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Morten Hylander Møller - One of the best experts on this subject based on the ideXlab platform.

  • Nebulised Dornase Alfa versus placebo or hypertonic saline in adult critically ill patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
    Systematic Reviews, 2015
    Co-Authors: Casper Claudius, Anders Perner, Morten Hylander Møller
    Abstract:

    Background Nebulised Dornase Alfa is used off-label in critically ill patients. We aimed to assess the benefits and harms of nebulised Dornase Alfa versus placebo, no prophylaxis, or hypertonic saline on patient-important outcome measures in adult critically ill patients. Methods We performed a systematic review with meta-analysis and trial sequential analysis (TSA) using the Cochrane Collaboration methodology. Eligible trials were randomised clinical trials comparing nebulised Dornase Alfa with placebo, no prophylaxis, or hypertonic saline. The predefined outcome measures were all-cause mortality, duration of mechanical ventilation, length of stay, and adverse events. Two reviewers independently assessed trials for inclusion, data extraction, and risk of bias. Risk ratios (RRs) with 95 % confidence intervals (CIs) were estimated by conventional cumulative meta-analysis, and the robustness of the primary estimate was assessed by TSA. Results Two trials ( n  = 63) were included; both were judged to have high risk of bias. There was no statistically significant difference in mortality (random effects model RR (95 % CI) 0.73 (0.09–5.77); P  = 0.24; I ^2 = 30 %). TSA could not be conducted because less than 1 % of the required information size had been accrued. None of the two trials reported adequate and detailed data on any of the secondary outcome measures. Conclusions We found very low quantity and quality of evidence for use of nebulised Dornase Alfa in adult critically ill patients in this systematic review with meta-analysis. Systematic review registration The International Prospective Register of Systematic Reviews (PROSPERO), no. CRD442015016047 .

  • Nebulised Dornase Alfa versus placebo or hypertonic saline in adult critically ill patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
    Systematic reviews, 2015
    Co-Authors: Casper Claudius, Anders Perner, Morten Hylander Møller
    Abstract:

    Nebulised Dornase Alfa is used off-label in critically ill patients. We aimed to assess the benefits and harms of nebulised Dornase Alfa versus placebo, no prophylaxis, or hypertonic saline on patient-important outcome measures in adult critically ill patients. We performed a systematic review with meta-analysis and trial sequential analysis (TSA) using the Cochrane Collaboration methodology. Eligible trials were randomised clinical trials comparing nebulised Dornase Alfa with placebo, no prophylaxis, or hypertonic saline. The predefined outcome measures were all-cause mortality, duration of mechanical ventilation, length of stay, and adverse events. Two reviewers independently assessed trials for inclusion, data extraction, and risk of bias. Risk ratios (RRs) with 95 % confidence intervals (CIs) were estimated by conventional cumulative meta-analysis, and the robustness of the primary estimate was assessed by TSA. Two trials (n = 63) were included; both were judged to have high risk of bias. There was no statistically significant difference in mortality (random effects model RR (95 % CI) 0.73 (0.09–5.77); P = 0.24; I2 = 30 %). TSA could not be conducted because less than 1 % of the required information size had been accrued. None of the two trials reported adequate and detailed data on any of the secondary outcome measures. We found very low quantity and quality of evidence for use of nebulised Dornase Alfa in adult critically ill patients in this systematic review with meta-analysis. The International Prospective Register of Systematic Reviews (PROSPERO), no. CRD442015016047 .

Harm A.w.m. Tiddens - One of the best experts on this subject based on the ideXlab platform.

  • Small airway deposition of Dornase Alfa during exacerbations in cystic fibrosis; a randomized controlled clinical trial.
    Pediatric pulmonology, 2013
    Co-Authors: E.m. Bakker, Sonia Volpi, Elena Salonini, B. Müllinger, P. Kroneberg, Marleen Bakker, Wim C. J. Hop, Baroukhmaurice Assael, Harm A.w.m. Tiddens
    Abstract:

