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Vol.97 (2003) (SUPPLEMENT B), S35-540

Comparison of the efficacy of beclometasone dipropionate and fluticasone propionate suspensions for nebulization in adult patients with persistent asthma

C.TERZANOI,A. RICCI~,Y BURINSCHI~,K. NEKAM~ AND J. LAHOVSKY~

‘University La Sapienza, Rome, Italy; *Institute of Physiopulmonology, Chisinau, Moldova; aDepartment of Allergology and Clinical Immunology, Budapest, Hungary; 4Department of Allergology, Prague, Czech Republic

Abstract The use of nebulization for the administration of inhaled steroids plays an important role in asthma patients who are unable to use pressurized aerosol or dry-powder inhalers effectively Moreover; the type of nebulizer used may affect how much drug is delivered to the lungs. The objective of this multinational, multicentre, randomized, active- controlled, parallel-group study was to compare the efficacy and safety of nebulized corticosteroids in adult patients with chronic asthma, Following a l-week placebo run-in period, 205 patients, aged l8-65years, with moderate persistent asthma were randomized to one of two treatment groups for I 2 weelfluticasone propionate (FP) suspension for nebulization 2000 pg day’ b.i.d. (n= IO2), both administered by a jet nebulizeu: Comparable efficacy in controlling asthma was demonstrated by the two treatments at study end, as evident when evaluating various efficacy parameters (pulmonary function tests, asthma exacerbations and symptoms, and the use of rescue salbutamol).The primary efficacy endpoint was the variation in the pulmonary expiratory flow (PEF) at treatment end over the baseline visit. For the intent-to-treat population, in the BDP group mean PEF values increased statistically significantly from 5.2 f I .3 I s-I to 5.7 * I .6 I s-1, while in the FP group the increase was from 5.2 k I .2 I s-l to 5.8 + I .8 I s-l. Mean PEF values as per cent of predicted also increased in a statistically significant way from 7 I % to 77. I % in the BDP group, and from 70. I % to 76.9% in the FP group.The two treatments were equally well to1erated.A total of 23 and 32 patients in the BDP and FP groups, respectively, reported adverse events during the treatment period, and these were generally mild. In conclusion, the results of this study demonstrate that BDP 2400 I-18 day’ and FP 2000 pg day’, both suspensions for nebulization administered via a jet nebulizer; are equally effective, with an acceptable safety and tolerability profile, when used in adult patients with moderate persistent asthma.

