Original Article
Effect of Aerosolized Recombinant Human DNase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis
N Engl J Med 1994; 331:637-642September 8, 1994
- Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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. .
Media in This Article
Figure 1
Proportion of Patients Free of Exacerbations of Respiratory Symptoms Requiring Parenteral Antibiotic Therapy.Figure 2
Mean Percent Change in FEV1 from Base Line Throughout the 24-Week Study Period.Article Activity
- Article
Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, recurrent exacerbations of respiratory symptoms, and progressive deterioration of lung function1. In such patients chronic bacterial colonization of the airways develops, usually with Staphylococcus aureus or Pseudomonas aeruginosa, and often before the age of three years2. Despite the use of potent antibiotics, often administered parenterally, airway infection persists. The average survival of patients with cystic fibrosis is approximately 29 years; more than 90 percent die of lung disease3.
Two macromolecules that contribute to the physical properties of secretions are mucus glycoproteins and DNA4. In patients with cystic fibrosis, extracellular DNA is released by leukocytes that accumulate in the airways in response to chronic bacterial infection. The mean content of DNA is approximately 10.2 percent of the dry weight of secretions from patients with cystic fibrosis,5 and DNA can accumulate at concentrations averaging 5.9 mg per milliliter6. Solutions containing purified high-molecular-weight DNA at this concentration are highly viscous. Deoxyribonuclease I (DNase I) is a human enzyme, normally present in saliva, urine, pancreatic secretions, and blood, that is responsible for the digestion of extracellular DNA7. On the basis of the hypothesis that an increased concentration of high-molecular-weight DNA contributes to the abnormal viscoelastic properties of sputum, airway obstruction, and recurrent exacerbations of respiratory symptoms requiring parenteral antibiotics, human DNase I has been delivered as an aerosol to the airways of patients with cystic fibrosis8. In phase 1 and 2 clinical trials, the administration of recombinant human DNase (rhDNase) in aerosol form to patients with cystic fibrosis for up to 10 days improved forced expiratory volume in one second (FEV1) by approximately 14 percent, decreased the perception of dyspnea, increased overall well-being, and was safe9-12. We designed this randomized, double-blind, placebo-controlled clinical trial to investigate whether the administration of rhDNase for 24 weeks would maintain the improvement in FEV1 and reduce the risk of exacerbations of respiratory symptoms requiring parenteral antibiotics.
Methods
The rhDNase (Pulmozyme, known generically as dornase alfa) used in the study was provided by Genentech as a solution (1.0 mg per milliliter) in 2.5 ml of excipient (150 mM sodium chloride, 1.5 mM calcium chloride, pH 6.0). The placebo used in the study was excipient alone. The drug or placebo solution was placed in the bowl of a T-Updraft II Neb-u-mist nebulizer (Hudson, Irvine, Calif.), and the nebulizer was connected to a PulmoAide compressor (DeVilbiss, Somerset, Pa.). Doses were expressed as the amount of rhDNase placed in the bowl of the nebulizer.
Study Design
All the patients received standard care for cystic fibrosis13. Patients were randomly assigned to one of three treatment regimens: 2.5 mg of rhDNase once daily, 2.5 mg of rhDNase twice daily, or placebo, for 24 weeks. Patients were given two vials per day, regardless of treatment group, containing rhDNase or placebo, to preserve blinding. A 24-week study was required in order to identify a significant reduction in the risk of exacerbations of respiratory symptoms requiring parenteral antibiotics, on the basis of data from the patient registry of the Cystic Fibrosis Foundation14. The total enrollment planned for the study was 900 patients; this sample provided 90 percent power at the 0.05 level of significance to detect a 50 percent reduction in the risk of exacerbations, assuming that 20 percent of the placebo-treated patients would have exacerbations. The dose was based on the results of a previous study11. The regimen in which 2.5 mg of rhDNase was administered once daily was chosen to evaluate the effect of a lower daily dose and a more convenient regimen. Randomization was stratified within each center. The study design was approved by the institutional review board at each center, and informed consent was obtained from all the patients or from their parents or guardians. The study was monitored by a safety advisory committee consisting of three pulmonologists experienced in the care of patients with cystic fibrosis in order to assess the character and frequency of adverse events.
