A 2 × 2 factorial, randomised, open-label trial to determine the clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care over 52 weeks in adults with bronchiectasis: a protocol for the CLEAR clinical trial.

BACKGROUND: Current guidelines for the management of bronchiectasis (BE) highlight the lack of evidence to recommend mucoactive agents, such as hypertonic saline (HTS) and carbocisteine, to aid sputum removal as part of standard care. We hypothesise that mucoactive agents (HTS or carbocisteine, or a combination) are effective in reducing exacerbations over a 52-week period, compared to usual care. METHODS: This is a 52-week, 2 × 2 factorial, randomized, open-label trial to determine the clinical effectiveness and cost effectiveness of HTS 6% and carbocisteine for airway clearance versus usual care - the Clinical and cost-effectiveness of hypertonic saline (HTS 6%) and carbocisteine for airway clearance versus usual care (CLEAR) trial. Patients will be randomised to (1) standard care and twice-daily nebulised HTS (6%), (2) standard care and carbocisteine (750 mg three times per day until visit 3, reducing to 750 mg twice per day), (3) standard care and combination of twice-daily nebulised HTS and carbocisteine, or (4) standard care. The primary outcome is the mean number of exacerbations over 52 weeks. Key inclusion criteria are as follows: adults with a diagnosis of BE on computed tomography, BE as the primary respiratory diagnosis, and two or more pulmonary exacerbations in the last year requiring antibiotics and production of daily sputum. DISCUSSION: This trial's pragmatic research design avoids the significant costs associated with double-blind trials whilst optimising rigour in other areas of trial delivery. The CLEAR trial will provide evidence as to whether HTS, carbocisteine or both are effective and cost effective for patients with BE. TRIAL REGISTRATION: EudraCT number: 2017-000664-14 (first entered in the database on 20 October 2017). ISRCTN.com, ISRCTN89040295. Registered on 6 July/2018. Funder: National Institute for Health Research, Health Technology Assessment Programme (15/100/01). SPONSOR: Belfast Health and Social Care Trust. Ethics Reference Number: 17/NE/0339. Protocol version: v3.0 Final_14052018.

Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial.

BACKGROUND: Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients. METHODS/DESIGN: The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis. DISCUSSION: The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients. TRIAL REGISTRATION: NCT02159196, registered on 6 June 2014.

A comprehensive evaluation of rationality of cough and cold medicines available in Indian market.

To analyse various cough and cold formulations available in the Indian market and to study their pharmacological rationale and cost effectiveness, a cross-sectional, observational study was carried out for evaluation of the drugs listed in Current Index of Medical Specialities (CIMS) India, September 2010.The formulations were assessed for their total number, type of dosage form, number of constituents in each formulation, their pharmacological group and rationality. The total daily cost and its association with type of dosage form was analysed. Out of a total 1297 preparations evaluated, 94% were fixed dose combination. The mean number of constituents was 3.20 +/- 1.03. Liquid oral formulations were largest in number (64.4%). The formulations contained various antitussives (30.30%), expectorants (33.92%), antihistamines (71.09%), mucolytics (35.62%), decongestants (56.28%), bronchodilators (16.81%) and analgesics/antipyretics (31.30%). None of the preparation was listed in the Model list of Essential Medicines, WHO (March 2011) under section 25 of "Medicines acting on the respiratory tract". Only 2% of the preparations had pharmacological rationale for their use in cough and common cold; 9.6% were containing more than one ingredient of the same pharmacological group and 6.85% were containing both antitussive and expectorant having opposing action. Highest number of preparations (36.85%) was having cost of therapy of Rs 6-10 per day. Liquid oral dosage forms had significantly higher cost than solid dosage form (p < 0.0001) and topical nasal dosage forms had significantly higher cost than liquid (p < 0.03) and solid (p < 0.001) dosage forms. It is conducted that various cough and cold medicines available in Indian market lacked therapeutic rationale for their use, leading to wasteful expenditure.

