Dornase alfa

Study objective: The 12-week efficacy and safety of aerosolized recombinant human DNase (dornase alfa) were evaluated in previously untreated patients with cystic fibrosis (CF) with advanced lung disease. Design: In this multicenter, double-blind, placebo-controlled study, CF patients with advanced lung disease were randomized to receive either dornase alfa or placebo once a day for 12 weeks. Patients: A total of 320 patients in clinically stable condition with documented CF and an FVC less than 40% of predicted were recruited from 65 CF Foundation care centers in the United States. The dornase alfa and placebo groups were comparable with respect to age (range, 7 to 57 years), height, and weight. Male subjects outnumbered female subjects (55% vs 45%) and few subjects were younger than 17 years of age (15%). The percentages of predicted [FEV.sub.1] and FVC were significantly lower in the dornase alfa group at baseline (p[less than or equal to]0.05). Intervention: Patients were randomly assigned to receive either 2.5 mg dornase alfa once daily (n = 158) or placebo once daily (n=162). All patients continued to receive standard medications and treatments administered for CF. Measurements and results: Dornase alfa improved the mean percent change in [FEV.sub.1] from baseline by 9.4% compared with 2.1% for placebo (p<0.001). The actively treated group showed a improvement in FVC compared with 7.3% for placebo (p<0.001). There were no differences between the treatment groups in dyspnea score, number of days receiving IV antibiotics, or length of hospital stay, the overall incidence of adverse events was comparable between treatment groups. Fifteen patients died: 9 in the dornase alfa group and 6 in the placebo group; no differentiating clinical characteristics were demonstrated. Conclusions: Pulmonary function as measured by [FEV.sub.1] and FVC improved significantly in the dornase alfa-treated patients. Dornase alfa was found to be safe and well tolerated over the 12-week study period.

In 1993, 5.5% of patients with cystic fibrosis (CF) older than 6 years of age in the United States, for whom pulmonary function test data are available, had advanced lung disease, as defined by a FVC less than 40% of predicted.[1] Most patients in this group are considered to have end-stage disease and are unlikely to show improvement in pulmonary function with standard medical therapy.[2] Lung or heart-lung transplantation is currently considered the only viable option for potential long-term survival in patients who are this sick.[3] However, because of a shortage of donor organs, transplantation may be substantially delayed, during which time mortality rates are high.[4]

There has been interest in the potential value of rhDNase for CF patients with advanced lung disease. It is currently available in aerosolized form as dornase alfa. Dornase alfa is believed to improve mucociliary clearance of CF sputum by hydrolyzing extracellular DNA released into CF airways from neutrophils that accumulate in response to Chronic bacterial infection.[5-9] A 24-week, phase 3 multicenter, double-blind, randomized, placebo-controlled study demonstrated the efficacy and safety of dornase alfa in patients in clinically stable condition aged older than 5 years with FVCs values of 40% or greater of predicted.[10] Inhalation of dornase alfa by these CF patients reduced the risk of pulmonary exacerbations (respiratory symptoms requiring parenteral antibiotics) and improved both [FEV.sub.1] and FVC, compared with placebo controls.

A multicenter, randomized, placebo-controlled study was conducted to determine the safety of short-term administration of dornase alfa in 70 patients with FVC values less than 40% of predicted.[11] Patients in this study were treated for 2 weeks with either 2.5 mg dornase alfa or placebo, inhaled twice daily. Pulmonary function improved in both groups of patients over the 2-week period but was not significantly better in patients exposed to dornase alfa. Although there had been concern that mobilization of secretions could be hazardous in patients with advanced lung disease, administration of dornase alfa did not appear to increase the major complications of CF in this study. In a 6-month, open-label follow-up of the same patients,[11] all participants received 2.5 mg dornase alfa twice daily and showed a mean percent improvement from baseline in [FEV.sub.1] and FVC of 9.3% and 17.8% respectively.

The current study was undertaken to examine this improvement more rigorously in a larger population of CF patients with advanced lung disease and to extend the safety and efficacy findings.

