Comparison of two budesonide powder inhalers, Easyhaler® and Turbuhaler®, in steroid-naı̈ve asthmatic patients

Comparison of two budesonide powder inhalers, Easyhaler® and Turbuhaler®, in steroid-naı̈ve asthmatic patients

Vol. 96 (2002) 599^ 606 Comparison of two budesonide powder inhalers, Easyhalers and Turbuhalers, in steroid-na|«ve asthmatic patients H. SCHWEISFURT...

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Vol. 96 (2002) 599^ 606

Comparison of two budesonide powder inhalers, Easyhalers and Turbuhalers, in steroid-na|«ve asthmatic patients H. SCHWEISFURTH*, A. MALINENw,T. KOSKELA, P.TOIVANENz M. RANKI-PESONEN}, ON BEHALF OF THE GERMAN STUDY GROUP. *III. Medical Department Carl Thiem Hospital,Cottbus, Acad. Hospital of the Humboldt University of Berlin (Charite¤), Germany, wOrion Pharma, Kuopio, Finland, zOrion Pharma, Biostatistics and Data Management, Kuopio, Finland and } Orion Pharma, Espoo, Finland Abstract The objective of this multicenter study was to compare the clinical efficacy, safety, and acceptability of Easyhalers and Turbuhalers for the delivery of budesonide 200 mg/dose twice daily in steroid-na|« ve asthmatic patients. Three hundred and twenty-six newly diagnosed, steroid-na|« ve adult patients with mild-to-moderate asthma were recruited into this randomized, double-blind, double-dummy, parallel-group study, comprising a 2-week run-in period and 8 weeks of treatment.Patients received budesonide inhalation powder 400 mg/day either via Easyhalers (n = 159) or via Turbuhalers (n = 167), plus salbutamolinhalation powder (100 mg/dose) via Easyhalers as rescue therapy.The study was completed by 292 patients:143 inthe Easyhalers group and149 intheTurbuhalers group.The primary outcome variable, mean morning peak expiratory flow (PEF), improved significantly and almost similarly by 36.3 and 30.6 l/min, respectively, from run-in to weeks 728. At weeks 728, the mean (SE) difference in morning PEF between the two treatments was 7.1 (9.4) l/min (90% CI from 8.4 to 22.6) on per protocol analysis, which was withinthe definedlimits for therapeutic equivalence. There were no significant differences between treatments in terms of secondary efficacy variables or adverse events.However, patients found Easyhalers more acceptable thanTurbuhalers.The results show that budesonide via Easyhalers is clinically as effective as Pulmicorts Turbuhalers when equal daily doses of budesonide are delivered to steroid-na|« ve asthmatic patients. Moreover, patients found Easyhalers more acceptable thanTurbuhalers, and a majority would prefer Easyhalers if given a choice.r 2002 Published by Elsevier Science Ltd doi:10.1053/rmed.2002.1311, available online at http://www.idealibrary.com on

Keywords budesonide, Easyhalers; Turbuhalers; steroid-na|« ve; asthmatic.

INTRODUCTION Current national and international guidelines for the treatment of patients with asthma recommend the early use of regular anti-in£ammatory therapy with inhaled corticosteroids. These agents have potent local activity: they decrease the accumulation and activation of in£ammatory cells in the asthmatic lung (1), inhibit the release of in£ammatory mediators from e¡ector cells (2), and upregulate beta2 -receptor function (3). As a result, they decrease microvascular permeability and mucus formation (4,5).

Received 9 October 2001, accepted is revised form 1 February 2002. Correspondence should be addressed to: A. Malinen, Orion Corporation, ORION PHARMA, P.O. Box 1780, FIN-70701 Kuopio, Finland. Fax: +358 -10 - 4286 - 444; E-mail: [email protected]

Clinical studies have provided extensive evidence that, irrespective of preparation, inhaled corticosteroids have minimal systemic e¡ects at doses up to 400 mg/day in children and up to 800 mg/day in adults (6). The most common adverse drug reactions of inhaled corticosteroids are dysphonia and oral candidiasis (7). Budesonide is a non-halogenated glucocorticosteroid derivative and is widely documented in the treatment of bronchial asthma (8). It is generally acknowledged that the inhaler is a key element in determining the e¡ectiveness of asthma therapy (9). The earliest form of inhaler was the pressurized metered dose inhaler (PMDI), which remains widely used in asthma management (10). However, many patients have di⁄culty using this device correctly (11) because of di⁄culty in co-ordinating drug release and inspiration (12). In addition, pMDIs contain lubricants that may irritate the bronchial membrane, resulting in paradoxical

