Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Composite spirometric-computed tomography outcome measure in early cystic fibrosis lung disease. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease. Pulmozyme Study Group. Efficacy and safety of short-term administration of aerosolised recombinant human DNase I in adults with stable stage cystic fibrosis. Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.
Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase. 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. Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme.
                We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients.
                One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset.
                In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated. Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis.
                In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care.
                Mean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments.
                Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase. With the advent of therapies aimed at young patients with cystic fibrosis, who have mildly reduced pulmonary function, the need for improved outcome measures that discriminate treatment effects has become important. Pulmonary function measurements or chest high-resolution computed tomography (HRCT) scores have been separately used to assess interventions. We evaluated these modalities separately and together during a treatment study to develop a more sensitive outcome measure. In a 1-year trial, 25 children randomized either to daily Pulmozyme or to normal saline aerosol were evaluated at randomization and at 3 and 12 months. Outcome variables were pulmonary function test (PFT) results, a global HRCT score, and a composite score incorporating PFTs and HRCT scoring. Regression analyses with generalized estimating equations permitted estimation of the difference in treatment effect between groups over time for each outcome. The largest difference in treatment effects observed at 12 months, measured by the percentage change from baseline, were with the composite total and maximal CT/PFT scores (35.4 and 30.4%), compared with mean forced expiratory flow during the middle half of the FVC (FEF25-75%) (13.0%) and total and maximal global HRCT scores (6.2%, 7.2%). The composite total and maximal CT/PFT scores were the most sensitive outcome measures for discriminating a treatment effect in children with cystic fibrosis with normal or mildly reduced pulmonary function during a 1-year trial of Pulmozyme. Chronic endobronchial bacterial infection evokes purulent airway secretions in patients with CF. The viscoelastic properties of these secretions is primarily due to the presence of polymerized DNA from degenerating leukocytes. Recombinant human DNase I (rhDNase) reduces the viscosity of CF sputum in vitro. To test the hypothesis that rhDNase would improve pulmonary function in children and adults with CF, we compared the efficacy and safety of 10-day administration of three doses of aerosolized rhDNase (0.6, 2.5, or 10.0 mg twice daily) in 181 outpatients using a randomized, placebo-controlled parallel design. Forced vital capacity (FVC) improved 10 to 12% (p < 0.05 to 0.001), and forced expiratory volume in one second (FEV1) improved 10 to 15% (p < 0.001) across all doses of rhDNase compared with placebo. The magnitude of effect was dose dependent for both FVC and FEV1 through study Day 21 (p < 0.001). rhDNase was associated with a decreased perception of dyspnea and an improved perception of well-being. No patients developed detectable anti-rhDNase antibodies or bronchial reactivity to rhDNase. Some patients experienced mild upper airway irritation, but no major adverse events were reported. Administration for 10 days of aerosolized rhDNase to pediatric and adult outpatients with CF improves lung function and is well tolerated. Although all three doses were efficacious, the greatest improvement in FEV1 and FEV1/FVC ratio was demonstrated in the 2.5 and 10.0 mg rhDNase treatment groups. 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. Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis. High levels of DNA in the sputum make the sputum viscous and difficult to expectorate. Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to reduce the viscoelasticity of the sputum from CF patients. We have done a phase II double-blind randomised placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for 10 days. All patients had forced vital capacity (FVC) above 40% predicted and were clinically stable. Patients were followed up for 42 days from the start of drug/placebo administration. All 71 randomised patients, aged 16-55, completed every aspect of the study and baseline characteristics were similar in the two groups. Baseline forced expiratory volume in one second (FEV1) was 46% of predicted for patients randomised to rhDNase, and 48% for those randomised to placebo; and baseline FVC was 76% of predicted for both groups. The mean percentage change in FEV1 from baseline was a 13.3% rise on rhDNase and a 0.2% fall on placebo (p < 0.001). FVC rose 7.2% in the rhDNase group and 2.3% in the placebo group (not significant). There were no life-threatening adverse events and no anaphylactic reactions. There was no significant difference in side-effects between the groups. This study confirms that short-term administration of rhDNase in stable patients with cystic fibrosis is safe and improves lung function. The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CF patients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy. 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. We tested the hypothesis that recombinant human deoxyribonuclease 1 (rhDNase) reduces airflow obstruction and improves mucociliary clearance in patients with cystic fibrosis (CF), and that improvements seen in FEV1 and FVC after rhDNase treatment are independent of chest physical therapy (CPT). CF patients inhaled placebo (10 patients) or 2.5 mg rhDNAse aerosol (10 patients) twice a day for six consecutive days. Compared with baseline, there were no statistically significant differences between the two study groups by Day 6 for indices of airflow obstruction obtained from gamma-camera images of the right lung following inhalation of 99mTc aerosol, or for mucociliary clearance or the rate of clearance of the radioaerosol, quantified over a 6-h period. By Day 6, FEV1 and FVC were significantly higher in the rhDNase-treated group than in the placebo group, increasing by an average of 9.4 +/- 3.5% and 12.7 +/- 2.6%, respectively, as compared with a decrease of 1.8 +/- 1.7% and an increase of 0.4 +/- 1.1%, respectively (p < 0.05). There was no significant change in the FEV1/FVC ratio on Day 6 (0.68 +/- 0.05) compared with baseline (0.70 +/- 0.05) in the rhDNase group. On Day 6, FEV1 and FVC decreased after CPT in both study groups, but the decreases were not significant. Our results indicate that aerosolized rhDNase improves FEV1 and FVC independent of CPT. We were unable to demonstrate that rhDNase reduces airflow obstruction or improves mucociliary clearance.
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.