Study Population
Patients were recruited from 51 institutions and were eligible if they were five years of age or older, had a confirmed diagnosis of cystic fibrosis (a sweat chloride value higher than 60 mmol per liter), and had a forced vital capacity (FVC) greater than 40 percent of the predicted value (based on sex, age, and height),15 as determined at an initial screening visit within seven days of randomization. To ensure that patients were enrolled when they were clinically stable, they had to have been receiving a consistent regimen of antibiotics, or no antibiotics, during the 14 days before randomization. Patients were seen twice more before randomization to determine their base-line values on pulmonary-function tests.
Assessments of Efficacy and Safety
An exacerbation of respiratory symptoms, prospectively defined in the study, was said to have occurred when a patient was treated with parenteral antibiotics for any 4 of the following 12 signs or symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38 °C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary infection.
The patients were evaluated 7 and 14 days after randomization and every 2 weeks thereafter. Pulmonary-function tests were performed at each visit according to standards established by the American Thoracic Society16. Dyspnea was quantitated with a vertical visual-analogue scale17. A questionnaire developed during phase 2 clinical studies12 was used to evaluate the patients' general well-being (with questions about general feeling, energy, physical activity, appetite, and sleep) and their cystic fibrosis-related symptoms (with questions about sputum production, frequency of cough, severity of cough, and chest congestion). The patients ranked their symptoms on a scale of 1 to 5. Also, the investigators recorded the number of days of school or work missed because of cystic fibrosis-related illness, the number of days in the hospital, and the number of days patients received parenteral antibiotics.
Serum samples obtained on enrollment and 4, 12, and 24 weeks after the start of therapy were assayed for antibodies to rhDNase and for the concentration of DNase. Antibodies specific to rhDNase were determined by a radioimmunoprecipitation assay that detected immunoglobulins of the IgG, IgM, and IgE classes18. The serum concentration of DNase was determined by an enzyme-linked immunosorbent assay using an antiserum that recognizes both rhDNase and native human DNase19. Human DNase is normally present in serum samples from patients with cystic fibrosis. Complete hematologic and chemical assessments were obtained on enrollment and 4, 12, and 24 weeks after the start of therapy.
Costs of Treating Exacerbations of Symptoms
Because it was not deemed feasible to collect primary data on costs for all the patients, secondary data sources were used to estimate the cost for each patient of all hospitalizations and outpatient antibiotic therapy related to exacerbations of respiratory symptoms, based on observed levels of resource use. The cost of each hospitalization was estimated with a model that related the total cost per patient to the length of stay, the duration of intravenous antibiotic therapy, and the performance of any surgery20-25. To estimate this model, itemized bills and discharge summaries were obtained from 20 hospitals for 385 patients with cystic fibrosis who were not involved in the study and who were admitted in 1990 or 1991 for treatment of respiratory symptoms. The billed charges were converted to costs with hospital-specific cost-to-charge ratios and were adjusted to 1992 price levels. The model was estimated with ordinary least-squares regression in quadratic form to allow for nonlinearity between costs and resource use. The model was validated against the actual costs (calculated from billed charges) for a sample of 51 hospital admissions not randomly selected that occurred during the trial at nine study centers. The predicted costs per admission were $10,942, as compared with actual costs of $11,043, or a mean error of $101 (range, -$4,443 to $11,363). The Pearson correlation coefficient for predicted and actual costs was 0.98 (P<0.01). The estimated cost of outpatient antibiotics was based on published average wholesale prices26 plus a dispensing fee ($5.50 for oral antibiotics)27. The cost of intravenous antibiotic administration at home, exclusive of drugs, was estimated to be $79 per day28. Because secondary data sources were used to estimate the cost of treating exacerbations of respiratory symptoms, no formal tests of statistical significance were used.