Emerging drugs for bronchiectasis.

INTRODUCTION: The global burden of disease due to bronchiectasis is high, disproportionately impacting developing countries and disadvantaged populations. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterized by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Although many therapies have been tested that address each of these three components, as well as the diseases that both cause and result from bronchiectasis, there have been few randomized, placebo-controlled trials. AREAS COVERED: In this review, current knowledge of the clinical features, pathophysiology and epidemiology of bronchiectasis among both adults and children is summarized. We discuss the quality and extent of evidence supporting current treatment strategies, focusing on therapies for which the strongest evidence of efficacy exists. We then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis. EXPERT OPINION: Significant advances in the prevention and treatment of bronchiectasis will require substantially improved understanding of the pathogenesis of this orphan disease. A concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of bronchiectasis, in its many forms, could lead to substantial improvements in outcomes.

Analysis of the impact of removing mucolytics and expectorants from the list of reimbursable drugs on prescription rates: a time-series analysis for France 1998-2010.

OBJECTIVES: After a comprehensive review of the therapeutic advantage of all drugs reimbursed by the French Public Health Insurance, a large number of drugs were removed from the list of reimbursable drugs, among them mucolytics and expectorants (ATC Class R05C) in March 2006. The aim of this study is to evaluate the impact of this measure on the mucolytic and expectorant class, on the prescription of possible substitute drugs (other bronchodilators, antitussives and antibacterials) and on the costs for Public Health Insurance. METHODS: Prescription data were taken from a 850 French physicians sample surveyed by the IMS-Health Permanent Survey on Medical Prescription from 1998 to 2010. We performed linear segmented regression to determine changes in the level and slope of the prescription rates and to estimate the budget impact. RESULTS: Following their removal from the list of reimbursable drugs, the prescription rate for mucolytics declined significantly and we recorded an increase in the prescription rates for antitussives and bronchodilators. The medically unexpected increase in antitussives can be viewed as a negative side-effect of the policy. Four years after the reform, total savings for Public Health Insurance were estimated at EUR 32.1 million. CONCLUSIONS: Further removals from the list of reimbursable drugs should take into account the possibility of negative impact on public health and potential savings.

Characteristics of chronic obstructive pulmonary disease in Spain from a gender perspective.

BACKGROUND: The objective of this study was to analyze the clinical and management characteristics of chronic obstructive pulmonary disease (COPD) in men and women, to determine possible gender-associated differences between the two groups of patients. METHODS: An observational and descriptive epidemiological study (EPIDEPOC study). The study included patients with stable COPD and aged >or= 40 years, evaluated in primary care. Data were collected relating to sociodemographic variables, clinical characteristics, quality of life (SF-12), severity of disease and treatment. The results obtained in men and women were compared. RESULTS: A total of 10,711 patients (75.6% males and 24.4% females) were evaluated. Significant differences were found between males and females in relation to the following parameters: age (67.4 +/- 9.2 years in men vs 66.1 +/- 10.8 in women, p < 0.05), smoking (91.9% of the men were smokers or ex-smokers vs 30% of the women), comorbidity (the frequency of hypertension, diabetes, anxiety and depression was greater in women, while ischemic heart disease was more common in men), mental component of quality of life (49.4 +/- 10.3 in men vs 44.6 +/- 11.9 in women, p < 0.05) and severity of disease (56.5 +/- 13.3% in men vs 60.7 +/- 3.2 in women, p < 0.05). As regards treatment, the percentage use of long-acting b2-adrenergic agonists, anticholinergic agents, theophyllines and mucolytic agents was significant greater in men. The total annual cost of COPD was greater in males than in females (1989.20 +/- 2364.47 euro vs 1724.53 +/- 2106.90, p < 0.05). CONCLUSION: The women with COPD evaluated in this study were younger, smoked less and have more comorbidity, a poorer quality of life, and lesser disease severity than men with COPD. However, they generated a lesser total annual cost of COPD than men.

