Use of dornase alfa in pediatric patients without cystic fibrosis.

OBJECTIVES: Literature regarding clinical benefits of dornase alfa (DNase) in pediatric patients without cystic fibrosis is lacking. In December 2020, the study institution implemented restrictions to limit DNase use in this patient population. The primary objective was adherence to DNase ordering restrictions. Secondary objectives included length of stay, respiratory function, and use of inhaled mucolytic agents. METHODS: This single-center retrospective chart review included patients less than 18 years of age who received DNase one year prior to through one year after order restriction implementation. Data collected included patient demographics and respiratory clinical parameters. Dosing regimens for DNase, n-acetylcysteine, and hypertonic saline were collected, as well as changes in length of stay (LOS) and adherence to ordering restrictions. RESULTS: Of 101 total DNase orders, 45 were placed after implementation of ordering restrictions and 16 (36%) met all ordering criteria. Hospital and intensive care unit (ICU) LOS after implementation of restrictions were not significantly different (p = 0.767 and p = 0.219, respectively). There was no significant change in patients' mean oxygenation index (p = 0.252) or FiO2% (p = 0.113) 24 hours after DA administration. CONCLUSION: Respiratory function did not significantly change after DNase administration. Implementing restrictions on DNase did not impact intensive care unit or hospital LOS. Adherence to DNase ordering restrictions could be improved.

Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials.

BACKGROUND: Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI). METHODS: The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEV1 (ppFEV1) of 70% or more, or those aged 18 years or older with ppFEV1 of 60% or more, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. Participants on both hypertonic saline and dornase alfa were randomly assigned to one of the two trials, and those on a single therapy were assigned to the applicable trial. All participants were then randomly assigned 1:1 to continue or discontinue therapy for 6 weeks using permuted blocks of varying size, stratified by baseline ppFEV1 (week 0; ≥90% or <90%), single or concurrent use of hypertonic saline and dornase alfa, previous SIMPLIFY study participation (yes or no), and age (≥18 or <18 years). For participants randomly assigned to continue their therapy during a given trial, this therapy was instructed to be taken at least once daily according to each participant's pre-existing, clinically prescribed regimen. Hypertonic saline concentration was required to be at least 3%. The primary objective for each trial was to determine whether discontinuing was non-inferior to continuing, measured by the 6-week change in ppFEV1 in the per-protocol population. We established a non-inferiority margin of -3% for the difference between groups in the 6-week change in ppFEV1. Safety outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04378153. FINDINGS: From Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEV1 of 96·9%. Discontinuing treatment was non-inferior to continuing treatment with respect to the absolute 6-week change in ppFEV1 in both the hypertonic saline trial (-0·19% [95% CI -0·85 to 0·48] in the discontinuation group [n=133] vs 0·14% [-0·51 to 0·78] in the continuation group [n=140]; between-group difference -0·32% [-1·25 to 0·60]) and dornase alfa trial (0·18% [-0·38 to 0·74] in the discontinuation group [n=199] vs -0·16% [-0·73 to 0·41] in the continuation group [n=193]; between-group difference 0·35% [-0·45 to 1·14]), with consistent results in the intention-to-treat populations. In the hypertonic saline trial, 64 (35%) of 184 in the discontinuation group versus 44 (24%) of 186 participants in the continuation group and, in the dornase alfa trial, 89 (37%) of 240 in the discontinuation group versus 55 (23%) of 237 in the continuation group had at least one adverse event. INTERPRETATION: In individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

Dornase alfa for cystic fibrosis.

BACKGROUND: Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 12 October 2020. Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 08 February 2021. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence. MAIN RESULTS: The searches identified 74 trials, of which 19 (2565 participants) met our inclusion criteria. 15 trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa probably improved forced expiratory volume at one second (FEV1) at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed treatment may make little or no difference  in quality of life. Dornase alfa probably reduced the number of pulmonary exacerbations in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found little or no difference between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed dornase alfa may lead to a greater improvement in FEV1 compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported little or no differences in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found dornase alfa may improve quality of life compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found little or no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash. AUTHORS' CONCLUSIONS: There is evidence to show that, compared with placebo, therapy with dornase alfa may improve lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer, probably due to treatment. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.

Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.

Dornase alfa for cystic fibrosis.