MATERIALS AND METHODS

Study Design

Patients were receiving regular medical care as outlined in the published guidelines of the CF Foundation.[12] Patients continued to receive medications and treatments administered for CF such as antibiotics, bronchodilators, corticosteroids, and chest physiotherapy (CPT). During the study, patients received CPT at least twice a day.

Patients were randomly assigned to 1 of 2 treatment regimens mg 2.5 mg of dornase alfa once daily or placebo once daily for a period of 12 weeks.

Study Population

Patients were recruited from 65 CF Foundation care centers in the United States. To be eligible for study admission, the patients were required to have a history of CF documented by sweat sodium or chloride concentration of 60 mEq/L or greater or homozygosity for the [Delta]F508 marker. They were also required to have an FVC less than 40% of predicted for height, age, add gender (Knudson et al[13] standards) at the initial screening visit held within 7 days of randomization. A small number of study patients were identified as having pulmonary function outside of the protocol criteria; their inclusion was determined not to affect the study results. Study patients were also required to have been on a stable regimen of CPT, ie, performed at least twice a day, at the initial screening. Exclusion criteria included the following: previous use of dornase alfa; use of other investigational drugs 28 days prior to randomization; a qualitative change in antibiotic therapy within 14 days prior to randomization; and severe acute respiratory failure.

Assessments of Efficacy and Safety

The two primary efficacy assessments were the time from randomization to the occurrence of the first pulmonary exacerbation and the mean percent change in [FEV.sub.1] from baseline. The secondary efficacy assessments included mean percent change from baseline in FVC and dyspnea (as measured by a 100-mm visual analog scale),[14] cumulative days receiving parenteral IV, antibiotics, and cumulative days spent in the hospital. The safety of dornase alfa was compared across treatment groups by tabular displays of adverse events and mortality rates; no other laboratory data were collected. After randomization, the patients were evaluated on days 8, 15, 29, 57, and 85. Pulmonary function tests were performed at each visit according to standards established by the American Thoracic Society.[15]

Statistical Analysis

An intent-to-treat approach was used in the analysis and interpretation of the efficacy data. All statistical tests were two tailed. Initial comparability of the treatment groups with regard to demographic and baseline disease characteristics was assessed using two-way analysis of variance, and [x.sup.2] tests were used for categorical data (eg, gender).

In pulmonary function test analyses, a Student's t test was used to compare treatment groups with respect to the mean percent change in [FEV.sub.1] from baseline, defined for each patient as follows:

(mean [FEV.sub.1] during treatment - mean baseline [FEV.sub.1]) x 100%

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mean baseline [FEV.sub.1]

The baseline [FEV.sub.1] was taken as the mean of the measurements taken on day -3 and before dosing on day 1.

The number of days from randomization to first pulmonary exacerbation was used to generate Kaplan-Meier curves[16] for each treatment group. The Cox proportional-hazard model[17] was used to compare the treatment groups and to estimate the relative risk (and 95% to confidence interval [CI]).

In the evaluation of secondary end points, percent change from baseline for mean FVC and mean change from baseline in dyspnea score were analyzed in the same manner as [FEV.sub.1]. Descriptive comparisons of treatment groups for accumulated days receiving parenteral antibiotics and days in the hospital were performed.

RESULTS

A total of 320 CF patients with advanced lung disease were enrolled and randomized, representing approximately 44% of the potentially eligible CF population in the United States in 1993. One hundred fifty-eight patients were randomized to dornase alfa and 162 to placebo. Of the patients randomized, 280 (88%) completed the study. A total of 40 patients did not complete the study; 5 patients discontinued treatment due to an adverse event or intercurrent illness; 10 withdrew consent; I did not comply with the treatment protocol; 15 died during the study period; 2 were unavailable for follow-up; and 7 stopped treatment before a medical procedure, ie, lung transplantation.