Stability of acetylcysteine solution repackaged in oral syringes and associated cost savings.

PURPOSE: The physical and chemical stability of repackaged acetylcysteine 600 mg/3 mL solution in oral syringes stored under refrigeration or at room temperature was studied for six months; a cost analysis was also conducted. METHODS: Acetylcysteine 20% solution for inhalation was repackaged undiluted as 600 mg/3 mL in capped oral syringes and stored either under refrigeration or at room temperature exposed to fluorescent light. Four samples for each storage condition were analyzed in duplicate on day zero, weekly for the first month, and then every two weeks during months 2-6. Physical stability was assessed, and the chemical stability of acetylcysteine was evaluated by high-performance liquid chromatography. RESULTS: Acetylcysteine solution in syringes was physically stable during the entire six-month study period. When stored at room temperature, acetylcysteine retained 99% of the original concentration at three months and 95% at six months after preparation of the syringes. Loss of acetylcysteine was <2% at six months when stored under refrigeration. Packaging acetylcysteine in batches of 100 syringes instead of preparing individual syringes reduced wastage to zero syringes, saving an estimated $247 in drug costs. The estimated pharmacy time savings was 30 hours ($702). CONCLUSION: Acetylcysteine 20% solution repackaged as 600 mg/3 mL in oral syringes is both physically and chemically stable under refrigeration or at room temperature under normal fluorescent lighting for six months. The total loss of acetylcysteine was approximately 5% at room temperature under fluorescent lighting and <2% under refrigeration. Repackaging the solution in syringes in bulk rather than in single doses demonstrated a measurable cost saving.

Air pollution and respiratory drug sales in the City of Le Havre, France, 1993-1996.

The aim of this study is to evaluate ambulatory respiratory drug sales data as health indicators for the short-term effects of ambient air pollution in the city of Le Havre. Daily respiratory drug sales data were crossed with daily ambient air concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), and black smoke (BS) using an autoregressive Poisson regression model adjusting for time trends, seasonal variations, influenza epidemics, and weather. Relative risks (RR) were expressed for an increase of two standard deviations above the mean of each pollutant. Respiratory drug sales were associated with most pollutants studied with lags varying from 1 to 9 days. For daily mean concentrations of BS, RR = 1.037 (95% confidence interval (CI) 1.009-1.066) for lag 1 and RR = 1.052 (95% CI 1.023-1.081) for lag 8. For daily mean concentrations of N02, RR = 1.033 (95% CI 1.001-1.066) for lag 1 and RR = 1.046 (95% CI 1.014-1.079) for lag 8. RR observed with a daily 1 h maximum of SO2 were RR= 1.027 (95% CI 1.004-1.051) for lag 3 and RR= 1.032 (95% CI 1.009-1.056) for lag 9. Our study concludes that ambulatory respiratory drug sales data could be useful for epidemiological surveillance of air pollutant health effects.

Dornase alpha and survival of patients with cystic fibrosis.

Dornase alpha can offer substantial clinical benefits to cystic fibrosis patients, but its long-term impact is as yet unknown. This article attempts to model the impact of continuous dornase alpha use on patient survival and its cost implications for the health-care provider.

rhDNase therapy for the treatment of cystic fibrosis patients with mild to moderate lung disease.