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bronchoconstriction (13). Furthermore, the most commonly used propellant (chloro£uorocarbon (CFC)) has been implicated in damage to the ozone layer, hence CFC-containing MDIs will be banned in the near future. In order to overcome these problems, breath-actuated powder inhalers were developed. One of the ¢rst multidose powder inhalers to become available wasTurbuhalers (AstraZeneca, Sweden), which is documented for the delivery of budesonide in asthma patients as Pulmicorts Turbuhalers (14 ^17). The environmental problems caused by CFC gases in pMDIs are circumvented by replacing those with alternative propellant, hydro£uoroalkane (HFA). Easyhalers is a new-generation, breath-actuated multidose powder inhaler developed by Orion Pharma. It has been shown to be safe and e¡ective for the delivery of salbutamol (18) and BDP (beclomethasone dipropionate) (19). Moreover, a meta-analysis of Easyhalers studies has demonstrated that patients prefer Easyhalers to pMDI and Turbuhalers (20). Additional advantages of Easyhalers include a dose counter, high dosing accuracy, insensitivity of ¢ne particle dose to inspiratory £ow rate, and ease of use (20). Easyhalers and Turbuhalers have been shown to deliver an equivalent ¢ne particle dose in vitro (21), with a comparable in vivo lung deposition of Tc-labeled budesonide (22).The present study was undertaken to compare the clinical e⁄cacy, safety, patient acceptability and tolerability of Easyhalers and Turbuhalers for the delivery of budesonide 200 mg/dose twice daily in steroid-na|« ve asthmatic patients.

MATERIALS AND METHODS Patients Adult asthmatic out-patients who had been diagnosed with bronchial asthma no more than 2 years previously were recruited into the study from 30 centers in Germany. Inclusion criteria were: age 18 ^70 years; non-smokers for at least 6 months prior to entry (maximum smoking history of one pack per day for 5 years); a forced expiratory volume in 1s (FEV1) 60 ^90% of the predicted value measured within 4 weeks before or during the ¢rst visit; additionally, at least one of the following criteria 4 weeks before study entry or during the ¢rst visit: (a) At least 15% increase in FEV1 or PEF after a sympathomimetic inhalation (200 ^ 400 mg salbutamol, 500 ^1000 mg terbutaline or 200 mg fenoterol). (b) At least 15% decrease in FEV1 after an exercise tolerance test. (c) At least 20% diurnal variability in PEF on at least 4 days during 1 week, based on the following

RESPIRATORY MEDICINE

formula (23): Diurnal variaability ¼

Highest PEF2Lowest PEF Highest PEF  100:

Exclusion criteria were: hypersensitivity to budesonide or lactose; any exacerbation of asthma or a respiratory infection during the preceding 4 weeks; hospitalization due to asthma during the previous 12 months; treatment with inhaled or systemic corticosteroids, sodium cromoglycate or nedocromil within 12 weeks before the ¢rst visit or for more than 30 days per year during the previous 5 years; manifest heart condition (NYHA Class II^IV); severe hepatic or renal disease; inadequately controlled hyperthyroidism; chronic bronchitis; diabetes mellitus (type I or II); any clinically signi¢cant deviation in safety laboratory parameters. Women were excluded if they were pregnant or breastfeeding or, if fertile, without reliable contraception. All patients who had participated in this or any other clinical trial within 8 weeks prior to study entry were also excluded.

Study design and treatments This study was carried out according to a randomized, double-blind, double-dummy, parallel-group design. After a 2-week run-in period during which all patients used salbutamol Easyhalers (Buventol Easyhalers 100 mg/dose, Orion Pharma, Finland) as needed, patients were randomized to receive 200 mg of budesonide either via Easyhaler (Gionas Easyhalers 200 mg/dose, Orion Pharma, Finland) or viaTurbuhalers (Pulmicorts Turbuhalers 200 mg/dose, AstraZeneca, Sweden) twice daily (at 0600 ^ 0800 and 1900 ^2100 hours) for 8 weeks (Fig.1).Those patients randomized to receive budesonide via Easyhalers concurrently inhaled placebo (lactose) via Turbuhalers and vice versa. The appearance and weight of placebo was indistinguishable from the active treatment. Patients were instructed to rinse their mouth with water and spit it out after inhalation of each drug. The patients were trained to use both inhalers properly according to manufacturer’s instructions.The inhaler technique was also checked during the control visits, which took place at 2-week (visits 1^ 4) and 4 -week (visit 5) intervals. Salbutamol Easyhalers could be used as rescue medication during the treatment period but preferably not during the 6 h prior to home PEF measurements or follow-up visits to the clinic for spirometry. Patients were also permitted to take a 1-week course of an oral corticosteroid if needed, but any further use resulted in withdrawal from the study. All study documents were reviewed and approved by the Ethics Committee of the LandesPrztekammer Bran-

BUDESONIDE EASYHALERs AND PULMICORT TURBUHALERs IN STEROID-NAIº VE ASTHMATICS

TREATMENT PERIOD TREATMENT PERIOD 2 weeks 2 weeks

RUN-IN 2 weeks

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TREATMENT PERIOD 4 weeks

Budesonide Easyhaler 200microg/dose 1x2 n = 155

Salbu EH as needed

Pulmicort Turbuha ler 200 mi crog/dose 1x2 n = 155

0 Visit 1

Initiation Physical examination Safety laboratory S-Cortisol Oropharyngeal candidiasis Spirometry Acceptability of devices

2 Follow-up visit 2

6

4 Follow-up visit 3

Folllow-up visit 4

Randomisation

10 weeks Follow-up visit 5

End ofthe study

X X

-

-

-

-

X X

X X X

X X

-

-

-

X X X

X

X X X

-

FIG. 1. Flow chart of the study (n= planned group size).

denburg, Germany. All patients were required to give written informed consent and the study was conducted according to the principles of the current revision of the Declaration of Helsinki (24).

Outcome variables The primary e⁄cacy variable was morning PEF measured at home. Daily morning (0600 ^ 0800 hours) and evening (1900 ^2200 hours) PEF was measured by the patient at home using a standard Vitalograph Peak Flow Meter (Vitalograph, Cat. No. 43.000G, Hamburg). Three successive exhalations were recorded and the best value was used for the ¢nal analysis. Mean PEF values were calculated for the run-in period and for treatment weeks1^ 2, 3^ 4 and 7^ 8. Secondary e⁄cacy variables consisted of evening PEF measured at home; FEV1 and FVC measured at follow-up visits; number of salbutamol inhalations per day during the treatment period; severity scores for asthma symptoms during the day and night; visual analog scale (VAS) scores for e⁄cacy, as determined by the patients and the investigators; and diurnal PEF variability. The intensity of asthma symptoms (dyspnea, wheeze and cough) was scored daily by the patients and entered onto their diary cards, where 0 = no symptoms,1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms. Patients were asked to specify whether the symptoms occurred during the day or night or early morning. Both patients and investigators evaluated the e⁄cacy of the treatment with a 100 mm VAS, ranging from ‘not e⁄cient’ (0 mm) to ‘very e⁄cient’ (100 mm). These evaluations were performed after the run-in period and after 8 weeks of treatment.

Patients were asked to record the occurrence of any adverse event into the diary. In addition, the investigator inquired on each visit whether patient had had any untoward medical events since last visit. The investigators performed a visual examination for oropharyngeal candidiasis at each follow-up visit. Morning (0700 ^ 0900 hours) serum cortisol measurements were performed before and after the treatment period to evaluate the possible e¡ect of budesonide on the HPA axis. Patient acceptability of the devices was determined after 4 weeks of treatment using a questionnaire consisting of 10 questions, and a VAS, ranging from ‘very poor’ (0 mm) to ‘very good’ (100 mm).

Statistical analysis The overall hypothesis tested in the study was therapeutic equivalence of Gionas (budesonide) Easyhalers and Pulmicorts Turbuhalers.This was de¢ned as a 90% con¢dence interval within 730 l/min for estimated treatment di¡erence in mean morning PEF during treatment weeks 7^ 8. Additional hypotheses were that improvement in morning PEF could be detected during treatment with Budesonide Easyhalers, and that treatments with Budesonide Easyhalers and Pulmicorts Turbuhalers were equally safe, tolerable and acceptable. A two-sided P value of o5% was considered statistically signi¢cant if not otherwise stated. For the primary e⁄cacy variable (morning PEF measurements), data were analyzed on both an intentionto-treat (ITT) and a per protocol (PP) basis. Secondary e⁄cacy variable data were analyzed only on an ITT basis. Data from all patients entered into the study were analyzed for safety and acceptability.

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TABLE 1. Demographic and baseline patient information.Values are means (SD) except for sex, number of atopics, number of patients with FEV1 o80% of predicted, and number of patients demonstrating the inclusion criteria (a)^(c) Parameter Age (years) Female/male Height (cm) Weight (kg) Duration of asthma symptoms (years) Number of atopics Morning PEF (l/min) Evening PEF (l/min) FEV1a Liters % Of predicted o80% Of predicted FVCa liters % Of predicted (a) At least15% increase in FEV1 or PEF after a sympathomimetic inhalation (b) At least15% decrease in FEV1 after exercise-tolerance test (c) At least 20% diurnal variability At leasttwo of the criteria above (a^c) None of criteria above (a^c) due to a screening failure or missing data a

Easyhalers n = 159

Turbuhalers n = 167

41 (14) 102/57 170 (9) 73 (15) 0.4 (0.7) 46 356 (103) 366 (104)

43 (13) 101/66 167 (9) 76 (17) 0.5 (0.7) 54 358 (110) 367 (112)

2.47 (0.64) 76.6 (12.8) 97

2.45 (0.67) 76.7 (13.0) 109

3.00 (0.82) 78.5 (14.9) 98

2.99 (0.80) 79.0 (14.5) 110

24

20

18 17 2

22 15 F

Baseline FEV1 and FVCvalues are from measurements performed at visit1, atthe beginning of the run-in period.

Therapeutic equivalence was analyzed using analysis of covariance (ANCOVA). Improvement in the Easyhalers group was analyzed using analysis of variance (ANOVA). Spirometry values were analyzed with a repeated measurements ANCOVA model, while the number of salbutamol inhalations per day, intensity scores for asthma symptoms,VAS scores for e⁄cacy and diurnal PEF variation were analyzed as change from run-in to treatment weeks 5^ 8. VAS scores for device acceptability were compared using the Wilcoxon signed rank test. Safety analyses included morning serum cortisol using the ANCOVA model, and adverse events, which were classi¢ed by System Organ Class and by preferred term according to the WHO coding system. Oropharyngeal candidiasis was analyzed descriptively.

RESULTS

TABLE 2. Reasons for study discontinuation

Adverse event E⁄cacy Loss to follow-up Protocol violation Withdrawal of consent Other

Easyhalers group

Turbuhalers group

1 F 10 1 2 2

3 1 4 1 9 F

Two hundred and ninety-two patients completed the study: 143 in the Easyhalers group and 149 in theTurbuhalers group. Sixteen patients in the Easyhalers group and 18 patients in the Turbuhalers group discontinued the study for various reasons (Table 2).

Patients A total of 326 patients were recruited into the study from 30 centers in Germany:159 in the Easyhalers group and 167 in the Turbuhalers group. Demographic and baseline features of all patients in each treatment group are shown in Table 1. There were no statistically signi¢cant di¡erences between the groups for any of the speci¢ed parameters.

E⁄cacy According to both the PP and ITTanalyses, mean morning PEF improved signi¢cantly from baseline (run-in) to weeks 7^ 8 with both preparations, with a mean (SD) increase of 36.3 (6.6) l/min in the Easyhalers group and 30.6 (5.7) l/min in the Turbuhalers group on PP analysis (Fig. 2, Table 3). At weeks 7^ 8, the mean (SE) di¡erence

BUDESONIDE EASYHALERs AND PULMICORT TURBUHALERs IN STEROID-NAIº VE ASTHMATICS

410 400

Morning PEF (L/min)

390 380 370 360 350 340

BUD Easyhaler BUD Turbuhaler

330 320 10 0 Run-in

Weeks 1-2

Weeks 3-4

Weeks 7-8

FIG. 2. Mean morning PEF values (per protocol analysis) with standard error of mean.

TABLE 3. Mean (SE ) improvementin morning PEF values (l/min) from run-in to weeks 7^8 Mean (SE) 90% CI improvement Easyhalers Per protocol Intention-to-treat Turbuhalers Per protocol Intention-to-treat

P value

36.3 (6.6) 34.3 (6.2)

23.3^49.3 o0.0001 21.9^46.6 o0.0001

30.6 (5.7) 28.5 (5.4)

19.4^41.9 17.7^39.2

o0.0001 o0.0001

in morning PEF between the two treatments was 7.2 (9.4) l/min (90% CI from 8.4 to 22.6) on PP analysis and 7.0 (9.0) l/min (90% CI from 7.9 to 21.9) on ITT analysis, which was within the de¢ned limits for therapeutic equivalence.The e¡ect of sympathomimetic use on treatment di¡erence was analyzed separately by excluding the patients who had used the rescue medication regularly. The result of this analysis did not di¡er from the original result. Evening PEF values improved in accordance with morning PEF values, with a mean (SE ) improvement from baseline to weeks 7^ 8 of 32.2 (5.7) l/min in the Easyhalers group and 27.9 (5.3) l/min in theTurbuhalers group. Spirometric indices also improved to a similar extent in both treatment groups over the study period (Table

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4). Between the end of run-in and the ¢nal visit at week 8, the mean (SD) improvement in FEV1 was 0.2 (0.5) l in the Easyhalers group and 0.2 (0.5) l in the Turbuhalers group. Similarly, the mean (SD) improvement in FVC was 0.2 (0.6) and 0.3 (0.7) L for the Easyhalers andTurbuhalers groups, respectively. The corresponding change in mean FEV1 as percent predicted was 5.1 (15.6) % points in the Easyhalers group and 7.5 (15.5) in the Turbuhalers group (treatment di¡erence 0.06 with a 95% CI from 0.22 to 0.09).The change in mean FVC as percent predicted was 4.8 (16.4) % points in the Easyhalers group and 7.2 (18.3) in theTurbuhalers group (treatment di¡erence 1.21 with a 95% CI from 4.85 to 2.43). Use of rescue medication decreased during the study in both treatment groups. In the Easyhalers group, the mean (SD) number of salbutamol inhalations per day decreased from1.8 (2.2) during the run-in period to 0.7 (1.3) during treatment weeks 5^ 8 (Po0.001). In the Turbuhalers group, the corresponding ¢gures were 1.5 (2.2) and 0.6 (1.0) (Po0.001), respectively. The incidence of asthma symptoms was higher during the run-in period than during the treatment period and was similar in both treatment groups (between treatments, weeks 5^ 8: day symptoms P=0.83, night symptoms P=0.74) (Table 5). Mean night-time symptom scores were lower than mean day-time symptom scores in both groups. There were also no statistically signi¢cant di¡erences between the treatments in terms of e⁄cacy based on VAS scores by investigator (P=0.61) or patient (P=0.58), which improved during the course of the study in both groups. Mean (SD) VAS e⁄cacy scores, as assessed by patient, increased by 24.4 (28.0) mm in the Easyhalers group and by 21.7 (28.3) mm in the Turbuhalers group, giving mean (SD) VAS e⁄cacy scores at the end of treatment of 78.2 (16.7) and 77.5 (17.0) mm in each group, respectively. Diurnal variability in PEF values decreased to a similar extent in both treatment groups.Thus, mean (SD) diurnal variability in PEF changed from 7.3 (4.4)% during run-in to 5.2 (4.3)% during weeks 7^ 8 in the Easyhalers group, and from 7.4 (5.0) to 5.5 (4.4)% in theTurbuhalers group.

Acceptability The mean (SD) VAS score for device acceptability was signi¢cantly higher for Easyhalers than for Turbuhalers

TABLE 4. Mean (SD) changes in spirometry (FEV1 and FVC) values (l) from the end of run-in to week 8. Easyhalers

FEV1 FVC

Turbuhalers

Treatment di¡erence (95% CI)

End of run-in

Week 8

End of run-in

Week 8

2.62 (0.70) 3.09 (0.88)

2.80 (0.76) 3.28 (0.93)

2.59 (0.79) 3.10 (1.01)

2.83 (0.84) 3.36 (1.14)

0.07 (^0.16^0.02) 0.07 (^0.190.05)

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RESPIRATORY MEDICINE

TABLE 5. Mean day- and night-time symptom scores (% of theoretical maximum) during run-in and treatment weeks 5^8 Easyhalers

Turbuhalers

Dyspnea

Wheezing

Cough

Dyspnea

Wheezing

Cough

Run-in Weeks 5^8

22.3 11.1

12.1 5.1

29.6 16.6

20.8 13.1

15.2 7.8

32.5 17.5

Run-in Weeks 5^8

12.2 4.8

8.3 2.8

20.2 9.6

14.2 7.7

10.0 4.2

22.1 9.8

Day

Night

Easyhaler

No difference

Turbuhaler

100

Percentage of patients (%)

90 80 69

70

54

53 47 45

46 47

40

47 41

35 36

35 27

30 20 10

64

60

60 50

67

8

12

7

27

10

27

23

21 8

5

2

30 23

13

0 Easier to learn

Easier to use

Dosing is easier

Inhalation through device easier

Easier to know getting the drug

Easier to know how much drug is left

Better shape

Handier to Easier to clean carry with you

Patient's choice

FIG. 3. Acceptability of the device according to questionnaire (% patients).

(74.8 [18.4] mm vs 56.3 [23.6] mm, respectively; Po0.0001). Easyhalers also scored higher thanTurbuhalers for most questions in the device acceptability questionnaire (Fig. 3). In particular, patients using Easyhalers found it easier to know when the drug had been received, and how much drug remained in the device. Furthermore, 63.8% patients said they would have chosen Easyhalers compared with 12.4% who preferred Turbuhalers and 22.8% who expressed no preference.

Safety Adverse events that were considered possibly or probably related to study treatment occurred in 3.1% of Easyhalers patients during both the ¢rst and the second half of the treatment period. In the Turbuhalers group, 4.8% of patients experienced such events during the ¢rst half of treatment and 2.4% during the second half of treatment. Overall, 12 adverse drug reactions (ADRs) were reported in the Easyhalers group and 16 in the Turbuhalers group. Most of these were mild or moderate in nature. Dysphonia (3 and 4 events, respectively) and pharyngitis (4 and 5

events, respectively) were the most common reported ADRs. Four patients withdrew from the study as a result of adverse events: one in the Easyhalers group (irritation of the oral mucosa and throat) and three in theTurbuhalers group (bacterial bronchitis; dyspnea and cough; and deterioration of asthma). Only two SAEs occurred during the study, neither of which was considered related to study treatment.These consisted of one neoplasm (cervical carcinoma) in the Easyhalers group and one respiratory system disorder (hospitalization because of dyspnoea and urinary tract infection) in theTurbuhalers group. In the Easyhalers group mean (SD) morning serum cortisol value was 424 (219) nmol/l after run-in, and slightly higher at visit 8 (443 [191] nmol/l). In the Turbuhalers group, the trend was similar (from 368 [187] to 419 [194] nmol/l). At the end of treatment, only seven patients had serum cortisol values below the reference range (138 ^ 690 nmol/l) (25): one in the Easyhalers group and six in the Turbuhalers group. The number of oral, 1-week steroid courses was three in the Easyhalers group and one in the Turbuhalers group.