Statistical Analysis
The relative risk of an exacerbation was compared in the rhDNase groups and the placebo group by the Cox proportional-hazards model29. Adjustments for covariates found to be imbalanced between groups at base line and to have prognostic significance were incorporated into the model. Kaplan-Meier curves30 were used to plot the cumulative proportion of patients in each treatment group who remained free of exacerbations of respiratory symptoms during the 24-week treatment period.
The mean percentage of change in FEV1 was determined by the following formula:
(Mean FEV1 during treatment - FEV1 at base line) × 100 /FEV1 at base line.
The base-line value for FEV1 was taken as the mean of the two measurements obtained before randomization but after the initial screening value was obtained, in order to avoid regression to the mean. The assessment of the change in FEV1 relative to the base-line value allowed an assessment of the effect of treatment in a population with heterogeneous values for pulmonary function, as suggested by the American Thoracic Society31. Changes in FEV1 were compared among study groups by analysis of variance.
Analyses of secondary end points, FVC, dyspnea, general well-being, cystic fibrosis-related symptoms, days in the hospital, days of antibiotic use, and days of school or work missed were performed by analysis of variance or by nonparametric methods, as appropriate. All the analyses were conducted under the intention-to-treat principle, and all statistical tests were two-sided.
Results
A total of 968 patients were randomized. The treatment groups were clinically comparable at enrollment (Table 1Table 1
Characteristics of the Study Population at Base Line.), except that there were more patients between 17 and 23 years of age in the once-daily treatment group than in the other groups. The use of concomitant treatments, including aerosolized or oral antibiotics, bronchodilators, and chest physiotherapy, was similar among the treatment groups. Twenty-five patients (3 percent) permanently discontinued administration of the study drug (eight patients each in the placebo and the once-daily rhDNase groups, and nine patients in the twice-daily rhDNase group).The administration of rhDNase once or twice daily reduced the risk of an exacerbation of respiratory symptoms requiring parenteral antibiotic therapy. The risk of such an exacerbation was reduced 22 percent by the administration of rhDNase once daily (relative risk, 0.78; 95 percent confidence interval, 0.57 to 1.06; P = 0.11) and 34 percent by the administration of rhDNase twice daily (relative risk, 0.66; 95 percent confidence interval, 0.48 to 0.91; P = 0.01) (Table 2Table 2
Risk of an Exacerbation of Respiratory Symptoms Requiring Parenteral Antibiotic Therapy.). A reduction in the risk of an exacerbation was observed in both rhDNase groups throughout the study period (Figure 1Figure 1Proportion of Patients Free of Exacerbations of Respiratory Symptoms Requiring Parenteral Antibiotic Therapy.).Patients from 17 to 23 years of age, regardless of treatment-group assignment, had a higher incidence of exacerbations. Because the treatment groups did not contain identical proportions of patients in the different age ranges, an adjustment was made in the estimated relative risk of such an exacerbation. The addition of a covariate adjustment based on age (in the categories of <17 years, 17 to 23 years, and >23 years, as determined on the basis of the relation between age and exacerbation of respiratory symptoms in a pooled analysis of all three treatment groups) was statistically significant (P<0.01). The age-adjusted risk of an exacerbation requiring parenteral antibiotics was reduced 28 percent by the administration of rhDNase once daily (relative risk, 0.72; 95 percent confidence interval, 0.52 to 0.98; P = 0.04) and 37 percent by the administration of rhDNase twice daily (relative risk, 0.63; 95 percent confidence interval, 0.46 to 0.87; P<0.01) (Table 3Table 3
Age-Adjusted Risk of Exacerbations of Respiratory Symptoms Requiring Parenteral Anti-biotic Therapy.).The administration of rhDNase reduced the risk of all exacerbations of respiratory symptoms requiring parenteral antibiotics, including those not meeting the criteria defined in the protocol. The age-adjusted risk of all types of exacerbation requiring parenteral antibiotics was reduced 31 percent (relative risk, 0.69; 95 percent confidence interval, 0.54 to 0.89; P<0.01) by the administration of rhDNase once daily and 32 percent (relative risk, 0.68; 95 percent confidence interval, 0.53 to 0.88; P<0.01) by the administration of rhDNase twice daily. The frequency of administration of oral quinolones and aerosolized antibiotics was similar among the rhDNase and placebo groups.