OBJECTIVE: To assess the cost-effectiveness of rhDNase (Pulmozyme(R)) for patients with cystic fibrosis (CF) aged 5 years or more, with mild to moderate lung disease. The review addresses four questions: a) does rhDNase therapy work in the short term?, b) does rhDNase therapy work more effectively in certain groups of patients?, c) does rhDNase therapy work in the long term? and d) what is the cost-effectiveness of rhDNase therapy? METHODS: A structured rapid review with modelling and cost-effectiveness calculations. Electronic searches were carried out to identify randomised controlled trials (RCTs), systematic reviews, epidemiological and economic information. Databases searched included Cochrane Library, Medline, Healthstar, Embase, PreMedline and NHS Economic Evaluation Database (NHS EED). Exclusion criteria were trials of very short duration (14 days or less) and those which looked at CF patients with severe lung disease. Open label extensions providing information on longer term outcomes were included. RESULTS: Nine published RCTs were identified, although only one met the inclusion criteria. This large RCT was of good methodological quality, and shows that treatment with rhDNase over a 6-month period improves lung function, and decreases the risk of respiratory exacerbations. Expert opinion suggests that there are identifiable subgroups of patients showing improvement, little or no change, and deterioration after treatment with rhDNase. However, the best supporting evidence for this comes from a retrospective case series, showing that response to rhDNase is highly variable, and that early improvement was a good predictive marker for long-term benefit. Evidence for the long-term impact of rhDNase is not yet available from any RCTs. A simplified model was therefore developed to estimate the decline in lung function for patients treated with rhDNase, compared with those who were not treated. From this model it appears that the continued use of rhDNase over the lifetime of a CF patient might extend their life expectancy by 2 years. If treatment is limited to a subgroup of patients with moderate lung disease who respond to treatment, the continued use of rhDNase might extend their life expectancy by 7 years. Using the model, the discounted cost per life year gained for all patients is estimated at approximately pound52 500, with a range of between approximately pound25 000-57 000 from sensitivity analysis. For the subgroup of patients, the discounted cost per life year gained is estimated at approximately pound16 000, with a range of between approximately pound18 000-36 600 from sensitivity analysis. CONCLUSIONS: Although there is short-term evidence that the use of rhDNase improves lung function and decreases the risk of respiratory exacerbations, at present there is no evidence from RCTs to indicate whether this effect is sustained over a longer time period, or whether rhDNase is associated with a reduction in mortality. RCTs to date have been of insufficient duration to answer important questions about long term outcomes, particularly the effects of rhDNase on lung function, respiratory exacerbations and mortality. Further long-term research is needed, with economic analysis to evaluate the long term cost-effectiveness of rhDNase. Research is also needed to identify, in advance, which patients would benefit most from this expensive treatment.

Cost-effective pharmacotherapy for allergic rhinitis.

This article provides guidelines for pharmacotherapy to maximize symptom relief from allergic rhinitis. Consideration of frequency, severity, and site of symptoms is important in directing pharmacotherapy efficacy and maximizing cost-effectiveness. The agents available include antihistamines, decongestants, steroids, mast cell stabilizers, anticholinergic agents, and mucolytics. Appropriate indications for each and combinations of various agents are discussed within the context of drug efficacy, side effects, affordability, and ease of compliance. The direct and indirect costs of allergic rhinitis are not well delineated but are explored to put the costs of therapy in perspective.

The German experience in reference pricing.

Price regulation schemes function both as a means for public authorities to contain costs, and as an economic tool to support the national pharmaceutical industry. This twofold contradictory aim of public intervention in pharmaceutical demand and supply makes such pricing schemes difficult to apply. This article concerns the reference price scheme which concerns setting a price cap for each active ingredient, or group of active ingredients considered equivalent according to some feature (e.g. therapeutic effects and chemical structure). In 1989, the reference price scheme for reimbursable drugs was introduced in Germany to reduce pharmaceutical expenditure, which had been steadily increasing in the past. The study investigates the economic effects of introducing reference prices in Germany in order to assess whether this system has been effective in containing public pharmaceutical expenditure. We conclude that the reference price scheme is an effective tool for price control, but cost containment requires further measures.

Dornase alfa. A review of pharmacoeconomic and quality-of-life aspects of its use in cystic fibrosis.