0 2003 Elsevler Science Ltd

INTRODUCTION administered via a new jet nebulizer in adult patients Nebulization of inhaled corticosteroids plays an with moderate persistent asthma.The jet nebulizer was important role in the management of asthma patients used on the basis of a previous study in which both BDP who cannot use other delivery systems effectively. and FP were delivered via nebulization with a mean Several clinical trials have shown that both beclo- MMAD (mass mean aerodynamic diameter) of 2.6 + 0.2. metasone dipropionate (BDP) and fluticasone propionate (FP) are effective and well tolerated in the MATERIALS AND METHODS management of asthma. Moreover, studies comparing these corticosteroids when administered using a Male and female outpatients, aged 18-65 years, with a pressurized metered-dose inhaler (pMDI) have clinical diagnosis of moderate persistent asthma (as demonstrated equivalent clinical efficacy when used in defined by the National Heart, Lung and Blood children and adults with asthma of varying severity (2-7). Institute/World Health Organization), peak expiratory However, to date direct comparison of BDP and FP flow (PEF) between 60% and 80% of predicted normal suspensions for nebulization has not been reported.The value, a positive response to the reversibility test purpose of this study was to compare the efficacy and [defined as an increase of 15% in forced expiratory safety of BDP and FP suspensions for nebulization volume in I second (FEV,) measured 30 minutes after a S36 RESPRATORY MEDICINE bronchodilator dose of salbutamol spray given via an three measurements recorded on a diary card. Diurnal MDI at the screening and baseline visits], and study and nocturnal asthma symptoms, rated on an eight-point medication compliance of 85% during the placebo run-in scale (scores l-8) ranging from ‘poor’ to ‘excellent’, period were eligible to participate in the study. Patients evaluation of activity and sleep, and the use of short-acting with chronic obstructive pulmonary disease, a history or &-agonists were also assessed daily by patients and current evidence of heart failure and ischaemic heart recorded on a diary card.The institutional review board disease, myocardial infarction/percutaneous transluminal for each treatment centre approved the protocol, and coronary angioplasty/coronary artery bypass grafts within written informed consent was obtained from the patients. the previous 6 months, haemodynamic relevant rhythm disturbances, clinically significant or unstable concurrent Assessments diseases, or intolerance to the study drugs and/or their constituents, or who received oral or parenteral steroids The primary efficacy endpoint was the variation in the or investigational new drugs in the previous I2 weeks, PEF value assessed by the investigator at I2 weeks vs the were excluded from the randomization. baseline/randomization visit. Secondary efficacy variables were the number of exacerbations, FEV,, forced vital capacity (FVC), morning and evening PEFs, improvements Study design in asthma symptoms, and daily consumption of short- This was a I3-week, randomized, active-controlled study acting j&agonists. Safety parameters included physical undertaken in two parallel groups at I I centres. Following examination, vital signs (electrocardiograms (ECGs), a l-week placebo run-in period, patients who met study blood pressure, and heart rate), routine blood and urine entry criteria were assigned by randomization to one of laboratory tests, and frequency, nature and severity of the two treatment groups for a treatment period of adverse events. I2 weeks: BDP suspension for nebulization 2400 Kg day-’ b.i.d. (Clenil-A@, Chiesi Farmaceutici SpA, Italy), or FP Statistical analysis suspension for nebulization 2000 pg day’ b.i.d. (Flixotide Nebules@, Allen & Hanburys, U.K.). Both drugs were Sample size calculation was based on the criteria of administered using the Clenny Aerosol Nebulizer (Chiesi equivalent efficacy between the two treatments (9), Farmaceutici SpA, Italy), and all patients were instructed taking as clinically not relevant a difference between in its use. Long-acting &-agonists, cromolyn sodium, groups in PEF values of 10%. Considering that the mean nedocromil, methylxanthines, leukotriene modifiers, expected value of final PEF (per cent of predicted) was anticholinergics, antihistamines, and parenteral and oral 75, with a common standard deviation of I7 and with an corticosteroids were excluded. The use of short-acting a error of 0.05 (two-sided test), a total sample of 186 &-agonists, and of inhaled corticosteroids during the run- patents (93 per arm) will provide 85% power rejecting in phase, only at the same daily dosage used during the the null hypothesis in favour of the alternative one when previous 4 weeks, was permitted. Patients were assessed a real difference between treatments will exist. at various clinic visits during the study: on screening, at Within-treatment comparisons for the variation of the baseline/randomization visit, and at 4 and I2 weeks PEF value assessed by the investigator at week I2 vs post-randomization. baseline visit were analysed by the t test for paired Lung function measurements were conducted samples, and between-treatment comparisons by means according to the ERS guidelines (8) at the same hour of of the non-parametric Kruskal-Wallis test. the day, with a variation equal to +2 h compared with the When indicated, continuous secondary efficacy baseline visit. Spirometric lung function parameters were variables were analysed by the ANOVA (analysis of measured at each clinic visit. The use of short-acting B2- variance) model, and categorical variables were analysed agonists had to be withdrawn at least 8 hours before the comparing the two groups by the Chi-square test and, if tests.Three measurements were performed, and the best necessary, by the Fisher’s exact test. was reported.Asthma exacerbation was defined if one of A descriptive analysis was provided for all safety data, the following criteria occurred: worsening of asthma with absolute and relative frequencies demonstrated, symptoms, which required treatment with systemic together with the 95% confidence interval for each steroids; a reduction in the morning PEF to >30% below estimate. Changes from baseline of vital signs were the baseline value on 2 consecutive days; use of five analysed by the Student’s t test, while between-treatment inhalations of rescue medication on each of any differences were analysed by the Chi-square statistic 3 consecutive days since the previous visit. Morning and (Fisher’s exact test) and within-treatment differences by evening PEFs were measured daily by patients using the the McNemar’s test. Significance testing was two-tailed, Mini-Wright peak flow meter (Clement Clarke with cc error fixed at the 5% level. International, U.K.) at the same hour each day All randomized patients with baseline evaluation of (8 + I a.m., and 7 -+ I p.m. when possible) and the best of each symptom and who received at least one dose of the BDPVS FP SUSPENSIONS FOR NEBULIZATION VIA A NEBULIZER IN ADULTS

study medication were to be included in the ITT and the PP population of 182 patients (95 treated with population analysis. Missing data were replaced with the BDP and 87 with FP).Assessment of safety of the two LOCF (last observation carried forward) method, except treatments was based on 202 patients. Patient in the analysis of the number of exacerbations, days and demography and values for lung function parameters at nights without asthma symptoms, physical examination, baseline were comparable for the two groups in the and ECGs. randomized population (Table I).