The administration of rhDNase once daily or twice daily improved pulmonary function (Figure 2Figure 2
Mean Percent Change in FEV1 from Base Line Throughout the 24-Week Study Period.). In the placebo group, the mean (±SE) change in FEV1 from base line throughout the study averaged 0.0 ±0.6 percent. The administration of rhDNase once daily or twice daily improved FEV1 throughout the study by an average of 5.8 ±0.7 percent and 5.6 ±0.7 percent, respectively (P<0.01 as compared with placebo). A larger percentage of rhDNase-treated patients than of placebo-treated patients had improvement of more than 10 percent in FEV1 -- namely, 30 percent of patients treated with rhDNase once daily and 28 percent of those treated with rhDNase twice daily, as compared with 15 percent of those receiving placebo. Fewer rhDNase-treated patients than placebo recipients had a decline of more than 10 percent in FEV1: 6 and 7 percent of patients treated with rhDNase once daily and twice daily, respectively, as compared with 14 percent of patients receiving placebo. The administration of rhDNase once daily or twice daily improved FVC by an average of 3.8 ±0.6 percent (P<0.01 as compared with placebo) and 3.0 ±0.6 percent (P = 0.01), respectively.The administration of rhDNase once or twice daily improved the quality of life and certain health-related economic end points for patients during the 24 weeks of the study (Table 4Table 4
Quality-of-Life and Health-Related Economic End Points.). As compared with the placebo group, the patients treated with rhDNase once daily spent 1.3 fewer days in the hospital (P = 0.06), 2.7 fewer days receiving parenteral antibiotics (P<0.05), and 1.5 fewer days at home because of cystic fibrosis-related illness (P<0.05). Those treated with rhDNase twice daily spent 1.0 fewer day in the hospital (P<0.05), 2.2 fewer days receiving parenteral antibiotics (P<0.05), and 0.3 fewer day at home due to cystic fibrosis-related illness (P = 0.13). As compared with the placebo group, the rhDNase-treated patients had less dyspnea, improved overall well-being, fewer symptoms of cystic fibrosis, and reduced costs related to exacerbations of respiratory symptoms.Major complications of cystic fibrosis, including death, occurred with comparable frequency in the three groups. The administration of rhDNase was associated with alteration in voice (principally described as hoarseness), pharyngitis, and laryngitis (Table 5Table 5
Adverse Events during the Study.). Voice alteration was most pronounced in female patients, and in most cases it resolved within 21 days of onset. An increased incidence of rash, chest pain, and conjunctivitis was also noted in patients treated with rhDNase as compared with those who received placebo. The administration of rhDNase was not associated with anaphylaxis.At the conclusion of the study, antibodies to rhDNase were measurable in 3 percent and 4 percent of the patients treated with rhDNase once daily or twice daily, respectively, and in 0 percent of the placebo-treated patients. No serum samples contained DNase-specific IgE antibody. There was no increase in serum DNase concentrations after the administration of rhDNase. The frequency of abnormal hematologic values or serum chemistry profiles was comparable among the three groups.
