Clinical efficacy and safety of fluticasone propionate 250 μg twice daily administered via a HFA 134a pressurized metered dose inhaler to patients with mild to moderate asthma

RESPIRATORYMEDICINE (2000) 94 (SUPPLEMENTB), $29-$34

Clinical efficacy and safety of fluticasone propionate 250 #g twice daily administered via a HFA 134a pressurized metered dose inhaler to patients with mild to moderate asthma

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A. B. TONNEL*, J. BONSIt, M. LEGENDRE~, A. PRUD'HOMME§, B. BUGNAS¶, I. EVANO-CELLIt, AND A. M. STUART** ON BEHALFOF A FRENCH STUDY GROUP *Clinique des Maladies Respiratoires, Chru de Lille, H6pital Cahnette, Lille, tMedical Department, Laboratoire Glaxo Wellcome SA, Marly le Roi, ~29 Boulevard Berthelot, 63400 Chamalieres, §H6pital de la Gespe, Boulevard de Lattre de Tassigny, 65013 Tarbes and ~13 rue Cronstadt, 06000 Nice, France **Respiratond Clinical Development, Glaxo Wellcome, Stockleay Park, U.K. This study compared the efficacy and safety of the fluticasone propionate 125/~g pressurized metered dose inhaler (pMDI) propelled by either hydrofluoroalkane (HFA) 134a or chlorofluorocarbon (CFC) propellants, in adult patients with asthma. H F A 134a is a non-ozone depleting propellant used as a replacement for the CFC propellants 11 and 12 which are being phased out in accordance with the Montreal Protocol. Three hundred and eighty patients with mild to moderate asthma and 'room for improvement' in their treatment were randomized to receive fluticasone propionate 250 pg twice daily via pMDIs propelled by either CFC propellants I1 and 12 01 = 195) or H F A 134a (n = 185). Fluticasone propionate significantly improved lung function over the 4-week treatment period in both treatment groups. The improvement in mean morning peak expiratory flow (PEF) after 7 days of treatment was approximately 12 I min - t in both groups, rising to approximately 22 1 min -1 at the end of the 4-week treatment period. The adjusted mean difference between the two formulations over weeks 1--4 was - 1 I rain - I (90% confidence interval: - 7 , 5 1 m i n - I ) , confirming their equivalence. Clinical comparability was also demonstrated with respect to secondary efficacy variables, including daily symptom scores, evening PEF and clinic visit expiratory measurements. There were no clinically relevant differences in adverse events or serum cortisol levels between the two groups. The fluticasone propionate 125 Fg H F A 134a pMDI is an effective and well tolerated product and is a suitable replacement for the ftuticasone propionate 125/ag CFC pMDI at a microgram equivalent dose. Key words: asthma; fluticasone propionate; hydrofluoroalkane 134a; H F A 134a; chloroftuorocarbons; CFC. RESPIR. MED. (2000) 94 (SUPPL. B), $29-$34

Introduction The non-ozone depleting hydrofluoroalkane (HFA) propellant, H F A 134a, has been selected as the alternative propellant for Glaxo Wellcome's pressurized metered-dose inhalers (pMDI). Preclinical and clinical studies have shown that H F A 134a behaves as an inert gas with a

Received 13 December 1999 and accepted in revised form 29 February 2000. Correspondence should be addressed to: Prof. A. B. Tonnel, Clinique des Maladies Respiratoires, Chru de Lille, H6pital Calmette, 59037 Lille Cedex, France. Fax: + 33 3 20 44 47 09. 0954-6111/00/0B00S29+06 $35-00/0

© 2000 HARCOURT PUBLISHERSLTD

similar pharmacokinetic and safety profile to that of the CFC propellants 11 and 12 (1,2). The pharmaceutical performance of pMDI fomulations containing H F A 134a as the propellant is also equivalent to that of the corresponding CFC p M D I product (3). Fluticasone propionate 250 ~g twice daily is an effective and well tolerated treatment for mild to moderate asthma. Furthermore, at this dose, fluticasone propionate is at least as effective as twice the microgram dose of budesonide and beclomethasone dipropionate in terms of improvements in lung function and symptom control (4,5). The objective of this study was to compare the efficacy and tolerability of fluticasone propionate 250/~g twice daily administered via a 125 ~Lg pMDI propelled by either H F A 134a or the CFC propellants 11 and 12. © 2000 HARCOURTPUBLISHERSLTD

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A.B. TONNELET AL.

