A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis. Dornase Alfa Nebulizer Group. Timing of dornase alpha inhalation does not affect the efficacy of an airway clearance regimen in adults with cystic fibrosis: a randomised crossover trial. Fluticasone propionate induced alterations to lung function and the immunopathology of asthma over time. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis. Nebulised amiloride in respiratory exacerbations of cystic fibrosis: a randomised controlled trial. Effects of single-dose fluticasone on exercise-induced asthma in asthmatic children: a pilot study. Do inhaled corticosteroids impair long-term growth in prepubertal cystic fibrosis patients?
Our objective was to determine whether long-term treatment of young patients with cystic fibrosis (CF) with dornase alfa maintains lung function and reduces respiratory tract exacerbations.
                This was a 96-week, randomized, double-blind, placebo-controlled trial involving 49 CF centers. Inclusion criteria were age 6 to 10 years and forced vital capacity > or = 85% predicted. Patients were excluded for hospitalization for complications of CF within 2 months and use of dornase alfa within 6 months. Patients were treated with dornase alfa 2.5 mg or placebo once daily with a jet nebulizer and a compressor.
                Patients were randomized, 239 to dornase alfa and 235 to placebo. At baseline the mean age was 8.4 years, the mean forced expiratory volume in 1 second 95% predicted, the mean forced expiratory flow, midexpiratory phase 85% predicted, and the mean forced vital capacity 102% predicted. At 96 weeks the treatment benefit for dornase alfa compared with placebo in percent predicted (mean +/- SE) was 3.2 +/- 1.2 for forced expiratory volume in 1 second (P =.006), 7.9 +/- 2.3 for forced expiratory flow between 25% and 75% of vital capacity (P =.0008), and 0.7 +/- 1.0 for forced vital capacity (P =.51). The risk of respiratory tract exacerbation was reduced by 34% in patients who received dornase alfa (relative risk 0.66, P =.048). There was no statistically significant difference between the groups in changes in weight-for-age percentile. Adverse event profiles for the treatment groups were similar.
                Treatment of young patients with CF with dornase alfa maintains lung function and reduces the risk of exacerbations over a 96-week period. The 12-week efficacy and safety of aerosolized recombinant human DNase (dornase alfa) were evaluated in previously untreated patients with cystic fibrosis (CF) with advanced lung disease.
                In this multicenter, double-blind, placebo-controlled study, CF patients with advanced lung disease were randomized to receive either dornase alfa or placebo once a day for 12 weeks.
                A total of 320 patients in clinically stable condition with documented CF and an FVC less than 40% of predicted were recruited from 65 CF Foundation care centers in the United States. The dornase alfa and placebo groups were comparable with respect to age (range, 7 to 57 years), height, and weight. Male subjects outnumbered female subjects (55% vs 45%) and few subjects were younger than 17 years of age (15%). The percentages of predicted FEV1 and FVC were significantly lower in the dornase alfa group at baseline (p < or = 0.05).
                Patients were randomly assigned to receive either 2.5 mg dornase alfa once daily (n = 158) or placebo once daily (n = 162). All patients continued to receive standard medications and treatments administered for CF.
                Dornase alfa improved the mean percent change in FEV1 from baseline by 9.4% compared with 2.1% for placebo (p < 0.001). The actively treated group showed a 12.4% improvement in FVC compared with 7.3% for placebo (p < 0.01). There were no differences between the treatment groups in dyspnea score number of days receiving i.v. antibiotics, or length of hospital stay; the overall incidence of adverse events was comparable between treatment groups. Fifteen patients died: 9 in the dornase alfa group and 6 in the placebo group; no differentiating clinical characteristics were demonstrated.
                Pulmonary function as measured by FEV1 and FVC improved significantly in the dornase alfa-treated patients. Dornase alfa was found to be safe and well tolerated over the 12-week study period. Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity > or = 70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 microm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 microm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents. Does the timing of inhalation of dornase alpha in relation to physical airway clearance techniques influence the effect of the entire airway clearance regimen?.
                A randomised crossover trial with concealed allocation, intention-to-treat analysis and blinding of patients, therapists, and assessors.
                Twenty adults with cystic fibrosis who were not taking dornase alpha were recruited, of whom 17 were randomised and completed the trial.