RESULTS Evaluation of efficacy: PEF

Patient population Statistically significant increases in PEF measured by the Of the 222 patients screened for the study, 205 were investigator were reported over baseline in the ITT randomized: 103 to the BDP group, and IO2 to the FP population for both treatment arms at study end, with group.Three patients (one in the BDP group and two in mean values rising from 5.2 I s-1 to 5.7 I s-1 in the BDP the FP group) were excluded from the efficacy analysis group (P=O.O002), and from 5.2 I s-1 to 5.8 I s-1 in the FP sample due to protocol violations at selection, and 20 group (P=O.O002), and with no significant difference patients (7 in the BDP group and I3 in the FP group) found between the two groups (Figure I). Mean PEF were excluded from the PP analysis due to various values as per cent of predicted also increased in a reasons.The ITT population was therefore made up of statistically significant way from 7 I % to 77. I % in the BDP 202 patients (I 02 treated with BDP and IO0 with FP), group (P=O.OOO I), and from 70. I % to 76.9% in the FP

Baseline End of treatment Baseline End of treatment P = 0.0002 versus baseline P = 0.0002 VPJTUSbaseline NS baween treatments NS between treatmenrs

FIGURE I. Mean values for peak expiratory flow in the (a) intent-to-treat and (b) per protocol populations of adults with moderate persistent asthma at baseline and after I2 weeks of treatment with beclometasone diproplonate or fluticasone propionate suspensions for nebulization. S38 RESPIRATORYMEDICINE

1.0, o-9- 0-8 - 2 0.7 - :: 0.7 5 g '3 0.6- 5 0.6 z 0.5 - ; 0.5 ;L z 0.4- 2 0.4 2 0.3

FIGURE 2. Mean changes over baseline rn forced expiratory volume in I second and forced vital capacity in the intent-to-treat population of adults with moderate persistent asthma after I2 weele of treatment with beclometasone dipropionate or flutlcasone propionate suspensions for nebulization.

400 A 350 7 .s CL5E 350 z e 300 ,g 300 5 E 250 250

200 200 BLWAlllC 4 12 Baseline 4 12 Time (weeks) Time (weeks) P = 0.0001 “crsus baseline P = 0.0001 versus bnreiine XS between treaments NS behveerz freaments

FIGURE 3. Mean values for (a) morning and (b) evening peal< expiratory flow in the Intent-to-treat population of adults with moderate persistent asthma at baseline, and after 4 and I2 weeks of treatment wrth beclometasone dipropionate or fluticasone propionate suspensions for nebulization

group (P=O.O002) (NS between treatments). Similarly, in Evaluation of efficacy: Other measures the PP population mean PEF values rose statistically of pulmonary function significant from 5.3 I s-l to 5.7 I s-1 in the BDP group (WO.000 I), and from 5.2 I s-1 to 5.8 I s-1 in the FP group At study end, significant mean changes of 0.3 litres were (P=O.O002), with the between-group difference again reported over baseline for both treatment groups in the being non-significant (Figure I). Mean values as per cent ITT population for both FEV, and FVC, with no of predicted also increased statistically significantly from significant between-treatment difference being found for 70.9% to 77.6% in the BDP group (P