Cystic fibrosis (CF) is a fatal hereditary disease; patients with CF have an average lifespan of 30 years. By cleaving neutrophil-derived DNA, dornase alfa (recombinant human deoxyribonuclease I) decreases the adhesiveness and visco-elasticity of sputum in the infected lungs of patients with CF. As a result, respiratory function is improved in patients with all degrees of disease severity, and the relative risk of pulmonary exacerbations is reduced in patients with mild to moderate disease. Resource utilisation (days spent in hospital or receiving parenteral antibiotics) in patients with mild to moderate disease is also reduced by dornase alfa, as evidenced by a placebo-controlled trial in > 900 patients. Cost savings generated by these reductions in resource use during 24 weeks of dornase alfa therapy offset about 17 to 37.5% of the acquisition cost of the drug, depending on local cost data for various countries. Reductions in resource utilisation with dornase alfa have not been observed in patients with severe disease. Available cost-effectiveness and cost-utility analyses are not fully published. One analysis estimated that the incremental cost of avoiding one hospitalisation was about $Can 15,000 relative to standard therapy after 1 year of treatment. Informal analysis in the UK suggests a cost per quality-adjusted life-year of 25,000 Pounds for dornase alfa. Some quality-of-life (QOL) domains (mainly cough frequency and chest congestion) have shown modest improvement in patients treated with dornase alfa, mainly those with mild CF. Persuasive evidence of QOL benefit is lacking in those with more severe disease. Identifying patients most likely to benefit from dornase alfa therapy is essential to maximise clinical and cost benefits. The lack of a demonstrated reduction in resource utilisation in patients with severe CF makes its use more difficult to justify economically in this group than in those with less severe disease. However, in the absence of other treatments for this group, economic considerations must be weighed against clinical benefits. In conclusion, the acquisition cost of dornase alfa is partially offset by savings gained by reducing resource utilisation in patients with mild to moderate CF, and the drug appears to improve quality of life in some patients, mostly those with less severe disease. However, in the absence of guidance from definitive cost-effectiveness analyses, individual healthcare providers must make their own decisions about how best to provide dornase alfa to patients with CF in a rational and cost-justifiable manner.

The role of dornase alfa in the treatment of cystic fibrosis.

OBJECTIVE: To review the current utility and proper role of dornase alfa (recombinant human DNase or rhDNase), which has been approved for use in cystic fibrosis. Several aspects related to these issues are addressed including the drug's mechanism of action, administration and dosing, and clinical safety and efficacy. We also critically examine the agent's role in the treatment of cysti fibrosis and consider the controversies involved with its use. DATA SOURCE: A MEDLINE search was conducted to identify pertinent literature, including review articles and clinical trials. STUDY SELECTION: Studies examining the efficacy and safety of dornase alfa in patients with cystic fibrosis. DATA EXTRACTION: Results from published, prospective, randomized trials are presented and critiqued. DATA SYNTHESIS: Production of viscous respiratory secretion is a hallmark phenomenon of cystic fibrosis, leading to a variety of symptoms. Dornase alfa targets this symptom and decreases the viscosity of these secretions. Clinical trials have indicated a small but statistically significant improvement in forced expiratory volume in 1 second and forced vital capacity. Enhancement in a patient's dyspnea and quality of life has varied between the trials, with few of the studies noting no statistically significant improvement. Adverse reactions are minimal and did not result in any patient withdrawals from the trials. A positive impact on infection rates, length of hospitalization, and need for intravenous antibiotic therapy was noted in one trial. However, reports of similar results have not yet been published, and thus the clinical significance or impact of this phenomenon is not fully understood. Moreover, results of more long-term use and in patients whose conditions are less stable have yet to undergo the scrutiny of peer/editorial review. Administration of the drug, which must be maintained continuously, is relatively expensive. CONCLUSIONS: Dornase alfa appears to produce small but sustained improvements in lung function in patients with cystic fibrosis. It may also slow the progression of pulmonary disease. Infection rates appear to be reduced, which may well have important long-term consequences. However, evidence to date has not clarified the most appropriate use of dornase alfa in the treatment of cystic fibrosis. Whether quality of life is affected in a meaningful and measurable way is yet to be clarified. A trial of the drug in patients with cystic fibrosis who have obvious lung disease is reasonable, but continued treatment should be based on clear clinical response. Therefore, questions about the drug's exact role in the overall management of cystic fibrosis remain to be answered. Although benefits received may not prove to be cost-effective, long-term effects on disease progression may well justify use of this agent.