                Participants performed an individually tailored session of physical airway clearance techniques for at least 15 minutes per day for 28 days. For 14 days, dornase alpha was inhaled before each session of airway clearance techniques and a placebo was inhaled after. For the other 14 days, placebo was inhaled before and dornase alpha after airway clearance techniques. The order of the two 14-day periods was randomised.
                The primary outcome was the forced expiratory volume in 1 sec (FEV(1)). Secondary outcomes were forced vital capacity, 24-hour sputum production, sputum production during the airway clearance regimen, oxygen saturation, peak oxygen consumption during an incremental exercise test, oxygen desaturation during exercise, and quality of life.
                Inhalation of dornase alpha after airway clearance techniques did not significantly affect the change in FEV(1) compared with inhalation before airway clearance techniques, mean difference 0.04 L, 95% CI -0.14 to 0.23. None of the secondary outcomes differed significantly between the study arms. There was good correlation between the change in FEV(1) and the change in quality of life scores.
                Timing of dornase alpha can be selected according to convenience, patient preference, or to accommodate the timing of other medications in the treatment regimen.
                ACTRN12611001041943.
                Copyright © 2011 Australian Physiotherapy Association. Published by .. All rights reserved. Inhaled corticosteroids are the most widely used treatment for asthma, a disease characterised by both functional and immunopathological abnormalities. This study investigated the relative effects of inhaled corticosteroids on these two features of asthma over time.
                A randomised, double blind, placebo controlled, parallel group study with inhaled fluticasone propionate, (FP 2 mg daily) was conducted in 27 patients with asthma. Following baseline analysis, the study tested the effects of short term (two weeks) and longer term (eight weeks) treatment. At each time point (0, 2, and 8 weeks) lung function tests were performed and endobronchial biopsy specimens obtained to determine the distribution and number of lymphocyte, macrophage and eosinophil subsets using immunohistological analysis. Twenty three patients completed the study, 11 on FP and 12 placebo.
                FEV1, delta FEV1, FEF25-75, and FEV1/FVC all improved after two weeks of FP treatment. This improvement was maintained but not increased after eight weeks. PC20FEV1 showed a trend to increase but was not significantly improved at eight weeks. No significant changes were seen in the placebo group. The numbers of T cells, macrophages, and eosinophils in the bronchial wall were reduced by two weeks of treatment with FP but were unaltered by placebo. The improvement offered by FP continued over the eight week period. Reductions in CD4:CD8 ratio and numbers of activated (EG2+) eosinophils were only significant after eight weeks of treatment.
                These results reveal that FP influences both functional and immunopathological parameters of asthma. Temporal relationships suggest that these are parallel but not necessarily interrelated effects. While short term treatment is effective in "normalising" the functional abnormalities in asthma, the impact of FP on bronchial inflammation appears to be progressive, taking up to eight weeks and more. Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment. Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).
                To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.
                Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)
                2 university medical centers in The Netherlands.
                114 steroid-naive current or former smokers with moderate to severe COPD.
                Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.
                Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).
                101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level.
                The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.
                ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. . Controlling lung inflammation may be the key to improving morbidity and mortality in cystic fibrosis.
                To assess the effects of inhaled corticosteroids on lung inflammation in cystic fibrosis.
                Double blind placebo controlled randomised sequence crossover trial. Fluticasone propionate (400 micrograms/day) was given as a dry powder inhaler for six weeks with a four week washout period before crossover.
                Sputum inflammatory markers (interleukin-8, tumour necrosis factor-alpha (TNF-alpha) and neutrophil elastase-both free and bound to alpha 1-antiprotease), sputum interleukin-10, lung function, and symptomatology.
                Twenty three children from a regional cystic fibrosis centre were enrolled into the study, with mean age 10.3 years (range 7 to 17 years) and mean baseline forced expiratory volume in one second (FEV1) of 64% (range 21% to 102%) predicted for sex and height. One patient was excluded for non-compliance to the study protocol.
                No significant benefit was shown for the use of fluticasone propionate in any of the outcomes. For sputum interleukin-8 there was an estimated true treatment median difference of 142 pg/ml (95% confidence interval (CI) 8 to 2866 pg/ml) in favour of placebo; while for maximal expiratory flow at 25% (MEF25%) remaining forced vital capacity predicted for sex and height there was a 15 percentage points (pp) (95% CI 4 to 26 pp) mean treatment difference in favour of placebo. Sputum interleukin-10 was undetected in any samples and unaffected by fluticasone propionate. Neither atopic status, baseline FEV1, nor concomitant DNase therapy had any effect on response to treatment.