Materials and methods SUBJECTS Adult patients aged >18 years were selected from outpatient clinics at 62 centres in France. Written informed consent was obtained from each patient before their participation in the study. All subjects had a documented history of mild to moderate asthma requiring at least 400-1000/lg day - I of inhaled beclomethasone dipropionate or equivalent, and a forced expiratory volume in I sec (FEV0 of between 5090% of the predicted value. They also had to be able to use a pMDI correctly. Patients were excluded if they had unstable asthma, had been hospitalized, or had taken oral or parenteral corticosteroids or antibiotics in the preceding 4 weeks. Patients who had received oral or parenteral corticosteroids on two or more occasions in the preceding 3 months, had a known hypersensitivity to any element of the formulations used in the study, or had received other research medication in the 12 weeks prior to the study were also excluded. Participants satisfying the above criteria exchanged their usual bronchodilator for salbutamol (administered vi~. a CFC pMDI), to be taken as required to relieve symptoms, for a 2-week run-in period. At the end of this period, study entry requirements were to demonstrate a mean morning peak expiratory flow (PEF) of <90% of the maximum PEF after inhalation of 400 or 800 tLg of salbutamol, and for at least four puffs of salbutamol to have been taken over the previous 7 days. These criteria were used to indicate that there was 'room for improvement' in patients treatment (6).

STUDY DESIGN AND PROCEDURES This multi-centre, double-blind, parallel-group study was approved for all study centres by the relevant Ethics Committee. Following the run-in period, patients were randomly assigned to 4 weeks of pMDI treatment with fluticasone propionate 250 pg twice daily, propelled by either HFA 134a or the CFC propellants 11 and 12. The study treatment was used as a replacement for the patients' current inhaled corticosteriod therapy and the use of short-acting fl2-agonists, anti-cholinergics or oral/parenteral corticosteroids was not permitted during the study period. Salbutamol was provided as rescue therapy for the duration of the study. All other concurrent medication was permitted. Appropriate large volume spacer devices (VolumaticTM) were supplied for those patients who required them. Those participants who used spacers did so throughout the treatment period and their use was recorded. Patients were given a mini-Wright peak flow meter to use at home, and recorded the best of three measurements of morning and evening PEF on a daily record card. PEF measurements were made before taking the study medication and, where possible, at least 4 h after the last dose of

salbutamol. Asthma symptoms and use of rescue salbutamol were also recorded on the daily record card. The clinic was attended 'by all participants on four scheduled occasions: at the start and end of the 2-week runin period, at the end of the 4-week treatment period, and after a 2-week follow-up period. At each clinic visit, FEVI and PEF were measured and airway reversibility was determined at the e n d of the run-in period. Airway reversibility was assessed by recording PEF using a miniWright peak flow meter, before and after the administration of salbutamol 400 llg via a pMDI (or 800 pg via a dry powder inhaler). Patients were therefore requested to refrain from using their salbutamol for at least 4 h before each clinic visit and any long-acting bronchodilator for 12 h beforehand. Where possible, all lung function assessments were made at the same time of day, preferably in the morning. The highest of three values was recorded for each lung function parameter. At the third clinic visit (at the end of the treatment period), treatment efficacy was assessed subjectively by both the patient and the physician. The assessment categories were 'very effective', 'effective', 'satisfactory', 'ineffective' or 'very ineffective', scoring 1-5 respectively. Fasting venous blood and urine ,samples were collected between 08.00 and 10.00 hours at the start of the run-in period and at the end of treatment for routine urinary and biochemical analysis. Serum samples were also analysed for cortisol concentrations.

DATA ANALYSES Data analyses were performed on the intent-to-treat population. Hypothesis testing was used to examine the possible equivalence of fluticasone propionate pMDls using either HFA 134a or CFCs as propellants. The primary efficacy parameter was mean morning PEF. Equivalence was established if the 90% confidence interval (CI) for the difference between mean morning PEF measurements for the two treatments was within + 15 1 m i n - t. Basing calculations on a standard deviation of 3040 1m i n - i 125 evaluable patients per treatment group were required to detect equivalence and to ensure a power of 80% (6,7). Morning PEF and clinic visit PEF and FEVI were adjusted for comparison of the two treatment groups using analysis of covariance, with baseline, gender, age and centre (pooled) as covariates. The baseline covariate for mean morning PEF was the mean value of the last week of the run-in period, and for clinic visit PEF and FEV1 results, the measurements taken at the end of the run-in period were used. Following logarithmic transformation, serum cortisol data were also analysed using analysis of covariance. The Wilcoxon rank sum test was used to assess the differences between treatment groups for symptom scores over weeks 1-4, percentage of days and nights with no additional bronchodilator mediation and patient and physician assessment of efficacy. The Wilcoxon rank sum test was stratified by centre (pooled) using the van Elteren method to provide a significance test (8).