The dornase alfa and placebo groups were comparable (Table 1) with respect to age, ethnicity, height, and weight. A moderately greater number of male subjects than female subjects was noted in the dornase alfa group (p=0.07). However, the percent of predicted [FEV.sub.1] and FVC measurements was significantly lower in the dornase alfa group at baseline (p[less than or equal to]0.05). Assessments using analysis of variance showed no interactions between the gender imbalance and observed treatment effects, ie, pulmonary function tests or the incidence of pulmonary exacerbations. Since the primary pulmonary function test end point, ie, percent change from baseline in [FEV.sub.1], was measured in liters, not by the change in percent of predicted, the significant difference between the treatment groups at baseline in percent of predicted [FEV.sub.1] and FVC did not affect the primary outcome measures.

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Efficacy Outcomes/Results

Administration of dornase alfa significantly improved [FEV.sub.1], (Table 2, Fig 1). The mean percent change in [FEV.sub.1] in the dornase alfa group improved by 9.4% (96% CI, 6.81 to 11.96) compared with a 2.1% (CI, 0.07 to 4.18) improvement in the placebo group. Two patients in the dornase alfa group did not provide pulmonary function measurements after baseline randomization, they were excluded from the analyses of pulmonary function.

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Administration of dornase alfa significantly improved FVC compared with placebo (Table 2). Mean percent improvement in FVC in the dornase alfa group was 12.4 [+ or -] 18.6% (CI, 9.46 to 15.33) compared with a 7.3 [+ or -] 16.5% (CI, 4.71 to 9.84) improvement in the placebo group (p<0.01). Although the CIs for mean percent change in FVC for the treatment groups overlap, the t test of no difference in means rejected the null hypothesis. This was because the variance for the difference in means was smaller than the sum of the variances of the group means.

There were no statistically significant differences in the risks of developing pulmonary exacerbations between the placebo and dornase alfa groups. The age-adjusted relative risk of one or more such events occurring over the study period in dornase alfa-treated patients, compared with the placebo group, was 0.925 (CI, 0.69 to 1.21; p=0.52). Based on initial calculations for power, a sample size of 500 patients was estimated to provide 75% power to detect a reduction in risk for developing a pulmonary exacerbation. The adjusted power for a recruited sample of 320 patients was 40%.

No difference was observed between the treatment groups math respect to the mean dyspnea scores. Both groups showed improvement in dyspnea scores throughout the study. No statistical difference existed between the two treatment groups for either the number of days spent receiving IV antibiotics or the number of days spent hospitalized.

Safety Results

The mean duration of drug therapy among the NO patients who completed,the study was 83 days for both the dornase alfa and placebo groups. Early termination of treatment with the study drug was recorded for 20 patients in each treatment arm.

Three patients received inconsistent drug kits. All three patients were randomized to placebo; however, they later received dornase alfa. In a conservative analysis of safety, the intent-to-treat principle was not followed; the patients were considered according to exposure to dornase alfa. This resulted in 159 placebo-treated patients and 161 dornase alfa-treated patients.

Adverse events were reported frequently (94%) with no overall difference between study groups. The most commonly reported adverse events involved the respiratory system. CF-related adverse events such as hemoptysis and chest pain occurred with similar frequency in both groups, as did dyspnea (60% in placebo-treated patients and 59% in dornase alfa recipients). Adverse events that were not considered serious, and that occurred more frequently ([greater than or equal to] 3%) in the dornase alfa recipients than in the placebo group, included fever, decrease in FVC ([greater than or equal to]10% of predicted), pharyngitis, rhinitis, voice alteration, and dyspepsia (Table 3).

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Fever was noted in both placebo-treated patients (28%) and dornase alfa-treated patients (32%), but it did not appear to be associated with a decline in pulmonary function and was listed as an adverse event for equal numbers of patients from both groups, who later died (4 in placebo group, 4 in dornase alfa group). Improved pulmonary function occurred despite fever in dornase alfa-treated patients. There was no tendency toward an increase in rash, laryngitis, or conjunctivitis in the dornase alfa group.

One or more serious adverse events were observed in 52% of the placebo-treated patients and 51% of the dornase alfa-treated patients. Of these events, only dyspnea (labeled serious) occurred at a frequency of 3% or greater in dornase alfa-treated patients (17.4%) compared with the placebo-treated group (11.9%) The 12-week mean percent change from baseline in [FEV.sub.1] for dornase alfa-treated patients who experienced dyspnea as a serious adverse event was +3.7%.

