Improvements In Morning Peak Expiratory Flow Research Articles

Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma

BackgroundBenralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. ObjectiveTo assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. MethodsMixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). ResultsLeast squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. ConclusionIn 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. Trial RegistrationClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma

To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated. In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough. FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified. ClinicalTrials.gov:NCT01563029.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Budesonide/Formoterol in a Single Inhaler for Maintenance and Relief in Mild-to-Moderate Asthma: A Randomized, Double-Blind Trial

To compare a novel asthma management strategy--budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief--with a higher dose of budesonide plus as-needed terbutaline. This was a 6-month, randomized, double-blind, parallel-group study in patients with mild-to-moderate asthma (n = 697; mean age, 38 years [range, 11 to 79 years]; mean baseline FEV1, 75% of predicted; mean inhaled corticosteroid [ICS] dosage, 348 microg/d). Following a 2-week run-in period, all patients received two blinded, dry powder inhalers, one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms. Patients were randomized to receive either budesonide/formoterol (80 microg/4.5 microg, two inhalations qd) for maintenance plus additional inhalations as needed for symptom relief, or budesonide (160 microg, two inhalations qd) for maintenance medication plus terbutaline (0.4 mg) as needed. The primary efficacy variable was morning peak expiratory flow (PEF). Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide (increases of 34.5 L/min vs 9.5 L/min, respectively; p < 0.001). The risk of having a severe exacerbation (hospitalization/emergency department [ED] treatment, oral steroids for asthma, or a > or = 30% decrease from baseline in morning PEF on 2 consecutive days) was 54% lower with budesonide/formoterol vs budesonide (p = 0.0011). Budesonide/formoterol patients experienced 90% fewer hospitalizations/ED treatments due to asthma than budesonide patients (1 vs 10, respectively; p = 0.026). The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group (mean dose, 240 microg/d vs 320 microg/d, respectively) and with 77% fewer oral steroid treatment days vs budesonide (114 days vs 498 days, respectively). Both treatments were well tolerated. Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline.

Cost-efficacy comparison of inhaled fluticasone propionate and budesonide in the treatment of asthma

Background: The results of a recent meta-analysis comparing 2 inhaled corticosteroids, fluticasone propionate (FP) and budesonide, demonstrated that FP had an improved efficacy-to-safety ratio compared with budesonide. However, limited data are available on the relative economic benefits of these 2 regimens. Objective: This pharmacoeconomic analysis used individual patient data from studies in the meta-analysis to compare the relative cost-efficacy of 2 asthma regimens from the perspective of a US third-party payer. Methods: This analysis included all 7 studies in the meta-analysis that compared budesonide with FP dosed at approximately half the dose of budesonide and that included measurement of daily morning peak expiratory flow (PEF). Results: The total daily per-person cost of asthma management was higher for patients treated with budesonide than with FP ($3.00 vs $2.25, respectively). Treatment with FP had greater cost-efficacy than treatment with budesonide, based on a range of outcome measures that included improvement in morning PEF, symptom-free days, and episode-free days. The daily cost per effectively treated patient (an increase in PEF of ≥ 10%) was $5.62 with FP and $10.05 with budesonide. The cost per symptom-free day was $4.36 with FP, compared with $6.67 with budesonide. The cost per episode-free day was $5.60 with FP and $9.42 with budesonide. The pharmacoeconomic difference continued to favor FP as the criteria for success were made more stringent and the cost of budesonide was lowered. Conclusion: Based on data from the 7 randomized, controlled trials, treatment of asthma with FP was more effective and less expensive, using US health care assumptions and costs, than treatment with budesonide.