Discussion
The administration of rhDNase for 24 weeks to patients with cystic fibrosis resulted in a modest reduction in the risk of exacerbations of respiratory symptoms requiring parenteral antibiotics and a slight improvement in lung function. The administration of rhDNase also lessened dyspnea, increased the perception of general well-being, and decreased the severity of cystic fibrosis-related symptoms. Upper airway irritation, manifested as voice alteration (hoarseness), pharyngitis, and laryngitis, was increased by rhDNase.
The improvement in FEV1 as compared with base line was maintained throughout the study period in the patients treated with rhDNase, but at a lower level than that observed during the first two weeks of treatment. The precise reason for this finding is unknown. Longer follow-up of the patients treated with rhDNase will aid in defining the effect of administering rhDNase for more than six months.
Perceptions of well-being, dyspnea, and cystic fibrosis-related symptoms were all significantly better among the patients receiving rhDNase. These findings were all consistent with the differences observed in the primary clinical outcomes.
Comparisons with other drugs acting on mucus are difficult because of differences in study design and patient populations. The aerosolized delivery of mucolytic agents, such as N-acetylcysteine, that modify secretions through their actions on mucus glycoproteins, has met with limited clinical success32. Amiloride, a diuretic agent that blocks sodium absorption in airway epithelial cells and thus directly modifies the physical properties of the respiratory secretions, has been reported to slow the decline in lung function in patients with cystic fibrosis33.
The cost effectiveness of rhDNase is unknown. Limited data on costs are presented in this study. Whereas the cost of therapy with rhDNase appears to be at least partly offset by a reduction in the costs of hospitalization and outpatient antibiotic administration, the effect of treatment on the total costs of care was not assessed. A complete assessment of cost effectiveness will also require follow-up of longer-term outcomes.
Supported by grants from Genentech and the Cystic Fibrosis Foundation of North America.
All authors and participants in the study, exclusive of those employed by Genentech, have affirmed that they have no financial interest in Genentech.
Source Information
From the Department of Medical Affairs, Genentech, Inc., South San Francisco (H.J.F., D.H.C., M.L.N.); the Children's Hospital of Buffalo, Buffalo, N.Y. (D.S.B.); G.H. Besselaar Associates, Princeton, N.J. (E.M.M.); Children's Hospital and Medical Center of Seattle, Seattle (B.W.R., A.L.S.); Johns Hopkins University, Baltimore (B.J.R); the Pulmozyme Study Group, and Children's Hospital, Boston (M.E.W.).
Address reprint requests to Dr. Fuchs at Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080.
The members of the Pulmozyme Study Group and the participating institutions are listed in the Appendix.
Appendix
The following persons and institutions participated in the Pulmozyme Study Group.
Safety Advisory Committee: C.M. Bowman, Children's Hospital of Los Angeles, Los Angeles; H.W. Parker, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.; and T. Murphy, University of Chicago, Chicago.
Health Care Utilization Study (coauthors of the sections pertaining to economic evaluations of health care): G. Oster, D.M. Huse, M.J. Lacey, and M.M. Regan, Policy Analysis, Inc., Brookline, Mass.; H.J. Fuchs, Genentech, Inc., South San Francisco; and A.M. Epstein, Brigham and Women's Hospital, Boston.