FLUTICASONEPROPIONATE250 #g HFA 134a pMDI

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TABLE 1. Patient demographic characteristics

Number of patients Males: female (%) Age (years) Mean + SD Range Use of Volumatic T M spacer (no. of pts) History of smoking (no. of pts): Never Ex-smoker Current Duration of reversible airways obstruction (no. of pts; years): 0-10 11-20 21-30 >30 Baseline FEV I l [mean _ SD] Asthma medication continued into the study (no. of pts): Long-acting fl2-agonists Methylxanthines Sodium cromoglycate

Fluticasone propionate H F A 134a p M D I

Fluticasone propionate CFC p M D I

185 96:89 (52:48)

195 97:98 (50:50)

45 __+15 18-80 60 (33%)

42 _+ 15 18-73 52 (27%)

118 (64%) 57 (31%) 10 (5%)

112 (57%) 65 (33%) 18 (9%)

83 (45%) 57 (31%) 26 (14%) 19 (10%) 2.31 +0"75

86 (44%) 56 (29%) 25 (13%) 28 (14%) 2.40+0.71

29 (16%) 25 (14%) I ( < 1%)

36 (18%) 32 (16%) 4 (2%)

CFC, chlorofluorcarbon; HFA, hydrofluoroalkane; pMDI, pressurized metered dose inhaler; SO, standard deviation.

Results Of the 380 patients randomized to receive treatment, 185 were assigned fluticasone propionate pMDIs propelled by the new propellant H F A 134a, and 195 received devices containing the CFC propellants I1 and 12. The treatment groups were well matched with respect to their demographic details (Table I). Eight patients were withdrawn from the study, four from each group. The reasons for withdrawal were adverse events (two patients from each group), failure to return (one patient from each group), and unknown (one patient in each group).

DIARY CARD MEASUREMENTS The two formulations of fluticasone propionate were shown to be equivalent in terms of the primary efficacy variable, mean morning PEF, despite the fact that there were baseline differences between the two groups. The estimated difference between means for the two treatment groups (adjusted for baseline, gender, age and centre) during weeks 1-4 was - 1 1 min - I (90% CI: - 7 , 5 1 min-I). Mean morning PEF improved over the study period in both treatment groups. After 4 weeks of treatment, PEF values had increased from baseline by 23 and 22 I m i n - I in the H F A 134a and CFC groups, respectively. Improvements in morning PEF of 12 and 13 1 m i n - i occurred in the H F A 134a and CFC groups, respectively, as early as 1 week after starting treatment. Mean morning PEF values are shown in Fig. 1 and adjusted means over weeks 1-4 are presented in Table 2.

Secondary efficacy variables including mean evening PEF, and percentage predicted mean morning and evening PEF also showed comparable adjusted increases in both treatment groups (Table 2). The use of large volume spacers had no significant effect on any efficacy variable (P = 0.191). Both treatment groups showed an increase in the percentage of days and nights with no additional bronchodilator medication. At the start of treatment, the H F A 134a pMDI group had a median of 29% of days with no additional bronchodilator use which rose to 83% by the end of week 4, whereas values in the CFC pMDI group rose from 43 to 83% over the same time period. The percentage of nights with no additional bronchodilator use increased from a median of 71% at baseline to 100% at the end of treatment in both groups. The median daytime and night-time symptom score was zero (no symptoms) in both treatment groups, at the start and end of treatment.

CLINIC VISIT DATA By the end of the 4oweek treatment period, clinic visit FEVI had increased by 0-15 and 0" 19 1 from baseline values in the H F A 134a and CFC p M D I groups, respectively. The two formulations were therefore comparable (90% CI for the treatment difference: - 0 . 1 1 , 0.02 1). Clinic visit PEF also increased during the treatment period. The adjusted increases from baseline were 27 and 34 1 m i n - ' in the H F A 134a and CFC p M D I groups, respectively.

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430 425 420 415 410 405 400 395 390 385 380 375 370 365 360 355 350 .~. -14

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7 Days Fluticasone propionate HFAI34a pMDI --

14

21

28

Fluticasone propionate CFC pMDI

The number of subjects varies over days FIc. 1. Mean morning peak expiratory flow 0aEF) during the 2-week run-in period and 4 weeks of treatment with fluticasone propionate 250/~g twice daily administered via a chlorofluorocarbon (CFC) or hydrofluoroalkane ( H F A ) 134a pressurized metered dose inhaler (pMDI).

TABLE 2. Change in diary card measurements of peak expiratory flow (PEF) in patients with mild to moderate asthma treated with fluticasone propionate 250 Izg twice daily for 4 weeks administered via a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) 134a pressurized metered dose inhaler (pMDI)

Mean morning P E F Baseline mean +_so Adjusted mean* +SE Mean evening P E F Baseline mean + so Adjusted mean* -t- SE % predicted mean moring P E F Baseline mean __+so Adjusted mean* +__SE % predicted mean evening P E F Baseline mean -+so Adjusted mean* _+SE

Fluticasone propionate H F A 134a p M D I (n = 185)

Fluticasone propionate CFC pMDI (n = 194)

Adjusted mean difference* (-+sE)

90% CI

P value*

371 -+ 107 399+3

391 _ 102 400+__2

-- 1 + 4

--7,5

0~839

388 _ 108 410 -t- 2

4 0 6 _ 99 412 _ 2

-- 3 -I- 3

-- 8,3

0"432

74+ 17 79--+ 1

77+ 16 80-+ 1

0-+ 1

-- 1,1

0"775

85-+ 17~; 89-+ I

8 7 + 15 90--+ 1

-- 1 _ 1

--2,1

0-425

*Adjusted for baseline, gender, age and centre. t p vaiue calculated using analysis of covariance. 184 patients. CI, confidence interval; so, standard deviation; sE, standard error. The two formulations of fiuticasone propionate were also shown to be comparable with respect to the patients' and physicians' assessment of efficacy. The median score for both formulations was 2 'effective', and there was no statistically significant difference between the two formulations.

SAFETY The number of adverse events reported during treatment was similar for the two treatment groups [48 patients (26%) in the H F A 134a group and 52 patients (27%) in the C F C group]. The most commonly occurring adverse event was

FLUTICASONEPROPIONATE250 /~g HFA 134a pMDI TABLE 3. Serum cortisol levels (nmol 1- i) at baseline and after 4 weeks of treatment

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Fluticasone propionate H F A 134a pMDI

Fluticasone propionate CFC p M D I

172 474 469 - 5.03

188 508 495 - 13.19

Number of patients Mean value at baseline Mean value after treatment Mean change*

*Mean change calculated from value post-treatment minus the baseline value. CFC, chlorofluorocarbon; HFA, hydrofluoroalkane; pMDI, pressurized metered-dose inhaler.

bronchitis [four patients (2%) and six patients (3%) in the two groups, respectively]. Adverse events commonly associated with inhaled corticosteriod therapy (including candidiasis of the mouth, hoarseness and rash/ skin eruption) were reported in <1% of patients in both groups. There were no reports of paradoxical bronchospasm. Eight cases of taste disturbance were noted: five in the H F A 134a pMDI group and three in the CFC pMDI group. No clinically relevant changes in mean serum cortisol values were apparent in either group over the treatment period (Table 3). In addition, no clinically relevant changes in vital signs were reported in either treatment group.

Discussion The results of this study demonstrate that fluticasone propionate formulated with the new non-CFC propellant, H F A 134a, at a dose of 250/~g twice daily, is as effective as the CFC formulation in treating patients with mild to moderate asthma who have room for improvement on existing therapy. Patients on inhaled corticosteroid therapy at a beclomethasone dosage of 400-1000 t~g day - t or equivalent showed comparable improvements in all efficacy variables following treatment with either formulation of fluticasone propionate. In addition, both propellants were well tolerated. These results are in accordance with other studies which demonstrate that the fluticasone propionate H F A 134a pMDI is a suitable alternative to the CFC pMDI (9-11). In order to establish true clinical equivalence of fluticasone propionate when propelled by H F A 134a or the CFC propellants 11 and 12, it was necessary for patients to show room for improvement. The reason for this is that if both treatments cannot be shown to improve symptoms, or if both treatments have maximum possible effect, the results may be interpreted in a different way, and considered as not being truly indicative of equivalence (12). The main purpose of the run-in period was to establish that all patients entering the study had room for improvement. Comparison of the maximum achievable PEF in response to salbutamol 400 or 800 pg and the mean PEF recorded during the study indicated that 90% of patients had not reached 95% of their maximum achievable PEF.

This confirmed that comparisons between the two p M D I groups were not made on the plateau of the dose response curve.

Thus, the comparable improvements observed in this study with the new H F A 134a formulation of fluticasone propionate and the existing CFC formulation are indicative of effective clinical equivalence. The improvement in the primary efficacy variable (mean morning PEF) was observed as early as 1 week after starting treatment and continued throughout the treatment period. This fast onset of action is a distinguishing feature of fluticasone propionate, and has been similarly reported in another study investigating the same dose of fluticasone propionate administered via the pressurized inhaler (CFC propellants) and via the Diskhaler TM inhaler (4). Secondary efficacy variables showing similar improvements from baseline in both treatment groups include diary card measurements and clinic visit FEVI and PEF measurements. Both formulations of fluticasone propionate were well tolerated, with a similar overall incidence and pattern of adverse events. Of the adverse events that are frequently associated with inhaled corticosteroid therapy, only candidiasis, hoarseness and rash/skin eruption were reported and these were in a very low percentage of patients in both groups. There was no evidence of paradoxical bronchospasm, an adverse event which has previously been reported with pressurized inhalers (13). No clinically relevant effects on serum cortisol or vital signs were observed in "either treatmen[ group. However, it is now known that measurement of 08-00-10.00 hours serum cortisol levels is not the best marker of safety (14). The pharmaceutical performance of the fluticasone propionate 125/~g H F A 134a p M D I is comparable to that of the CFC pMDI, particularly with respect to particle size distribution and fine particle mass (3). However, a slightly lower systemic exposure has been demonstrated for the H F A 134a compared with the CFC fluticasone propionate p M D I (15). These data are supported by the results of this large multicentre study showing that the fluticasone propionate H F A 134a pMDI has less tendency to reduce serum cortisol levels than the CFC product without a detrimental effect on clinically relevant lung function. These data indicate that transition from the fluticasone propionate CFC to H F A 134a p M D I is possible at a microgram equivalent dose.

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A.B. TONNELETAL.

The results of this study demonstrate that fluticasone propionate formulated with a new non-CFC propella'nt, HFA 134a, is an effective treatment for patients with mild to moderate asthma. The data indicate that substitution of ozone-depleting CFCs with HFA 134a in pMDls delivering fluticasone propionate is possible without affecting treatment efficacy or tolerability.

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Acknowledgements The study (FLIT93) was supported by a grant from Glaxo Wellcome Research and Development, U.K. The authors would like to thank all investigators who took part in this study which was conducted in France: Dr Andrieu, Dr Arfi, Dr Beraud, Dr Blanchon, Dr Bourcereau, Prof. Bousquet, Dr Boutry, Prof. Brambilla, Dr Braun, Dr Breuil, Dr Cabrera, Prof. Caillaud, Prof. Caries, Dr Carre, Dr Chalmet, Dr ChavaiUon, Dr Chavez, Dr Colas, Dr Copreaux, Dr Coste, Dr Dansin, Dr Darneau, Dr Dennwald, Dr Douay, Dr Epstein, Dr Fiaud, Dr Fournier, Dr Gamier, Dr Guillemot, Dr Guinnepain, Dr Greiller, Dr Grosclaude, Dr Grunchec, Dr Hyvernat, Prof. Lavandier, Dr Madru, Dr Maffre, Dr Martin, Dr Martinat, Dr Mathieu, Dr Monchatre, Prof. Moneret-Vautrin, Dr Morales, Dr Morin, Dr Mouraire, Prof. Muir, Prof. Pariente, Prof. Perrin-Fayolle, Dr Poignie, Dr Pujet, Dr Roullier, Dr Rufin, Dr Saint-Martin, Dr Severac, Dr Stern, Dr Taieb, Dr Taulelle, Dr Vincent. Diskhaler and Vohlmatic are trademarks of the Glaxo Wellcome group of companies.

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