Salmeterol vs Theophylline: Sleep and Efficacy Outcomes in Patients With Nocturnal Asthma

To compare the efficacy, safety, and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma.Randomized, double-blind, double-dummy, three-period crossover.Outpatients at a single center. Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies.Male and female patients who were at least 18 years old with nocturnal asthma (baseline FEV1, 50 to 90% of predicted) and who required regular bronchodilator therapy. Patients on inhaled corticosteroids, cromolyn, and nedocromil were allowed into the study if their dosing remained constant throughout the study.Inhaled salmeterol (42 microg per actuation), extended-release oral theophylline (titrated to serum levels of 10 to 20 microg/mL), and placebo taken twice daily.Efficacy measurements included nocturnal spirometry, nocturnal polysomnography, sleep questionnaires, and daily measurements of lung function and symptoms. Salmeterol was superior to theophylline (p < or = 0.05) in maintaining nocturnal FEV1 levels and was superior to placebo (p < or = 0.05) in improving morning and evening peak expiratory flow (PEF) and in decreasing nighttime albuterol use. The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo (p < or = 0.05). Sleep quality global scores significantly improved with salmeterol and placebo (p < 0.001) but not with theophylline. The effects on sleep architecture were similar across treatment groups.Salmeterol (but not theophylline) was associated with sustained improvements in morning PEF, protection from nighttime lung function deterioration, reductions in albuterol use, and improvements in patient perceptions of sleep. No differences were seen in polysomnographic measures of sleep quality.

Efficacy of once- and twice-daily administration of budesonide via Turbuhaler ® as initial therapy in patients with mild persistent asthma

Inhaled glucocorticosteroids such as budesonide have an important role in the management of asthma. Although these agents have traditionally been given twice daily, evidence is accumulating that once-daily treatment may be as effective as twice-daily administration. The efficacy of budesonide Turbuhaler ® (Astra, Lund, Sweden), 400 μg once daily in the evening or 200 μg twice daily, was compared in a randomized, double-blind study involving 181 patients (75 men, 106 women; mean age 30·8 years) with mild asthma [mean forced expiratory volume in 1 s (FEV 1) 92·8% pred.] who had not previously been treated with inhaled glucocorticosteroids. After a 2-week run-in period, patients were randomized to either regimen and treated for 6 weeks. This was followed by two 8-week open treatment periods, during which all patients received budesonide Turbuhaler ®, 200 μg once daily during the first period and 100 μg once daily during the second period. The mean change in morning peak expiratory flow (PEF) during the double-blind treatment period was 16·91 min −1 in patients receiving once-daily treatment and 17·21 min −1 in those receiving twice-daily treatment. Similarly, there were no significant differences in evening PEF, symptom scores, bronchodilator use or spirometry data between patients receiving once- and twice-daily treatments. The improvements in morning PEF, symptom scores and bronchodilator use seen during the double-blind treatment period were maintained during the two open treatment periods. It is concluded that once-daily treatment with budesonide Turbuhaler ® is as effective as an initial therapy twice-daily treatment in patients with mild persistent asthma, and that the initial dose can be reduced to maintenance levels (including 100 μg) without loss of asthma control.

A Dose-Finding Study with the Once-Daily Oral ??2-Agonist Bambuterol in Asian Children with Asthma

Objective: The primary objective was to compare the efficacy of two dosages of bambuterol, a once-daily oral bronchodilator, with placebo in Asian children with asthma. The secondary objective was to assess the tolerability of bambuterol in this population. Design: This was a multicentre, randomised, double-blind, placebo-controlled crossover study, with a run-in period of 2 weeks. The study consisted of three treatment periods of 2 weeks each, separated by washout periods of 2 weeks, with 7 clinic visits in total. Setting: Outpatients were recruited from 10 centres in Indonesia, Malaysia, The Philippines, Singapore and Thailand. Patients: Seventy Asian children aged 6 to 12 years (53 boys and 17 girls) with asthma for at least 6 months were randomised to treatment, and 62 patients completed the study. Interventions: During the three treatment periods, patients received either placebo or 5 or 10mg bambuterol tablets once daily for 2 weeks. Morning peak expiratory flow (PEF) was the primary efficacy variable. Secondary efficacy variables were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diary card data including evening PEF. Results: At baseline, FEV1 predicted was 82.9% and the reversibility was 22.2%. The study results suggest that the change from baseline in both morning and evening PEF recorded on the diary cards on days 4 to 14 of each treatment period was dose dependent, but only the difference in morning PEF between bambuterol 10mg and placebo was statistically significant (9.1 L/min; 95% confidence interval 0.2 to 18.0 L/min). FEV1, FVC, asthma symptom scores and the use of supplementary β2-agonists did not differ significantly between placebo and the two bambuterol treatments. Blood pressure and pulse rate remained consistent throughout the study. The number of spontaneously reported adverse events was similar for the three treatment groups. Conclusions: Bambuterol 10mg once daily is an effective bronchodilator in 6-to 12-year-old Asian children in terms of improvement in morning PEF.