BACKGROUND: Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 23 April 2018.Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 07 June 2018. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence. MAIN RESULTS: The searches identified 69 trials, of which 19 (2565 participants) met our inclusion criteria. Fifteen trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Dornase alfa compared to placebo or no treatmentDornase alfa improved forced expiratory volume at one second at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed no difference between groups for changes in quality of life. There was a decrease in pulmonary exacerbations with dornase alfa in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.Dornase alfa: daily versus alternate dayOne cross-over trial (43 children) found no differences between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence).Dornase alfa compared to other medications that improve airway clearanceResults for these comparisons were mixed. One trial (43 children) showed a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found a difference in quality of life favouring dornase alfa when compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence).When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash. AUTHORS' CONCLUSIONS: There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.

Clinical Application of Polysialylated Deoxyribonuclease and Erythropoietin.

BACKGROUND: While protein therapeutics are invaluable in managing numerous diseases, many require frequent injections to maintain therapeutically effective concentrations, due to their short half-life in circulation. PolyXen™, a platform and patented technology employing biodegradable, non-immunogenic and hydrophilic Polysialic Acids (PSA) for drug delivery, is being utilized to overcome such limitations, thereby potentially enabling the clinical utility of a broad range of protein therapeutics. Here, we report the recent progress on two development candidates, polysialylated deoxyribonuclease I (PSA-DNase) and polysialylated erythropoietin (PSA-EPO). METHODS AND RESULTS: Chemical polysialylation of DNase I (DNase) using PSA with different chain length at various conjugation sites led to improved stability against proteases and thermal stress, and slightly reduced enzymatic activity. Polysialylation of EPO resulted in retention of protein structure and PSA-EPO remained biologically active. PSA-EPO had a significantly prolonged circulating half-life (e.g. t1/2 of PSA-EPO = ~400 h in patients after subcutaneous administration, aimed for once monthly administration, vs. t1/2 of EPO = ~22 h; administered twice or thrice weekly), and retained in vivo efficacy. CONCLUSION: This approach has been clinically validated in phase I (in healthy volunteers) and II studies of PSA-EPO [for managing anemia in patients with chronic kidney disease (CKD)].

Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial.

BACKGROUND: A randomized controlled trial of adults with empyema recently demonstrated decreased length of stay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared to fibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown. METHODS/DESIGN: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. The participants are previously well children admitted to a children's hospital with a diagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will be randomized after the treating physician has decided that pleural drainage is required but prior to chest tube insertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administered tissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group will receive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. All participants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome is length of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meeting discharge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospital readmission, cost of hospitalization, and mortality. DISCUSSION: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectiveness of combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatment of empyema in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01717742 . Registered on 8 October 2012.

Dornase alfa for cystic fibrosis.

BACKGROUND: Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 30 November 2015.Clinicaltrials.gov was also searched to identify unpublished or ongoing trials. Date of most recent search: 28 November 2015. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. MAIN RESULTS: The searches identified 54 trials, of which 19 (including a total of 2565 participants) met our inclusion criteria. Three additional papers examined the healthcare cost from one of the clinical trials. Fifteen trials compared dornase alfa to placebo or no dornase alfa treatment (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Compared to placebo, forced expiratory volume at one second improved in the intervention groups, with significant differences at one, three, six months and two years. There was also a significant improvement in lung clearance index at one month. There was a decrease in pulmonary exacerbations compared to placebo in trials of longer duration. The quality of the evidence from placebo-controlled trials was moderate to high for outcomes of lung function and pulmonary exacerbations. Limited, low quality evidence was available for changes in quality of life from baseline. One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.The results for trials comparing dornase alfa to other medications that improve airway clearance (hypertonic saline or mannitol) were mixed, with one trial showing a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline, and three trials finding no difference between medications. In the only trial to assess the combination of dornase alfa with another medication compared to dornase alone, there was no benefit seen with the combination of dornase alfa and mannitol. Evidence of dornase alfa compared to other medications was limited and the open-label design of the trials may have induced bias, therefore the quality of the evidence was judged to be low.Dornase alfa did not cause significantly more adverse effects, except voice alteration and rash. AUTHORS' CONCLUSIONS: There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to hyperosmolar agents in improving lung function.

Evaluation of Inhaled Dornase Alfa Administration in Non-Cystic Fibrosis Patients at a Tertiary Academic Medical Center.