    Introduction Small airway obstruction is important in the pathophysiology of cystic fibrosis (CF) lung disease. Additionally, many CF patients lose lung function in the long term as a result of respiratory tract exacerbations (RTEs). No trials have been performed to optimize mucolytic therapy during a RTE. We investigated whether specifically targeting Dornase Alfa to the small airways improves small airway obstruction during RTEs. Methods In a multi-center, double-blind, randomized controlled trial CF patients hospitalized for a RTE and on maintenance treatment with Dornase Alfa were switched to a smart nebulizer. Patients were randomized to small airway deposition (n = 19) or large airway deposition (n = 19) of Dornase Alfa for at least 7 days. Primary endpoint was forced expiratory flow at 75% of forced vital capacity (FEF75). Main Results Spirometry parameters improved significantly during admission, but the difference in mean change in FEF75 between treatment groups was not significant: 0.7 SD, P = 0.30. FEF25–75, FEV1, nocturnal oxygen saturation and diary symptom scores also did not differ between groups. Conclusions This study did not detect a difference if inhaled Dornase Alfa was targeted to small versus large airways during a RTE. However, the 95% confidence interval for the change in FEF75 was wide. Further studies are needed to improve the effectiveness of RTE treatment in CF. Pediatr Pulmonol. 2014; 49:154–161. © 2013 Wiley Periodicals, Inc.

  • Editorial for effect of Dornase Alfa on inflammation and lung function: Potential role in the early treatment of cystic fibrosis
    Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2012
    Co-Authors: Harm A.w.m. Tiddens
    Abstract:

    Treat or lose? The review by Konstan and Ratjen in this issue of the Journal of CF underlines the importance of early treatment of CF lung disease using Dornase Alfa [1]. Dornase Alfa has been important as mucolytic therapy for CF lung disease since the mid-nineties. Dornase Alfa was the first drug developed specifically for the treatment of CF patients [2]. The Dornase Alfa development program included the two-year randomized controlled Pulmozyme Early Intervention Trial (PEIT) [3]. The PEIT included patients with well-preserved lung function (Forced Vital CapacityN85%). In the Dornase Alfa group lung function was maintained over the two-year study period. As reviewed by Konstan and Ratjen a large body of evidence on the efficacy of Dornase Alfa and its potential mechanisms has been added to the pivotal studies. Based on this evidence Dornase Alfa has been recommended in guidelines as a standard of treatment for children 6 years and above with mild to severe lung disease. Despite these recommendations a large number of young patients with high lung function but without Dornase Alfa treatment could be found in the database of the Epidemiologic Study of CF (ESCF). In an analysis of the ESCF database by Konstan elevated risk of immediate rapid decline in these untreated patients was shown underscoring the need for early and aggressive treatment to preserve lung function. Why is it that, despite all the evidence on Dornase Alfa in early disease, its implementation is incomplete? Some patients are probably considered too good to benefit from the treatment by their clinicians. This reminds me of a discussion I had 15 years ago with one of the inventors of Dornase Alfa. We discussed the results of the PEIT study and he challenged me on my conclusion that I was reluctant to start Dornase Alfa treatment in CF patients with normal lung function. ‘So you want patients with wellpreserved lung function to lose function’ he argued. He was right, the PEIT data showed us that we should aim for preservation of ‘healthy’ lungs and not only focus on the obviously sick lungs. It is now well recognized that normal spirometry does not exclude chronic lower airway inflammation, infection, and structural damage. Unfortunately, large randomized controlled trials like the PEIT have major limitations. It does not help us to determine whether a patient sitting in front of us in our outpatient clinic will be a responder or non-responder. It only teaches us that patients who met the PEIT inclusion criteria and who were randomized to Dornase Alfa had on average no loss of FEV1 over a 2-year study period in contrast to the placebo treated patients. Hence, evidence-based medicine defines for us what works for a group of patients that meet certain inclusion characteristics. Until we have developed reliable prediction models that allow us to predict outcome from an intervention for an individual based on key characteristics we are stuck to ‘one size fits all’. Hence, as advocated by Konstan and Ratjen in their review there is ‘a greater role for Dornase Alfa therapy in the early treatment of CF, where it may help preserve lung function and potentially extend survival’.