Dornase alfa: a new option in the management of cystic fibrosis.

Recombinant human DNase I, or dornase alfa, is the first new therapy developed specifically for cystic fibrosis in almost 30 years. It selectively digests extracellular DNA and reduces the viscosity of purulent sputum. In clinical trials dornase alfa modestly improved pulmonary function, slightly decreasing the number of respiratory exacerbations requiring parenteral antibiotics compared with placebo. Phase III studies suggest that patients receiving dornase alfa also spend slightly fewer days in the hospital than those treated with placebo. The aerosolized preparation is safe and generally well tolerated. Voice alteration and sore throat are the most commonly reported adverse effects. Further research is necessary to determine the optimum time to initiate therapy and to evaluate the agent's pharmacoeconomic impact on the treatment of cystic fibrosis. Aerosolized dornase alfa should always be given in conjunction with standard cystic fibrosis therapies including antibiotics, chest physiotherapy, and pancreatic enzyme supplementation.

A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis.

Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials.

[Socioeconomic evaluation of the effect of rhDNase on the cost of treating infections of the respiratory tract in patients with cystic fibrosis]. / Sozioökonomische Evaluation des Einflusses von rhDNase auf die Kosten der Behandlung von Infektionen der Atemwege bei Patienten mit zystischer Fibrose.

BACKGROUND: Data from a multicenter, placebo-controlled, double-blind, parallel clinical trial on the use of aerosolized recombinant human DNase (rhDNase), known as Pulmozyme produced by Genentech, about the treating of respiratory-tract infections among patients with cystic fibrosis (CF), has been used to evaluate possible economic effects by identifying the direct medical costs. To calculate the cost an intention-to-treat approach has been used. PATIENTS AND METHOD: The patients were randomly placed in one of three treatment groups. The first group was treated with a 2.5 mg dose of rhDNase and one dose of placebo daily, the second group with placebo twice a day. The third patient group (treated with a 2.5 mg dose of rhDNase twice a day) was not included in this study. RESULTS: The main measurements of resource utilization of services for treatment of respiratory-tract infections were the number of hospitalizations in the follow-up period of 24 weeks (0.41 rhDNase once daily, 0.56 placebo), the number of total days in hospital (4.9 rhDNase, 6.4 placebo), the number of total days of outpatient intravenous antibiotic therapy (2.9 rhDNase, 4.4 placebo), the number of total days of inpatient intravenous antibiotic therapy (4.8 rhDNase, 6.2 placebo), the number of total days of outpatient oral antibiotic therapy (23.5 rhDNase, 25.2 placebo) and the number of total days of inpatient oral antibiotic therapy (0.59 rhDNase, 0.55 placebo). From a health insurance perspective the total direct cost based on a weighted per diem for German CF-centres was 5,879 DM (rhDNase) vs 7,849 DM (placebo) per patient respectively. Costs of antibiotics were estimated using all available information on the consumption of antibiotic drugs revealing 2,954 DM per patient in the rhDNase-group and 4,213 DM in the placebo-group. The large cost differences remain also true in a sensitivity analysis introducing minima and maxima as key factors. CONCLUSION: As a result of this study we conclude that the use of rhDNase in treatment of respiratory-tract infections in patients with cystic fibrosis is cost saving and less burdened for the patients. However, all cost estimates do not include the cost of rhDNase itself, which are DM 9,094 for the period of follow-up.