PURPOSE: The use of dornase alfa in a non-cystic fibrosis population has been proposed to help improve atelectasis and secretions. Data evaluating dornase alfa in a non-cystic fibrosis population are limited, and the prescribing practices at a tertiary academic medical center are unknown. METHODS: Adult patients ≥18 years of age were included if they received inhaled dornase alfa. Patients were excluded if they had cystic fibrosis. Data collected included demographic data, dornase alfa prescribing patterns, concomitant inhaled therapy, blood gas data, and documented efficacy and safety data. RESULTS: Seventy-six orders for dornase alfa therapy were included in the analysis. Of the patients, 18% had asthma and 19% had chronic obstructive pulmonary disease. Seventy-seven percent of the patients received concomitant inhaled therapy. Eighty-three percent of orders were for 2.5 mg of dornase alfa twice daily. The median (interquartile range [IQR]) number of doses received per patient was 6 (4-13) with a median (IQR) duration of 3 (2-7) days. After inhaled dornase alfa administration, 11% of patients were able to cough productively. No safety issues related to inhaled dornase alfa therapy were noted. CONCLUSIONS: Inhaled dornase alfa is commonly prescribed to improve atelectasis and secretions in a non-cystic fibrosis patient population at a tertiary academic medical center.

Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients.

BACKGROUND: Dornase alfa administered via jet nebulizer is indicated as a chronic respiratory medication for cystic fibrosis (CF) patients. Efficacy and safety of dornase alfa via an electronic nebulizer with vibrating membrane technology have not been formally assessed in randomized clinical trials. METHODS: 87 CF patients (≥6 years) were randomized in a crossover study to receive dornase alfa 2.5 mg/d in 2-week periods with the Pari eRapid and Pari LC Plus jet nebulizers. The primary end point was comparison of forced expiratory volume in the first second. Safety, quality of life, and treatment satisfaction/preference were also compared between devices. RESULTS: Lung function was equivalent between nebulizers. Most domain scores from the Cystic Fibrosis Questionnaire-Revised and Treatment Satisfaction Questionnaire for Medication instruments were similar but patients strongly preferred the eRapid. Mean patient-reported administration times were shorter with the eRapid vs the LC Plus (2.7 vs 10.2 min). Adverse events were similar between devices. CONCLUSIONS: Administration of dornase alfa via the eRapid nebulizer resulted in comparable efficacy and safety, shorter nebulization times, and higher patient preference.

The use of rhDNAse in severely ill, non-intubated adult asthmatics refractory to bronchodilators: a pilot study.

INTRODUCTION: Mucous plugging is associated with fatal asthma and may have a causative role for non-fatal cases of severe acute asthma. However, mucolytic agents have not been found effective in reversing the obstruction of acute asthma. We test the hypothesis that rhDNAse, an agent that reduces viscoelasticity of sputum in patients with cystic fibrosis, has a therapeutic role in acute asthma. METHODS: Symptomatic asthmatics aged 18-55 years presenting to an Emergency Department with an FEV(1) < 60% predicted after 2 nebulized albuterol and ipratropium treatments were included. Patients were randomized into one of three nebulized rhDNAse treatment groups of 2.5, 5.0 or 7.5 mg, or placebo. Standardized bronchodilator therapy was continued throughout the protocol and the FEV(1) at 6 h was the primary study endpoint. RESULTS: 50 patients were enrolled. There were no significant differences in FEV(1)% predicted between the rhDNAse and placebo patients at any of the post-randomization time points. The dose of rhDNAse administered did not influence response. In a post-hoc stratification, patients with the lowest pre-randomization FEV(1) tended to improve more from rhDNAse, particularly at times 60 and 120 min post-randomization. CONCLUSION: In this pilot study rhDNAse did not cause clinical improvement among severely ill adults refractory to standardized care. The observed trend to higher FEV(1) among the most severely obstructed patients is an exploratory finding that may warrant further study. This clinical trial was registered as NCT00169962 under the name "Study of Pulmozyme to Treat Severe Asthma Episodes".

Dornase alfa for cystic fibrosis.

BACKGROUND: Dornase alfa is currently used to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other mucolytics and to identify any adverse events associated with its use. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences.Date of the most recent search of the Group's Cystic Fibrosis Register: 17 July 2009. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials where dornase alfa was compared to placebo, standard therapy or another mucolytic. DATA COLLECTION AND ANALYSIS: Authors independently assessed trials for inclusion criteria; the lead author and a colleague carried out analysis of methodological quality and data extraction. MAIN RESULTS: The searches identified 43 trials, of which 15 met our inclusion criteria, including a total of 2469 participants. Three additional studies examined the healthcare cost from one of the clinical trials. Twelve studies compared dornase alfa to placebo or no dornase alfa treatment; one compared daily dornase alfa with hypertonic saline and alternate day dornase alfa; and two compared daily dornase alfa to hypertonic saline. Study duration varied from six days to two years. The number of deaths was not significant between treatment groups. Spirometric lung function improved in the treated groups, with significant differences at one month, three months, six months and two years, there was a non-significant difference at three years. There was no excess of adverse effects except voice alteration and rash, which were reported more frequently in one trial in the treated groups. Insufficient data were available to analyse differences in antibiotic treatment, inpatient stay and quality of life. AUTHORS' CONCLUSIONS: 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 FEV(1) 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.