Fluticasone propionate 50 μg BID versus 100 μg BID in the treatment of children with persistent asthma

The aim of this multicenter, double-masked study was to compare the efficacy and safety of two different doses of inhaled fluticasone propionate dry powder—50 μg and 100 μg—administered BID via a multidose powder inhaler with those of placebo in the treatment of children with persistent asthma. After a 2-week run-in period, 263 patients were randomized to treatment with twice-daily placebo (n = 92), fluticasone 50 μg (n = 85), or fluticasone 100 μg (n = 86) for 12 weeks. One hundred sixty-six (63%) patients were male, and 224 (85%) were white, with a mean age of 8 years. Two hundred twenty-one (84%) patients were atopic, and 167 (63%) had been asthmatic for 1 to 5 years. Baseline mean morning peak expiratory flow (PEF) values were 207 L/min, 199 L/min, and 194 L/min, and baseline percentages of predicted normal values were 86%, 80%, and 81% for the groups receiving placebo, fluticasone 50 μg, and fluticasone 100 μg, respectively. At the end of the first week of treatment, patients in both fluticasone groups had significantly greater improvements in morning PEF than did those receiving placebo. Patients experienced mean increases of 4 L/min, 22 L/min, and 26 L/min with placebo, fluticasone 50 μg, and fluticasone 100 μg, respectively. At the end point (the last evaluable visit), patients in both fluticasone groups continued to have significantly greater improvements in morning PEF than did patients receiving placebo. Patients experienced mean increases of 17 L/min, 50 L/min, and 57 L/min with placebo, fluticasone 50 μg, and fluticasone 100 μg, respectively. Changes in the percentage of predicted values by end point were 8%, 20%, and 26% with placebo, fluticasone 50 μg, and fluticasone 100 μg, respectively. The probability of remaining in the study, according to predefined withdrawal criteria, indicated a significant treatment difference in favor of fluticasone. Withdrawal criteria were met by 63%, 42%, and 29% of patients receiving placebo, fluticasone 50 μg, and fluticasone 100 μg, respectively. This study clearly demonstrates the superiority of fluticasone 50 and 100 μg BID over placebo in the treatment of persistent asthma in children.

Salmeterol xinafoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. UK Study Group

In severe chronic asthma, long-term oral steroids may be necessary to control symptoms. In patients in whom such treatment was under consideration, the efficacy and safety of salmeterol xinafoate 100 micrograms b.i.d. was investigated in a randomized, double-blind, placebo-controlled parallel-group, multicentre study. One hundred and nineteen chronic symptomatic asthmatics were randomized to receive either salmeterol, 100 micrograms b.i.d. (n = 55; baseline % predicted morning peak expiratory flow (PEF) 59%; forced expiratory volume in one second (FEV1) 66%) or placebo (n = 64; baseline % predicted morning PEF 63%; FEV1 66%) both via the Diskhaler. Morning and evening PEF and asthma symptoms were recorded in daily record booklets by the patient over a 12 week period. A significant improvement in morning PEF was achieved after 1 month in the salmeterol treated group; this persisted throughout the treatment period (estimated treatment difference 22 L.min-1). There was a significant increase in the proportion of symptom-free nights experienced by the salmeterol treated group (33 (SD 32) %) compared with placebo (13 (26) %), and a significant decrease in daily use of relief medication (mean decrease 5.1 (4.7) doses per day with salmeterol, 2.5 (4.0) doses with placebo). Both treatments were well-tolerated, with no evidence of any difference in the side-effects associated with beta 2-agonists. In conclusion, the addition of salmeterol (100 micrograms daily) to the existing treatment of chronic asthmatics under consideration for maintenance oral corticosteroid therapy is well-tolerated, improves lung function and provides additional symptom control.