Study participants: R. McKey, G. Moccia-Loos, and J.R. Haft (deceased), University of Miami, Miami; M.L. Aitken and P. Kushmerick, University of Washington, Seattle; J. Andersen and L.M. Quittel, Columbia Presbyterian Medical Center, New York; C. Atkins and R.A. Schoumacher, the Children's Hospital of Alabama, Birmingham; D. Borowitz and A. Wilcox, the Children's Hospital of Buffalo, Buffalo, N.Y.; M.G. Boyle and C. Johnson, Washington University School of Medicine, St. Louis; D. Buffington and B.M. Schnapf, University of South Florida, Tampa; K. Bynum and J.E. Jones, Polyclinic Medical Center, Harrisburg, Pa.; A. Calvi and K. Kirchner, University of Colorado Health Sciences Center, Denver; H. Chaney and R.J. Fink, Children's National Medical Center, Washington, D.C.; J. Cheatham and L.A. Lester, University of Chicago, Chicago; A. Colin and M.E. Wohl, Children's Hospital, Boston; J.L. Colombo and P.H. Sammut, University of Nebraska Medical Center, Omaha; S. Davis and M.P. Kiernan, Tulane University Medical Center, New Orleans; G. Davis and D.R. Swartz, Cystic Fibrosis and Pediatric Pulmonary Center, S. Burlington, Vt.; S. Delaney and P.T. Swender, State University of New York Health Science Center, Syracuse; C.R. Denning and R.D. Gonzalez, St. Vincent's Hospital and Medical Center of New York, New York; A.J. Dozor and S.A. Schroeder, New York Medical College, Valhalla; G. Drake and W.J. Morgan, University of Arizona, Tucson; J. Eisenberg and S. Rae, Oregon Health Sciences University, Portland; J. Fahy and T. Ward, University of California, San Francisco; S.B. Fiel and B.R. Levin, Medical College of Pennsylvania, Philadelphia; S.B. Fitzpatrick and L. Kulczycki, Georgetown University Medical Center, Washington, D.C.; A. Pellet and R.S. Gerstle, Baystate Medical Center, Springfield, Mass.; R. Gibson and S. Marshall, Children's Hospital and Medical Center, Seattle; L.M. Glasser and S. Lukenbaugh, Texas Children's Hospital, Baylor College of Medicine, Houston; C.G. Green and P. Knight, University of Wisconsin, Madison; M. Guill, Medical College of Georgia, Augusta; A. Harkins and R. Moss, Lucille Salter Packard Hospital, Palo Alto, Calif.; E.R. Hartigan and B.E. Noyes, Children's Hospital of Pittsburgh, Pittsburgh; I. Harwood and M. Lepage, Cystic Fibrosis Center, San Diego, Calif.; M.L. Hendricks and B.G. Nickerson, Children's Hospital of Orange County, Orange, Calif.; L.S. Hernried and C.F. Robinson, Phoenix Children's Hospital, Phoenix, Ariz.; P. Hilbert and E. Spiritus, Pulmonary Consultants of Orange County, Orange, Calif.; E. Hogvall and G.F. Shay, Cystic Fibrosis Center, Northern California Region of Kaiser Permanente Medical Care Program, Oakland; V. Hudson and W. Regelmann, University of Minnesota, Minneapolis; K. Hyman and D.V. Schidlow, St. Christopher's Hospital for Children, Philadelphia; R.A. Kaslovsky and G.B. Winnie, Albany Medical College, Albany, N.Y.; R. Kishore and R.T. Stone, Children's Hospital Medical Center of Akron, Akron, Ohio; V. Kociela and R.W. Wilmott, Children's Hospital and Medical Center, Cincinnati; A. Kriseman and K. Thee, All Children's Hospital, St. Petersburg, Fla.; J. Lloyd-Still and C. Powers, Children's Memorial Hospital, Chicago; K. McCoy, Children's Hospital, Columbus, Ohio; M. Majure and W.M. Samuelson, Duke University Medical Center, Durham, N.C.; J. Marciel and D.C. Stokes, Vanderbilt University Medical Center, Nashville; B. Marshall and C. Pope, the University of Utah, Salt Lake City; J. Minarik and D. Roberts, Cystic Fibrosis Clinic, Anchorage, Alaska; S.Z. Nasr and G.M. Sanders, University of Michigan Medical Center, Ann Arbor; D.D. Oliver and B.J. Rosenstein, Johns Hopkins Hospital, Baltimore; J. Oren and J. McNamara, New England Medical Center, Boston; K.W. Rowland and N.L. Turcios, New Jersey Medical School, Newark; and L.J. Sindel and K. Smith, University of South Alabama, Mobile.
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