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. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis. Proventil HFA provides bronchodilation comparable to ventolin over 12 weeks of regular use in asthmatics. A controlled trial of long-term inhaled hypertonic saline in patients with 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. 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. 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. 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. To compare the bronchodilator effectiveness of albuterol reformulated in the chlorofluorocarbon-free propellant hydrofluoroalkane (HFA)134a (Proventil HFA) to that of Ventolin and HFA placebo over 12 weeks of regular dosing.
                Randomized, double-blind, double-dummy, parallel group, placebo-controlled, multi-center trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control.
                Treatment qid with Proventil HFA, Ventolin, or HFA-134a placebo for 12 weeks.
                At weeks 0, 4, 8, and 12, spirometry was performed predose and serially over 6 h after dosing with study drug. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve (AUC).
                Demographic and baseline characteristics were similar for patients randomized to Proventil HFA (193), Ventolin (186), and HFA-134a placebo (186). No significant differences were found between the Proventil HFA and Ventolin treatment groups for any FEV1 efficacy variable, either predose or during 6 h of serial spirometry, at weeks 0, 4, 8, and 12. For all efficacy variables, except time to onset of effect, the Proventil HFA and Ventolin results were significantly greater than placebo. Time to onset of effect for the HFA-134a placebo group is misleading; only 13 patients (7%) were found to be responders in the intent-to-treat database. These efficacy results were found to be consistent across subgroup analyses of inhaled and nasal corticosteroid use, age (18 to 35 and 36 to 66 years), sex, race, weight (<60, 60 to 100, and >100 kg), and baseline FEV1 (< or =55% and >55% predicted). The peak FEV1 effect, duration of FEV1 effect, and AUC for FEV1 were all significantly smaller at weeks 4, 8, and 12 than week 0 for both the Proventil HFA and Ventolin treatment groups.
                Proventil HFA provided bronchodilation comparable to Ventolin and superior effects to HFA-134a placebo over 12 weeks of regular dosing. There was a diminution in bronchodilator response to both Proventil HFA and Ventolin after 4 weeks of use. Inhaled hypertonic saline acutely increases mucociliary clearance and, in short-term trials, improves lung function in people with cystic fibrosis. We tested the safety and efficacy of inhaled hypertonic saline in a long-term trial.
                In this double-blind, parallel-group trial, 164 patients with stable cystic fibrosis who were at least six years old were randomly assigned to inhale 4 ml of either 7 percent hypertonic saline or 0.9 percent (control) saline twice daily for 48 weeks, with quinine sulfate (0.25 mg per milliliter) added to each solution to mask the taste. A bronchodilator was given before each dose, and other standard therapies were continued during the trial.
                The primary outcome measure, the rate of change (slope) in lung function (reflected by the forced vital capacity [FVC], forced expiratory volume in one second [FEV1], and forced expiratory flow at 25 to 75 percent of FVC [FEF25-75]) during the 48 weeks of treatment, did not differ significantly between groups (P=0.79). However, the absolute difference in lung function between groups was significant (P=0.03) when averaged across all post-randomization visits in the 48-week treatment period. As compared with the control group, the hypertonic-saline group had significantly higher FVC (by 82 ml; 95 percent confidence interval, 12 to 153) and FEV1 (by 68 ml; 95 percent confidence interval, 3 to 132) values, but similar FEF25-75 values. The hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative reduction, 56 percent; P=0.02) and a significantly higher percentage of patients without exacerbations (76 percent, as compared with 62 percent in the control group; P=0.03). Hypertonic saline was not associated with worsening bacterial infection or inflammation.
                Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis. (ClinicalTrials.gov number, NCT00271310.)
                Copyright 2006 Massachusetts Medical Society.
Treatment with 7% HS for 48 weeks showed a small improvement in FEV1 at four weeks; however, this was not sustained at 48 weeks (primary outcome measure of the only long-term trial). Unlike RhDNAse, HS can't, in the long term, be said to improve lung function. However, it did improve quality of life and reduce pulmonary exacerbations. Delivered following a bronchodilator, HS appears inexpensive and safe with no increased infection risk.
We believe there is sufficient evidence to recommend using HS in CF; qualifying this we highlight that the only long-term trial failed to demonstrate a significant difference in its primary outcome (lung function) with improvements only in secondary outcomes.