  • improved treatment response to Dornase Alfa in cystic fibrosis patients using controlled inhalation
    European Respiratory Journal, 2011
    Co-Authors: E.m. Bakker, Sonia Volpi, Wim C. J. Hop, E Salonini, E C Van Der Wielkooij, C Sintnicolaas, B M Assael, P J F M Merkus, Harm A.w.m. Tiddens
    Abstract:

    Better treatment of obstructed small airways is needed in cystic fibrosis. This study investigated whether efficient deposition of Dornase Alfa in the small airways improves small airway obstruction. In a multicentre, double-blind, randomised controlled clinical trial, cystic fibrosis patients on maintenance treatment with 2.5 mL Dornase Alfa once daily were switched to a smart nebuliser and randomised to small airway deposition (n = 24) or large airway deposition (n = 25) for 4 weeks. The primary outcome parameter was forced expiratory flow at 75% of forced vital capacity (FEF(75%)). FEF(75%) increased significantly by 0.7 sd (5.2% predicted) in the large airways group and 1.2 sd (8.8% pred) in the small airways group. Intention-to-treat analysis did not show a significant difference in treatment effect between groups. Per-protocol analysis, excluding patients not completing the trial or with adherence <70%, showed a trend (p = 0.06) in FEF(75%) Z-score and a significant difference (p = 0.04) between groups in absolute FEF(75%) (L · s(-1)) favouring small airway deposition. Improved delivery of Dornase Alfa using a smart nebuliser that aids patients in correct inhalation technique resulted in significant improvement of FEF(75%) in children with stable cystic fibrosis. Adherent children showed a larger treatment response for small airway deposition.

  • Improved treatment response to Dornase Alfa in cystic fibrosis patients using controlled inhalation
    The European respiratory journal, 2011
    Co-Authors: E.m. Bakker, Sonia Volpi, Wim C. J. Hop, E Salonini, C Sintnicolaas, B M Assael, P J F M Merkus, E.c. Van Der Wiel-kooij, Harm A.w.m. Tiddens
    Abstract:

    Better treatment of obstructed small airways is needed in cystic fibrosis. This study investigated whether efficient deposition of Dornase Alfa in the small airways improves small airway obstruction. In a multicentre, double-blind, randomised controlled clinical trial, cystic fibrosis patients on maintenance treatment with 2.5 mL Dornase Alfa once daily were switched to a smart nebuliser and randomised to small airway deposition (n = 24) or large airway deposition (n = 25) for 4 weeks. The primary outcome parameter was forced expiratory flow at 75% of forced vital capacity (FEF(75%)). FEF(75%) increased significantly by 0.7 sd (5.2% predicted) in the large airways group and 1.2 sd (8.8% pred) in the small airways group. Intention-to-treat analysis did not show a significant difference in treatment effect between groups. Per-protocol analysis, excluding patients not completing the trial or with adherence

  • a two year randomized placebo controlled trial of Dornase Alfa in young patients with cystic fibrosis with mild lung function abnormalities
    The Journal of Pediatrics, 2001
    Co-Authors: Joanne M Quan, Philip J. Robinson, Harm A.w.m. Tiddens, Sheila G Mckenzie, Mark D Montgomery, Mary Ellen B Wohl, Michael W. Konstan
    Abstract:

    Abstract Objective: 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. Study design: 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 ≥ 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. Results: 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. Conclusions: Treatment of young patients with CF with Dornase Alfa maintains lung function and reduces the risk of exacerbations over a 96-week period. (J Pediatr 2001;139:813–20)

Margaret E. Hodson - One of the best experts on this subject based on the ideXlab platform.

  • Dornase Alfa is well tolerated: data from the epidemiologic registry of cystic fibrosis.
    Pediatric pulmonology, 2007
    Co-Authors: S.g. Mckenzie, S. Chowdhury, Birgitta Strandvik, Margaret E. Hodson
    Abstract:

    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.

  • Dornase Alfa in the treatment of cystic fibrosis in europe a report from the epidemiologic registry of cystic fibrosis
    Pediatric Pulmonology, 2003
    Co-Authors: Margaret E. Hodson, S.g. Mckenzie, H K Harms, Christian Koch, G Mastella, J Navarro, Birgitta Strandvik
    Abstract:

    Dornase Alfa (Pulmozyme) treatment for patients with cystic fibrosis (CF) has been shown to improve pulmonary function and reduce exacerbations of infection in a number of placebo-controlled double-blind studies. Data in the Epidemiologic Registry of Cystic Fibrosis (ERCF) in November 1998 were used to assess the long-term effectiveness in routine clinical practice of Dornase Alfa in terms of pulmonary function and frequency of acute pulmonary exacerbations in CF. At that time, the ERCF contained data on 13,684 CF patients, with a mean observation period of 2.3 years. To be included in the analysis, patients had to have 2 years of data in the Registry in appropriate detail. Overall, untreated patients showed a decline in forced expiratory volume in 1 sec over a 2-year period of -2.3% predicted, but treated patients were stable, showing a change of 0.3% predicted, i.e., a treatment benefit of 2.5%. Compared to untreated patients, there were 25 fewer exacerbations per 100 treated patients per year. The analysis suggested that younger patients were likely to benefit more from treatment. The findings of randomized clinical trials were supported by the data collected in routine clinical practice.