Evaluation of efficacy: Signs and reported one or more adverse events (Table 2). The symptoms and rescue medication number of adverse events reported was 30 (39.5%) and 46 (60.5%) in the BDP and FP groups, respectively, and In the ITT population, significant improvements in asthma these were generally mild (NS between treatments for symptoms over baseline were noted for both treatment both variables). In total, six patients reported adverse groups at the end of the study. The number of patients drug reactions: two (2%) in the BDP group, and four (4%) reporting symptoms scores defined as ‘excellent’ rose in the FP group, with two (25%) and six (75%) adverse from I6 (15.7%) at baseline to 54 (52.9%) at treatment drug reactions seen in the respective groups (NS end in the BDP group, and from I2 (I 2%) to 46 (46%) in between treatments for both parameters). Furthermore, the FP group, with the difference between the two only one patient (0.9%) in the BDP group discontinued groups being non-significant.When examining the means treatment due to treatment-related adverse events. of the symptoms scores sum, values increased Moreover, no significant difference was found between statistically significantly from 4.7 at baseline to 6.3 at the two treatments with regard to laboratory tests, and treatment end in the BDP group (Psteroid (3). Another study in 274 adults found that tolerated. During the treatment period, 23 (22.5%) treatment with 1500 ygdayr FP pMDl resulted in patients in the BDP group and 32 (32%) in the FP group significantly higher morning and evening PEF values and 840 RESPR4TORYMEDICINE fewer exacerbations than the same dose of BDP pMDl REFERENCES (4).Three studies have compared BDP with half the dose O’Callaghan C, Barry P. Delivering inhaled corticosteroids to of FP; no difference in clinical effect was found between patients. BMJ 1999; 8: 4 I @-4 I I. the two treatments in any of them. One compared BDP Dahl R, Lundback B, Malo JL, Mazza JA, et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. (400 pg day’) and FP (200 pg day-r), both given by pMDl Chest 1993; 104: 1352-f 358. with plastic spacer to 398 children with asthma (5). Boe J, Bakke P Rodolen T Skovlund E, GulsvikA. High-dose inhaled Another compared BDP (2000 ,ugday-1) and FP steroids in asthmatics: Moderate efficacy gain and suppression of (I 000 yg day-l) in I54 adults with severe asthma (6).The the hypothalamic-pituitary-adrenal (HPA) axis. Research Council third compared BDP (400 pg day’) and FP (200 pg day-r), of the Norwegian Thoracic Society. Eur Respir j 1994; 7: 2 I 79-2 184. both given by pMDl to 261 adult patients with mild to 4. Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of moderate asthma (7). fluticasone propionate with beclomethasone dipropionate in Based on these studies comparing BDP and FP moderate to severe asthma treated for one year. International delivered via pMDI, it is not possible to draw any firm Study Group. Thorax 1993; 48: 817-823. conclusion about the comparative potencies of BDP and 5. Gustafsson PTsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone Fl? Furthermore, comparisons between the effects of propionate 200 micrograms/day with inhaled beclomethasone BDP and FP delivered via nebulizer have not previously dipropionate 400 micrograms/day in mild and moderate asthma. been available. Therefore, ours is the first study that Arch Dis Child 1993; 69: 206-2 I I. compares, in asthmatic patients, the clinical effects of 6. Barnes NC, Marone G, Di Maria GUVisser S, Utama I, Payne SL. BDP and FP delivered via a jet nebulizer, adding to our A comparison of fluticasone propionate, I mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of two recently published studies: flunisolide 500 pg vs severe asthma. International Study Group. Eur Respir / 1993; 6: budesonide 500 pg, both administered twice-daily by jet 877-885. nebulizer for 4 weeks in I33 children (I 2), and BDP 7. Leblanc F: Mink S, KeistinenT Saarelainen PA, Ringdal N, Payne SL. 800 pg day’ b.i.d. or budesonide IO00 pg day’ b.i.d. A comparison of fluticasone propionate 200 micrograms/day with both administered by jet nebulizer in 127 children with beclomethasone dipropionate 400 micrograms/day in adult asthma. Allergy 1994; 49: 380-385. mild to moderate persistent asthma (I 3). Both studies a. European Respiratory Society. Standardized lung function testing. highlight the equivalent clinical responses and good Official statement of the European Respiratory Society. Eur Resp safety profiles of nebulized corticosteroids in children. J 1993;6: l-100. This study demonstrates that suspension for 9. Jones B, Jarvis P Lewis JA, Ebbutt AETrials to assess equivalence: nebulization forms of BDP 2400 pg day-’ and FP The importance of rigorous methods. EM] 1996; 3 13: 36-39. I 0. Barnes PJ. Inhaled glucocorticoids for asthma. N Eng/J Med 1995; 2000 pg day-r, given via a jet nebulizer, are effective and 332: 868-875. therapeutically equivalent and have a good safety and I I. Busse WW What role for inhaled steroids in chronic asthma? tolerability profile when used to control moderate Chest 1993; 104: 1565-l 571. persistent asthma in adult patients. Corticosteroids 12. Terzano C, Barkai L, Cremonesi G. Corticosteroids administered delivered via nebulizer may be an effective and attractive by nebulization to children with bronchial asthma. Adv Jher 200 I; 18: 253-260. alternative to pMDls, especially when it is necessary to 13. Terzano C, Allegra L, Barkai L, Cremonesi G. Beclomethasone administer high doses of drug (>500 pg), and to avoid dipropionate vs budesonide inhalation suspension in children with problems related to poor hand-respiration coordination mild to moderate persistent asthma. Eur Rev Med Pharmocol Sci that are seen in some patients that use pMDls. 200 I ; 5: 17-24.