Dornase alfa is well tolerated: data from the epidemiologic registry of cystic fibrosis.

After closure of the Epidemiologic Registry of Cystic Fibrosis (ERCF), a comprehensive safety analysis of dornase alfa was performed. A planned subanalysis focused on children under 5 years old. Reported serious adverse events (SAEs) were assigned a preferred term and ascribed to a specific organ system. Possible serious adverse reactions to dornase alfa (SADRs) were identified by reporting clinics. Twenty-eight of 15,865 SAEs (0.18%), occurring in 26 of 6,829 patients ever treated with dornase alfa (0.38%), and no deaths were reported as possible SADRs: most were typical complications of cystic fibrosis (CF). There was no evidence of any unrecognized risk of treatment. During 24,586 patient-years of follow-up (FU) of ever-treated patients, SAEs (mostly typical respiratory complications of CF) were more frequent on-treatment (0.4999/patient-year; 95% CI 0.4921-0.5076) than off-treatment (0.3889; 0.3787-0.3992). This was likely caused by within-patient prescription bias. During 655 patient-years of FU in 328 ever-treated patients under 5 years old, SAEs (mostly pulmonary exacerbations of CF) were slightly less frequent during treatment: 0.2911 (0.2367-0.3455) versus 0.3563 (0.3086-0.4040; ns). Results confirm the safety of dornase alfa in CF patients of all ages. Children under 5 years old tolerate dornase alfa at least as well as older patients.

The use of human deoxyribonuclease (rhDNase) in the management of cystic fibrosis.

In patients with cystic fibrosis (CF), the poor clearance of airway secretions promotes recurrent cycles of pulmonary infection and inflammation. In recent years, novel drugs have been developed to alter the properties of the secretions in an attempt to aid chest physiotherapy in improving airway clearance. Once-daily nebulised recombinant human deoxyribonuclease (rhDNase; dornase alfa; Pulmozyme) is the most widely used mucoactive therapy in patients with CF. It has been shown to reduce the viscoelasticity of sputum from patients with CF and enhance the clearance of secretions. Clinical trials have shown rhDNase to be a well tolerated treatment that improves pulmonary function and reduces respiratory exacerbations. However, the response to treatment is heterogeneous and only a proportion of patients with CF actually benefit from the treatment. At present, we are unable to predict which patients will benefit from rhDNase. Many CF centers have developed formal n-of-1 trials of treatment to find out who benefits and to justify prescribing the agent. rhDNase is an expensive therapy and is mainly used in patients over the age of 5 years with moderate to severe lung disease. However, studies have shown that rhDNase may be useful in patients with milder lung disease. Comparisons with another mucoactive drug, hypertonic saline, have shown rhDNase to be more effective. Recently, it has been shown that giving rhDNase on an alternate-day basis, rather than daily, is equally effective, potentially reducing costs and treatment time.

[Outcomes of the long-term treatment with a novel mucolytic drug pulmozin in mucoviscidosis patients]. / Opyt dlitel'nogo primeneniia novogo mukoliticheskogo preparata "pul'mozim" u bol'nykh mukovistsidozom.

AIM: To study clinical effectiveness and safety of a new mucolytic drug pulmozim (Switzerland) adjuvant to basic therapy in mucoviscidosis patients of different age in Russia. MATERIAL AND METHODS: 15 patients with mucoviscidosis aged 5-36 years, functional lung capacity and FEV-1 at least 40% received pulmozim for 30 days. The drug was given in a single daily dose 2.5 mg in inhalations. The study included three stages: initial 14 days--discontinuation of all mucolytic drugs, 30-day course of pulmozim, 14-day follow-up without pulmozim and other mucolytics. RESULTS: Pulmozim in the above regimen was effective in patients with mixed and moderate mucoviscidosis. The drug facilitates respiration, improves sputum rheology, normalizes general condition of the patient, is simple for use, has good organoleptic properties. CONCLUSION: Pulmozim is an effective mucolytic drug in combined treatment of mucoviscidosis.

Recombinant human Dnase I (rhDNase) in patients with lupus nephritis.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 microg/kg rhDNase (n = 8); (2) 125 microg/kg rhDNase (n=6); or (3) placebo (n = 3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre- and post-treatment were studied for immune complex deposition by immunofluorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-alpha) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 microg/kg, but not after SC administration at either dose. A t 1/2 of 3-4h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre- and post-treatment] for the 25 microg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 microg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-alpha. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre- and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.