Mobilization of secretions in patients with a documented negative outcome was one of the safety concerns of this study. The analysis undertaken in this study was based on the assumption that excessive mobilization of secretions would be reported by the patient as an adverse event if it was troublesome. Sputum adverse events were grouped into three categories: change in sputum (defined as change in consistency or color), increase in sputum, and decrease in sputum ("more congested, unable to bring up sputum"). It was assumed that inability to remove these mobilized secretions would result in worsening of airway obstruction and a measurable decline in pulmonary function. A greater than 20% decline was considered to be significant for an individual, since that was greater than the inherent variability, of the measurement in these patients (15%).

Sputum-related adverse events, regardless of severity, occurred uniformly across age, gender, and treatment. Baseline pulmonary function was predictive of such events in both treatment groups, ie, the lower the pulmonary function the more likely the occurrence of a severe sputum adverse event, regardless of study treatment. Eighteen dornase alfa-treated patients and patients receiving placebo experienced severe sputum adverse events.

During the study period, there were six deaths in the placebo group and nine deaths in the dornase alfa group. Baseline FVC values for all patients who died were similar, ranging from 8.4 to 25.3% of predicted in the 6 placebo recipients and from 10.4 to 24.3% of predicted in the 9 dornase alfa-treated patients. In neither group was there a precipitous decline in pulmonary function following entry into the trial nor an accelerated occurrence of pulmonary exacerbations. Adverse-event profiles in patients from both treatment groups who died were similar. Changes in sputum were distributed equally in both dornase alfa-treated patients and placebo recipients who died. In the 15 patients who died, investigators attributed the cause of death as possibly remotely related to dornase alfa in only 3 patients, 1 of whom turned out to have received placebo.

DISCUSSION

Administration of 2.5 mg dornase alfa once daily to CF patients math advanced lung disease (FVC <49% of predicted) for 12 weeks significantly improved both [FEV.sub.1] (p<0.001) and FVC (p<0.01), compared with placebo, and proved to be safe and generally well tolerated.

The significant improvement in pulmonary function in the dornase alfa-treated patients is an important finding given that relentless decline is expected in this very sick group of patients. Patients with a mean baseline [FEV.sub.1] of 21% of predicted have an expected survival of approximately 50% at 1 year, according to the data of Kerem et al.[2] Lung or heart-lung transplantation may require a long waiting period. At the University of Pittsburgh, CF patients awaiting transplant had an overall mortality of 37%.[4] By reducing the rate of pulmonary function decline, dornase alfa may allow prolonged survival and thus enhance the opportunities for a successful outcome.

The frequency of pulmonary exacerbations requiring parenteral antibiotics was not significantly reduced in the dornase alfa-treated patients compared with placebo recipients. Although a trend toward reduction in overall hospitalization was observed in the dornase alfa group, no significant difference was seen. The lack of a decrease in frequency of pulmonary exacerbations in the dornase alfa-treated patients in this study stands in contrast to findings of the phase 3 study of CF patients with baseline FVC values of 40% or great of predicted,[10] in which significant reductions in rate of pulmonary exacerbations were demonstrated. Antibiotic intervention, whether intermittent or continuous, is likely to be a part of the routine treatment of patients with advanced lung disease; pulmonary exacerbations are thus more difficult to define as discrete events and are likely to be less responsive to the tested intervention.

This study demonstrates that dornase alfa is not only effective but also safe in CF patients with advanced lung disease. Evaluation of the impact of dornase alfa on the complications of advanced CF lung disease is made difficult by the relative severity of disease in the two treatment groups. The patients assigned to dornase alfa had more advanced disease than the placebo recipients, with a significantly lower [FEV.sub.1] and FVC at baseline (p[less than or equal to]0.05). There was a correlation between increased incidence of adverse events and severity of disease that was independent of treatment effect.