  • Dornase Alfa in the treatment of cystic fibrosis in Europe: a report from the Epidemiologic Registry of Cystic Fibrosis.
    Pediatric pulmonology, 2003
    Co-Authors: Margaret E. Hodson, S.g. Mckenzie, H K Harms, Christian Koch, G Mastella, J Navarro, Birgitta Strandvik
    Abstract:

    Dornase Alfa (Pulmozyme®) treatment for patients with cystic fibrosis (CF) has been shown to improve pulmonary function and reduce exacerbations of infection in a number of placebo-controlled double-blind studies. Data in the Epidemiologic Registry of Cystic Fibrosis (ERCF) in November 1998 were used to assess the long-term effectiveness in routine clinical practice of Dornase Alfa in terms of pulmonary function and frequency of acute pulmonary exacerbations in CF. At that time, the ERCF contained data on 13,684 CF patients, with a mean observation period of 2.3 years. To be included in the analysis, patients had to have 2 years of data in the Registry in appropriate detail. Overall, untreated patients showed a decline in forced expiratory volume in 1 sec over a 2-year period of −2.3% predicted, but treated patients were stable, showing a change of 0.3% predicted, i.e., a treatment benefit of 2.5%. Compared to untreated patients, there were 25 fewer exacerbations per 100 treated patients per year. The analysis suggested that younger patients were likely to benefit more from treatment. The findings of randomized clinical trials were supported by the data collected in routine clinical practice. Pediatr Pulmonol. 2003; 36:427–432. © 2003 Wiley-Liss, Inc.

  • A case-controlled study with Dornase Alfa to evaluate impact on disease progression over a 4-year period
    Respiration; international review of thoracic diseases, 2001
    Co-Authors: Pallav L. Shah, Steven P. Conway, S. F. Scott, Maurizio Rainisio, Martin Wildman, D. E. Stableforth, Margaret E. Hodson
    Abstract:

    Background: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (Dornase Alfa) reduces the viscoelast

  • Dornase Alfa
    BioDrugs, 1997
    Co-Authors: Pallav L. Shah, Margaret E. Hodson
    Abstract:

    Cystic fibrosis is characterised by chronic bronchopulmonary sepsis. Various therapeutic modalities attempt to enhance the clearance of airway secretions. Dornase Alfa (recombinant human deoxyribonuclease) reduces the viscoelasticity of sputum from patients with cystic fibrosis by depolymerising extracellular DNA. The drug is administered as an aerosol using a jet nebuliser at a dosage of 2.5mg once daily. It improves pulmonary function and reduces the risk of respiratory exacerbations requiring parenteral antibacterials. Various clinical trials have demonstrated a heterogeneous response to Dornase Alfa and have been unable to predict which groups of patients benefit from treatment. Patient selection is further complicated because some individuals do not exhibit improvements in lung function, but benefit in terms of a decrease in infective exacerbations. All patients with cystic fibrosis who produce purulent sputum are potential candidates for Dornase Alfa therapy. We suggest that compliant patients be considered for treatment with Dornase Alfa, irrespective of disease severity, but should be closely monitored and be assessed at regular intervals to monitor treatment response.

R. Zengin - One of the best experts on this subject based on the ideXlab platform.

  • Preliminary report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 infection.
    New microbes and new infections, 2020
    Co-Authors: H.k. Okur, Koray Yalcin, Cihan Tastan, Sevda Demir, Bulut Yurtsever, Gozde Sir Karakus, Derya Dilek Kancagi, Selen Abanuz, Utku Seyis, R. Zengin
    Abstract:

    Abstract Dornase Alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase Alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). It is well known that novel coronavirus disease 2019 (COVID-19) pneumonia progresses to ARDS and even multiple organ failure. High blood neutrophil levels are an early indicator of COVID-19 and predict severe respiratory diseases. Also it is reported that mucus structure in COVID-19 is very similar to that in cystic fibrosis due to the accumulation of excessive NET in the lungs. In this study, we showed the recovery of three individuals with COVID-19 after including Dornase Alfa in their treatment. We followed clinical improvement in the radiological analysis (two of three cases), oxygen saturation (Sp o 2), respiratory rate, disappearance of dyspnoea, coughing and a decrease in NET formation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load after the treatment. Also here, we share our preliminary results suggesting that Dornase Alfa has an anti-viral effect against SARS-CoV-2 infection in a green monkey kidney cell line, Vero, and a bovine kidney cell line, MDBK, without determined cytotoxicity on healthy peripheral blood mononuclear cells.

  • Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)
    2020
    Co-Authors: Hacer Kuzu Okur, Koray Yalcin, Cihan Tastan, Sevda Demir, Bulut Yurtsever, Utku Seyis, R. Zengin, Gozde Sir, Derya Dilek Kancagi, Cansu Hemsinlioglu
    Abstract:

    UNSTRUCTURED Dornase Alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase Alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with Dornase Alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that Dornase Alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

Michael W. Konstan - One of the best experts on this subject based on the ideXlab platform.

  • Cystic fibrosis clinical characteristics associated with Dornase Alfa treatment regimen change.
    Pediatric pulmonology, 2017
    Co-Authors: Donald R. Vandevanter, Marcia L. Craib, David J. Pasta, Stefanie J. Millar, Wayne J. Morgan, Michael W. Konstan
    Abstract:

    Background When the chronic respiratory therapy Dornase Alfa was made commercially available for cystic fibrosis (CF) more than 20 years ago, two regimens were approved: 2.5 mg inhaled once daily (QD) or twice daily (BID). In the intervening years, there has been little guidance as to when to use each regimen. We have studied clinical practice patterns captured in the Epidemiologic Study of CF (ESCF) during the decade following Dornase Alfa approval (1994-2005) to better understand clinical characteristics associated with QD versus BID Dornase Alfa use. Methods We studied the characteristics of ESCF patients who received either Dornase Alfa regimen for at least 12 months and who were then switched to the alternate regimen for at least 6 months and who had adequate data available around the time of the switch. Average lung function and weight-for-age (WFA) z-scores, numbers of intravenous (IV) antibiotic-treated pulmonary exacerbations, and prevalence of signs and symptoms were determined for 6-month periods capturing the beginning (FIRST) and the end (LAST) of the initial regimen, the 6 months preceding the final 6 months of the initial regimen (PRIOR), and the beginning of the second regimen (POST). Changes in values from FIRST to LAST, PRIOR to LAST, and LAST to POST were studied to better understand clinical scenarios associated with decisions to change regimens. Results A total of 1342 QD and 574 BID regimens were studied with median durations of 3.19 and 2.09 years, respectively. On average, patients beginning BID regimens had worse lung function and a greater number of pulmonary exacerbations treated with IV antibiotics than those beginning QD regimens. However, by the time of regimen switch, patients switching from QD to BID Dornase Alfa had experienced substantial deterioration with respect to pulmonary exacerbations and signs and symptoms, whereas patients switching from BID to QD had not. Interestingly, incidence of IV-treated pulmonary exacerbations and signs and symptom prevalence decreased for both populations after regimen switch. Conclusions We have studied populations of patients with CF receiving Dornase Alfa who were switched between regimens to characterize clinical course. Our results suggest that the most common clinical attribute associated with switching from QD to BID Dornase Alfa was a marked deterioration in stability characterized by increased incidence and frequency of pulmonary exacerbation. For this population, deterioration in lung function did not appear to be a driver for this switch. In contrast, patients receiving BID Dornase Alfa who were ultimately switched to QD appeared to be clinically stable, on average, suggesting that treatment burden and cost may have been drivers of the decision to switch regimens.

  • Randomized trial of efficacy and safety of Dornase Alfa delivered by eRapid nebulizer in cystic fibrosis patients
    Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2015
    Co-Authors: Gregory S. Sawicki, Will Chou, Karina Raimundo, Ben Trzaskoma, Michael W. Konstan
    Abstract:

    Abstract 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 (≥6years) were randomized in a crossover study to receive Dornase Alfa 2.5mg/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 10.2min). 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.