                Lack of benefit from fluticasone propionate was most likely due to failure of the drug to penetrate the viscid mucus lining the airways. It is suggested a large multicentre trial with higher doses given for a longer time by a different delivery system is required to assess efficacy. To assess the benefit of nebulised amiloride added to the standard inpatient treatment of a respiratory exacerbation in cystic fibrosis.
                Prospective, randomised, double blind, placebo controlled trial.
                27 cystic fibrosis patients (mean age 12.8 years).
                Two hospitals in Leeds, UK.
                Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) showed improvements over the course of treatment, although there was no difference in respiratory function between the two groups at any of three time periods during the study. The time to reach peak FVC was significantly reduced in the amiloride group (4.2 v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time to reach peak FEV1 (5.7 v 7.9 days; 95% CI -1.2 to 5.6 days).
                Amiloride did not result in a greater overall improvement in respiratory function. There was a suggestion that it may have an effect on the rate of improvement, and thus may possibly influence the duration of treatment. This hypothesis deserves further evaluation. A single high dose of inhaled corticosteroid (ICS) can increase airway caliber in children with asthma attacks and laryngitis subglottica. Presumably the effect is due to the vasoconstrictive and antiedematous properties of topical steroids. Enlarged vessels have been suggested to play a role in the pathophysiology of exercise-induced bronchial obstruction (EIB). To investigate this, we evaluated the effect of a single high dose of fluticasone propionate (FP) on EIB in asthmatic children. Nine children aged 8-16 years with mild to moderate asthma were included. All children had a history of EIB, which was confirmed by an exercise test. None was taking ICS maintenance therapy. The children inhaled either a single dose of 1 mg FP or placebo on 2 separate days within 7-14 days. After inhalation, airway caliber (FEV(1)) was assessed for 4 hr before exercise. Then an exercise challenge was performed on a treadmill to assess EIB (% fall FEV(1)). A significant increase in FEV(1) was observed 1 hr after inhalation of FP compared to placebo. Response to exercise was expressed as maximal % fall in FEV(1) from baseline (% fall) and as area under the curve (AUC) of the 30-min time/response curve. The % fall FEV(1) after exercise and the AUC were significantly reduced when FP was inhaled compared to placebo inhalation (% fall 9.7% vs. 19.2%, respectively, P = 0.038 and AUC 92.0%.min vs. 205.7%.min, respectively, P = 0.03). There was considerable individual variability in reduction of EIB, with 5 out of 9 children having a clinically significant response. We conclude that a single high dose of inhaled FP has an acute protective effect on the bronchial response to exercise in a substantial proportion of asthmatic children.
                Copyright 2001 Wiley-Liss, Inc. Despite absence of clear proof of efficacy, the use of inhaled corticosteroids (ICS) is widespread in cystic fibrosis (CF) patients. Therefore, the effect of ICS on lung function and other clinical variables was studied in 27 prepubertal CF children with mild to moderate lung disease. In a prospective double-blind case-controlled study, fluticasone propionate 500 microg or placebo were administered twice daily during 12 months. The mean (standard error of the mean, SEM) patient age was 8.2 (0.6) years in the placebo group and 9.0 (0.5) years in the fluticasone group. The mean (SEM) forced expiratory volume in 1 s (FEV(1)) was 91% (4%) in the placebo group and 86% (4%) in the fluticasone group. There was no statistically significant difference in the evolution of lung function and the number of respiratory exacerbations between groups. However, longitudinal growth in fluticasone patients was significantly slower than in placebo patients: 3.96 (0.29) cm versus 5.49 (0.38) cm [p<0.005, analysis of variance (ANOVA)] over the 12-month study duration. This resulted in a significant change in height standard deviation score (SDS) of -0.38 (0.09) in the fluticasone group versus -0.01 (0.07) in the placebo group (p<0.003, ANOVA). No catch-up growth was noted 1-2 years after discontinuation of inhaled steroids. The use of high-dose ICS in CF patients with mild lung disease may lead to persistent growth impairment.
There is evidence to show that therapy with dornase alfa over a one-month period is associated with an improvement in lung function in CF; results from a trial lasting six months also showed the same effect. Therapy over a two-year period (based on one trial) significantly improved FEV1 in children and there was a non-significant reduction in the risk of infective exacerbations. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials.