrate the efficacy of fluticasone/formoterol using other pulmonary function tests and clinical end points. Tolerability was assessed based on adverse events, clinical laboratory tests and vital sign evaluations. RESULTS: Statistically significant differences were demonstrated for the 2 coprimary end points. Fluticasone/formoterol combination therapy showed significantly greater improvements from baseline to end of study in the change in predose FEV(1) compared with formoterol (least squares [LS] mean treatment difference, 0.118 L [95% CI, 0.034-0.201; P = 0.006]) and the change in predose compared with 2 hours postdose FEV(1) versus fluticasone (LS mean treatment difference, 0.122 L [95% CI, 0.040-0.204; P = 0.004]). Statistical analyses of the secondary efficacy endpoints revealed that evaluations of lung function, asthma exacerbations, asthma symptoms, rescue medication use and asthma control were supportive overall of the superior efficacy of fluticasone/formoterol combination therapy compared with its individual components; were supportive overall of the efficacy of fluticasone/formoterol combination therapy compared with its individual components. Since the secondary endpoints were analyzed using the sequential gatekeeper approach, only the mean change from baseline to final week in morning peak expiratory flow rate between the combination-therapy and formoterol groups returned statistically significant results (least squares mean difference, 20.05 [95% CI, 7.631-32.472; P = 0.002]). The fluticasone/formoterol combination therapy had a good tolerability profile over the 12-week treatment period. CONCLUSIONS: Fluticasone/formoterol had a good tolerability profile and showed statistically superior efficacy for the two co-primary endpoints compared to fluticasone or formoterol, in adolescents and adults with mild to moderate asthma. ClinicalTrials.gov identifier: NCT00394199.

Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma.

BACKGROUND: Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics. METHODS: Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both. RESULTS: In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation. CONCLUSIONS: In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.

Baseline predictors of placebo response in exercise-induced bronchoconstriction (EIB): pooled regression analysis >from three studies of montelukast in EIB.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient-related factors driving placebo response could facilitate more efficient clinical trials for EIB. METHODS: Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15-45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV1) ≥20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5-12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV1 while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the "best" model. RESULTS: Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV1 % predicted (p <.001), smaller maximum % fall in FEV1 in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011). CONCLUSION: Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients.

Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma.

BACKGROUND: Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions. METHODS: Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval. RESULTS: Of 373 subjects challenged twice 161 were positive (≥ 10% fall FEV1 on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (< 10% fall FEV1) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥ 10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥ 15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative. CONCLUSIONS: Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when prescribing prophylactic treatment to prevent EIB and when designing protocols for clinical trials.

Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids.

Asthma is a heterogeneous condition characterized by reduced lung function, chronic inflammation, and periodic asthma deteriorations. This study was performed to evaluate the effect of mometasone furoate (MF)/formoterol (F) combination, 200/10 microg, administered twice daily (b.i.d.) on asthma deteriorations and pulmonary function in patients with asthma uncontrolled on medium-dose inhaled corticosteroid (ICS). After 2- to 3-week open-label run-in with MF 200 microg b.i.d., patients (>or=12 years) were randomized to 26 weeks of treatment with MF/F 200/10 microg, MF 200 microg, F 10 microg, or placebo b.i.d. Coprimary end points were time to first asthma deterioration (MF/F versus F) and bronchodilation, assessed by the area under the curve of the change in forced expiratory volume in 1 second 0-12 hours (FEV(1) AUC(0-12h); MF/F versus MF). A total of 781 patients were randomized. Treatment with MF/F 200/10 microg reduced asthma deteriorations and clinically judged deteriorations (i.e., deterioration resulting in emergency treatment, hospitalization, or treatment with additional excluded asthma medication [i.e., systemic corticosteroids]). The proportion of patients experiencing asthma deteriorations was MF/F, 30.4%; MF, 33.9%; F, 54.0%; placebo, 55.6% (p < 0.001, MF/F versus F and placebo). There was a sixfold reduction in clinically judged deteriorations with MF/F versus F and placebo (p < 0.001). Lung function improved more rapidly with MF/F than MF and placebo. Mean change from baseline FEV(1) AUC(0-12h) at week 12 was MF/F, 11.7% versus MF, 5.7%; F, 8.5%; and placebo, 3.9% (p < 0.001). Treatment-related AEs were rare and similar across groups. Treatment with MF/F 200/10 microg was effective in reducing the risk of asthma deteriorations. MF/F was safe and provided rapid and sustained bronchodilation in patients with asthma.

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma.

BACKGROUND: Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma. METHODS: 509 people (6-50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a > or = 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 < or = 16 mg/ml and to mannitol a 15% fall in FEV1 at < or = 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results. RESULTS: Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6) mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive. CONCLUSION: In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations. TRIAL REGISTRATION: This was a multi-center trial comprising 25 sites across the United States of America.

Bronchodilator efficacy of indacaterol, a novel once-daily beta2-agonist, in patients with persistent asthma.

BACKGROUND: Indacaterol is a novel once-daily inhaled beta2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease. OBJECTIVE: To investigate the bronchodilator efficacy of indacaterol in patients with persistent asthma. METHODS: Patients received a randomized sequence of single doses of indacaterol, 400 microg, via single-dose dry powder inhaler (SDDPI); indacaterol, 200 microg, via multidose dry powder inhaler (MDDPI); and placebo. At each visit, the forced expiratory volume in 1 second (FEV1) was recorded at a series of time points during a 24-hour period. RESULTS: Of 33 patients screened, 25 were randomized to treatment. Adjusted mean FEV1 was significantly higher (P < or = .005) for both indacaterol doses vs placebo at most time points. The first time points at which statistically significant treatment differences were observed for indacaterol and placebo in FEV1 were 0.17 L at 5 minutes after dosing for 400 microg of indacaterol (SDDPI) and 0.21 L at 10 minutes for 200 microg of indacaterol (MDDPI) (both P < .001 vs placebo). Differences relative to placebo at the final time point, 24 hours after dosing, were 0.29 L and 0.15 L for indacaterol, 400 microg and 200 microg, respectively (both P < or = .003 vs placebo). Overall, FEV1 was significantly higher for the 400-microg dose compared with the 200-microg dose from 15 minutes to 2 hours after dosing (P < or = .013) and from 5 hours onward (P < or = .022). Indacaterol was associated with good tolerability and safety. CONCLUSIONS: Indacaterol demonstrates sustained bronchodilator efficacy throughout the full 24-hour period, with a rapid onset of action and a good overall safety profile.