  • Effect of Dornase Alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis.
    Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2011
    Co-Authors: Michael W. Konstan, Felix Ratjen
    Abstract:

    Dornase Alfa has been shown to reduce markers of inflammation and neutrophil-associated metalloproteinases in cystic fibrosis (CF), suggesting a potential benefit from use of this therapy early in the disease. However, observational studies indicate that Dornase Alfa is often reserved for “sicker” patients. A 2-year, early intervention study of Dornase Alfa in CF patients with early lung disease demonstrated significant improvements in lung function and risk of exacerbation compared to placebo. A more recent analysis, using the database of the large observational Epidemiologic Study of Cystic Fibrosis (ESCF), found that initiation of Dornase Alfa has the potential to alter the course of CF by decreasing the rate of lung function decline in children and adults. These encouraging results, possibly linked to indirect effects on inflammation, suggest a greater role for Dornase Alfa therapy in the early treatment of CF, where it may help preserve lung function and potentially extend survival.

  • Clinical Use of Dornase Alfa Is Associated with a Slower Rate of FEV1 Decline in Cystic Fibrosis
    Pediatric pulmonology, 2011
    Co-Authors: Michael W. Konstan, Jeffrey S. Wagener, David J. Pasta, Stefanie J. Millar, Joan R. Jacobs, Ashley Yegin, Wayne J. Morgan
    Abstract:

    Objectives Randomized controlled trials of Dornase Alfa have shown forced expiratory volume in 1 sec (FEV1) to improve in patients with cystic fibrosis (CF) but have not assessed change in the rate of lung function decline. We assessed the relationship of Dornase Alfa use and FEV1 decline using the Epidemiologic Study of Cystic Fibrosis (ESCF). Methodology Patients aged 8–38 years who had been enrolled in ESCF for 2 years when initially treated with Dornase Alfa were selected if they remained on treatment during the following 2 years. A comparator group included patients aged 8–38 who were not yet reported to have received Dornase Alfa. For each patient we estimated the annual rate of decline in FEV1% predicted before and after the index using a mixed-effects model adjusted for age, gender, pulmonary exacerbations, respiratory therapies, and nutritional supplements. Results The Dornase Alfa group (n = 2,230) had a lower FEV1% predicted at index and a more rapid decline during the pre-index period. The mean rate of FEV1 decline improved for the Dornase Alfa group; the improvement was similar in adults and children 8–17 years old but was not statistically significant in adults. The comparator group (n = 5,970) showed no change among adults and an increased rate of decline among children 8–17 years old. Conclusions The use of Dornase Alfa for a 2-year period is associated with a reduction in the rate of FEV1 decline. These results also demonstrate the value of using an observational study to assess the association of instituting new therapies in the clinical setting with changes in the rate of FEV1 decline in patients with CF. Pediatr. Pulmonol. 2011; 46:545–553. © 2011 Wiley-Liss, Inc.

  • Dornase Alfa and progression of lung disease in cystic fibrosis
    Pediatric Pulmonology, 2008
    Co-Authors: Michael W. Konstan
    Abstract:

    Obstruction, infection, and inflammation lead to progressive and irreversible lung destruction in cystic fibrosis (CF). Neutrophil-derived DNA contributes to thick, viscous secretions. Dornase Alfa hydrolyzes DNA, reducing the viscosity of CF sputum. Clinical trials have shown that Dornase Alfa improves forced expiratory volume in one second (FEV1). Immediate improvement is important, but long term survival requires slowing the rate of lung function decline. Demonstrating changes in rate of decline requires long term studies with many patients, which are impractical for clinical trials. Observational studies such as the Epidemiologic Study of Cystic Fibrosis (ESCF) can address rate of decline in lung function, and is being used to evaluate the long-term effectiveness of Dornase Alfa. CF patients age 8–38 years when initially treated with Dornase Alfa (index event) were compared to patients not treated (for 2 years before and 2 years after index). In a preliminary analysis, FEV1 at index for the Dornase Alfa group (n = 2,706) was 80.5% predicted, and for the comparator group (n = 3,991) 86.7% predicted. The estimated rate of FEV1 decline before index for the Dornase Alfa group was −2.81 and for the comparator group −0.85% predicted/year. After index, the rate of decline for the Dornase Alfa group was −1.53% predicted/year (46% reduction, P < 0.001), with no change in the comparator group. These preliminary results suggest that initiating Dornase Alfa is associated with both an acute improvement in FEV1 and a slowing of the rate of FEV1 decline. Analysis is ongoing to further evaluate this association. Pediatr Pulmonol. 2008; 43:S24–S28. © 2008 Wiley-Liss, Inc.