BUDESONIDE EASYHALERs AND PULMICORT TURBUHALERs IN STEROID-NAIº VE ASTHMATICS

DISCUSSION The results of this study demonstrated that Gionas (budesonide) Easyhalers is as e¡ective as Pulmicorts Turbuhalers when equal daily doses of budesonide are delivered to steroid-na|« ve asthmatic patients. This was evident from measurements of pulmonary function; diurnal PEF variability; asthma symptom scores; number of salbutamol inhalations per day; and VAS scores for e⁄cacy. The design of this study was carefully considered to ensure the optimal conditions for a rigorous comparison of the e⁄cacy of two budesonide inhalers: Gionas Easyhalers and Pulmicorts Turbuhalers. Firstly, since inhaled corticosteroids may take days or weeks to exert their maximal e¡ect, the recommended minimum duration for this type of study is 4 weeks (26). Hence, in the present study an 8 -week treatment period was selected in order to obtain a reliable assessment of the e⁄cacy, safety and acceptability of the devices under investigation. In addition, the dosage of budesonide used in this study (400 mg/day) is low compared with the average starting dose in adults (27,28) and should be in the steep part of the budesonide dose ^ response curve (7), thus, enhancing the reliability of comparison between the two preparations investigated. The inclusion of a separate placebo control group was considered to be unethical in this population of newly diagnosed, untreated asthmatic patients. Joyce et al. studied the placebo e¡ect in a meta-analysis of 33 asthma drug therapy trials (29). According to their observations, a mean absolute decrease of 2.24 l/min in PEF was observed among placebo groups, which supports the rationale for not including a placebo group in our study. During the trial, the primary e⁄cacy variable and all secondary e⁄cacy variables improved clearly during treatment and to a similar extent in both groups. An improvement in PEF of similar magnitude has been reported in previous studies with corticosteroids in steroid-na|« ve asthmatic patients (15,19). The safety and tolerability of the two preparations was good, and was comparable between the two treatment groups. The frequencies of adverse events (whether considered potentially drug-related or not) were also similar with both treatments, with no signi¢cant e¡ect on the HPA axis. Although morning serum cortisol is not an ideal method for assessing such an effect, because of large diurnal variation, a single blood sample is the only practical method for determination of serum cortisol in a large, multicenter study of this type. Tests to assess the acceptability of the devices revealed a clear preference for Easyhalers by a majority of patients. In all,10 questions on the questionnaire, Easyhalers was considered at least as good as Turbuhalers, and 63.8% of patients said they would prefer Easyhalers,

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given the choice. Moreover, Easyhalers scored statistically signi¢cantly better than Turbuhalers on the VAS test for acceptability. While evaluating the acceptability results it should be noticed that patients had a somewhat more thorough experience of the Easyhalers device than of the Turbuhalers, because salbutamol Easyhalers was used as a rescue medication in both groups. However, the ¢ndings of this study are supported by the meta-analysis of nine Easyhalers clinical studies, which showed that the majority of patients (60%) preferred Easyhalers to Turbuhalers, and found Easyhalers easier to use (64%) thanTurbuhalers (20). The questionnaire also revealed that a majority of patients found it easier to know when the drug had been received with Easyhalers (69.3%), compared withTurbuhalers (2.1%).This ¢nding is likely to re£ect an additional bene¢t of incorporating a small amount (8 mg) of lactose to the budesonide dry powder, which is used to ensure a high level of dose reproducibility (20).The amount of lactose is su⁄cient for the patient to detect, but below the level likely to cause a reaction in lactose intolerant patients (30).

CONCLUSIONS The results of this study indicate that Gionas (budesonide) Easyhalers is as e¡ective as Pulmicorts Turbuhalers when equal daily doses of budesonide are delivered to steroid-na|« ve asthmatic patients. The mean improvement in morning the primary e⁄cacy variable (PEF) seen in both treatment groups was statistically signi¢cant. There were no signi¢cant di¡erences between the treatment groups in terms of any of the secondary e⁄cacy variables. Similarly, there were no clinically signi¢cant di¡erences in terms of adverse events between the study groups, and these were mostly mild or moderate in nature. Neither treatment suppressed the HPA axis, as determined by morning serum cortisol values. Both VAS testing and the use of a questionnaire demonstrated better patient acceptability of Easyhalers compared with Turbuhalers. In addition, the majority of patients said that they would choose Easyhalers.

Acknowledgements The authors wish to thank the participating investigators for their valuable contribution to the study: C. BPstlein, Berlin; M. Dˇnzel, Niesky; M. Korduan, Berlin; S. Poner, Berlin; R. Schnorr, Berlin ; H.Olbrich, Augsburg; J. Adler, Ludwigshafen; B. Romberg, Berlin; M. Kaiser, Parsberg; I. Naudts, Dudenhofen; G. Riedel, Koblenz; H. Wiswedel, Fˇrth; P. Witzany, Markheidenfeld; E. Beck, Rˇdersdorf; G. Lammert-Hˇnger, Eberswalde; T. Schultz, Berlin; Ch. Seevers, Hamburg; L-H.Versen, Berlin; Ch. Witt, Berlin; R. Braun, Unterschneidheim; C. Uhde, Mˇnchen; O.J.

606

Brˇckner, Mˇnchen; U. Harnest, Mˇnchen; E. Ho¡mann, Augsburg; B. Kroemer, Kaufbeuren; A. Bisping-Arnold, Freising; K.D. Rost, Augsburg; J. Schreiegg, Augsburg; D. Stiller, Fˇrstenwalde; W.Tzimas, Mˇnchen.

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