Evaluation of efficacy and safety of budesonide delivered via two dry powder inhalers.

BACKGROUND: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 microg (DPI-A) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 microg and 180 microg; DPI-B). OBJECTIVE: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device. METHODS: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6-17 years with mild asthma (N = 516) received budesonide DPI-B 360 microg or DPI-A 400 microg twice-daily (total daily dose 720 microg or 800 microg), budesonide DPI-B 180 microg or DPI-A 200 microg once daily (total daily dose 180 microg or 200 microg), or matching placebo. Change in forced expiratory volume in 1 second (FEV(1)) and secondary variables (asthma symptoms, beta(2)-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured. RESULTS: In both studies, FEV(1) significantly (p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI-B 180 mug in adults. In the adult study, significantly (p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p or= 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.

Single-dose montelukast or salmeterol as protection against exercise-induced bronchoconstriction.

BACKGROUND AND OBJECTIVE: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls. METHODS: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV(1) following exercise (DeltaFEV(1)). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 microg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum DeltaFEV(1) at 2 h postdose. Secondary end points included maximum DeltaFEV(1) at the two later time points, and other measures (including recovery time and need for beta-agonist rescue) at all time points. RESULTS: The maximum DeltaFEV(1) magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [+/- SE], 13.2 +/- 1.2%, 11.7 +/- 1.2%, and 10.0 +/- 1.1% vs 21.8 +/- 1.2%, 16.8 +/- 1.3%, and 14.0 +/- 1.1%, respectively; p

Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast.

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV(1)) > or = 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV(1) (from pre-exercise FEV(1)) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean +/- SD = 11.7% +/- 10.8) versus placebo (17.5% +/- 13.8) (p < or = 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p < or = 0.001) and a smaller area under the curve for percent-fall in FEV(1) during 60 minutes after challenge (p < or = 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.

Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast.

BACKGROUND: Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing. OBJECTIVE: To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist. METHODS: In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (> or = 20% postexercise decrease in forced expiratory volume in 1 second [FEV1]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV1 from preexercise baseline during 60 minutes after the 2-hour challenge. RESULTS: At 2, 12, and 24 hours after dosing, the maximum decrease in FEV1 was 10.8% +/- 7.9%, 8.4% +/- 7.5%, and 8.3% +/- 7.3% for montelukast and 22.3% +/- 13.1%, 16.1% +/- 10.2%, and 16.9% +/- 11.7% for placebo, respectively (P < or = .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P < or = .001); mean (95% confidence interval) differences were -26.8 minutes (-35.1 to -18.4 minutes), -16.0 minutes (-22.9 to -9.2 minutes), and -17.4 minutes (-24.9 to -9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV1 during 60 minutes after exercise was smaller after montelukast (P < or = .001); montelukast protected more patients against EIB (P < or = .001). Fewer patients required postexercise beta-agonist rescue at 2 hours after dosing with montelukast (P = .03). CONCLUSION: Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

Efficacy of desloratadine, 5 mg, compared with fexofenadine, 180 mg, in patients with symptomatic seasonal allergic rhinitis.

This is the first U.S.-based study to compare efficacy and safety of desloratadine with fexofenadine in subjects with symptomatic seasonal allergic rhinitis (SAR). In this double-blind study, subjects were randomized to desloratadine, 5 mg (n = 290),fexofenadine, 180 mg (n = 288), or placebo (n = 144) once daily for 15 days. Primary end point was mean change from baseline to study end in morning instantaneous total symptom score (AM NOW TSS) excluding congestion. Secondary measures included change from baseline in the morning/evening reflective TSS (AM/PM PRIOR TSS) excluding congestion, AM NOW individual symptom score (AM NOW ISS) including congestion, and the AM/PM PRIOR ISS including congestion. Subjects self-evaluated their symptoms on a five-point scale. Mean AM NOW TSSs were significantly reduced from baseline at day 15 with desloratadine (p = 0.006) and fexofenadine (p = 0.024) versus placebo. Desloratadine and fexofenadine were not statistically different (p = 0.491); the upper limit of the 95% CI for desloratadine to fexofenadine (0.259) was within the prespecified noninferiority margin of 0.7 U. Decrease in mean AM/PM PRIOR TSS excluding congestion was comparable between desloratadine and fexofenadine (p = 0.405; CI = 0.221) but was significantly greater with both active treatments versus placebo (desloratadine, p < 0.001;fexofenadine, p = 0.003). Desloratadine and fexofenadine provided greater reduction in the AM NOW ISS and AM/PM PRIOR ISS (both including congestion) versus placebo; reductions were comparable between active treatments. All treatments were well tolerated. Desloratadine, 5 mg, and fexofenadine, 180 mg, provide comparable efficacy and tolerability in the treatment of SAR. Both treatments are significantly more effective than placebo.

Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroids.

BACKGROUND: Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants. OBJECTIVE: To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS. METHODS: Randomized, double-blind, parallel-group, 12-week study. RESULTS: Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups. CONCLUSIONS: Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.