In the evaluation of patients' ability to handle excessive secretions, sputum change was more frequently reported in the dornase alfa-treated patients (Table 4). This was not an unexpected finding given that the therapeutic purpose of the drug is to alter the characteristics of CF sputum. Further analysis showed, however, that when a sputum adverse event was examined in the context of significant pulmonary function decline (ie, >20%), placebo recipients experienced more of these events than did dornase alfa-treated patients (14% vs 11%, respectively). Regardless of treatment assignment, the frequency of such events appeared to be correlated with the severity of lung disease at baseline.

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Fifteen patients died during the study period. Although more deaths occurred in patients receiving dornase alfa than in the placebo group (nine vs six, respectively), the frequency of this outcome is too low to draw any conclusions as to trends. The pulmonary function values for all patients who died were uniformly low and did not change after initiation of therapy.

The adverse-event profile was consistent with earlier studies of dornase alfa in CF patients.[10] There appeared to be an increased frequency of pharyngitis and voice alteration in the dornase alfa group but no tendency toward an increase in hemoptysis or chest pain. Although fever and dyspnea appeared more frequently in the dornase alfa-treated patients, pulmonary function improved in actively treated patients. Examination of individual patient patterns with respect to fever, dyspnea, sputum change, and decreased FVC showed no trend toward clustering of these events in the dornase alfa group (Table 5). The overall frequency of these adverse events did not increase with prolonged exposure to dornase alfa.

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In conclusion, this study examined the efficacy and safety of dornase alfa in 320 CF patients with advanced lung disease. Pulmonary function, as measured by [FEV.sub.1] and FVC, improved significantly in the dornase alfa-treated patients, but the study was underpowered to examine the effect of dornase alfa on pulmonary exacerbations. Dornase alfa was found to be safe and well tolerated over the 12-week study period.

REFERENCES

[1] Patient Registry 1993 Annual Data Report. Bethesda, Md; Cystic Fibrosis Foundation; 1994 [2] Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326:1187-91 [3] Hodson ME, Madden BP, Steven MH, et al. Noninvasive mechanical ventilation for cystic fibrosis patients: a potential bridge to transplantation. Eur Respir J 1991; 4:524-27 [4] Bauldoff GS, Nunley DR, Manzetti JD, et al. Predictors of survival in cystic fibrosis before and after lung transplantation. Am J Respir Crit Care Med 1995; 151:A81 [5] Shak S, Capon DJ, Hellmiss R, et al. Recombinant human DNase reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 1990; 87:9188-92 [6] Rubin BK, Ramirez OE, Baharav AL, et al. The physical and transport properties of CF sputum after treatment with rhDNase [abstract]. Pediatr Pulmonol 1993; 9(suppl):A251 [7] Tomkiewicz RP, Shak S, King M. Effects of rhDNase on cystic fibrosis sputum viscoelasticity in vitro [abstract]. Pediatr Pulmonol 1993; 9(suppl):A251 [8] Zahm JM, Girod de Bentzmann S, Deneuville E, et al. Dose-dependent effect of recombinant human DNase on the transport properties of cystic fibrosis respiratory mucus [abstract]. Am Rev Respir Dis 1994; 149:A671 [9] Shah PL, Ingham S, Marriott C, et al. The in vitro effects of two novel drugs on the rheology of cystic fibrosis and bronchiectasis sputum. Eur Respir J 1994; 7(suppl 18):12S [10] Fuchs HJ, Borowitz DS, Christiansen DH, et al. 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; 331:637-42 [11] Shah PI, Bush A, Canny GJ, et al. Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by 6 months open-label treatment. Eur Respir J 1995; 8:954-58 [12] The Cystic Fibrosis Foundation Center Committee and Guidelines Subcommittee. The Cystic Fibrosis Foundation guidelines for patient services, evaluation, add monitoring in cystic fibrosis centers. Am J Dis Child 1990; 144:1311-12 [13] Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725-34 [14] Gift AG. Validation of a vertical visual analogue scale as a measure of clinical dyspnea. Rehabil Nurs 1989; 14:323-25 [15] American Thoracic Society. Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987; 136:1285-98 [16] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81 [17] Cox DR. Regression models and life tables. J R Stat Soc (B) 1972; 34:187-220

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