RESPIRATORY MEDICINE (1998) 9.2, 95-104

Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less

N. C. BARNES”, C. HALLETT+, AND T. A. J. HARRIS+

“The London Chest Hospital, London, U.K. and ‘Glaxo Wellcombe plc., Uxbridge, U.K.

The relative clinical efficacy and systemic effects of different inhaled corticosteroids is controversial. To obtain further information on this matter, the authors have performed meta-analyses of seven trials comparing fluticasone propionate (FP) with budesonide (Bud), and seven trials comparing FP with beclomethasone dipropionate (BDP) for the treatment of asthma of all severities in adult and paediatric patients. In all cases, the drugs were compared at clinically equivalent doses, i.e. FP was given at half (or less) the microgram dose. The total number of patients was 1980 (1000 treated with FP 200-800,~~g day- ’ and 980 with Bud 400-1600pg day- ‘); and 1584 patients in the second analysis (780 treated with FP 200-1000 lug day- ’ and 804 with BDP 400-2000 pg day - ‘). FP significantly improved mean morning peak expiratory flow rate (PEFR) compared with Bud, with an overall difference of +ll lmin-’ . Analysis of serum cortisols showed no differences between FP and Bud treatment at low doses, but at higher dosages, and overall, significant differences in favour of FP were observed. In the second meta-analysis, no significant differences in PEFR were observed between FP and BDP in any of the seven individual studies or in the pooled analysis. Analysis of serum cortisols showed a similar trend to the previous analysis, however, no overall difference in serum cortisol results were seen between FP and BDP. In conclusion, the pooled analysis shows that FP at half the dose (or less) is more effective than Bud and as effective as BDP in improving PEFR; in addition, these improvements were achieved with a reduction in cortisol suppression compared with BUD and with no greater degree of cortisol suppression compared with BDP. This demonstrates, in patients with asthma, that FP has an improved efficacy to safety ratio compared with older inhaled corticosteroids.

RESPIR. MED. (1998) 92, 95-104

Introduction led to concern over the potential for systemic adverse effects, most notably suppression of the hypothalamic The efficacy of inhaled corticosteroids for the treatment of pituitary adrenal (HPA) axis, effects on bone metabolism asthma is well documented, with national and international and effects on growth of children (4-6). These systemic treatment guidelines recommending their use as first-line effects are due to a combination of the swaIlowed and therapy for all except mild asthma (1,2). These guidelines inhaled portion of the drug. use a step-wise approach to therapy with increases in Fluticasone propionate (FP) is a new generation, topical the dose of inhaled corticosteroids recommended if glucocorticosteroid for the treatment of asthma in adults disease control is considered inadequate. In practice, many and children. In vitro data have shown FP to be more physicians establish the optimum maintenance dose by potent at a given microgram dose than either budesonide initiating therapy at a high dose, which is then reduced once (Bud) or beclomethasone dipropionate (BDP) (7). Further- symptoms have been controlled, a practice now endorsed more, FP exhibits minimal oral systemic availability com- by the new British Asthma Guidelines (3). pared to Bud (< 1 vs 1 l%, respectively) (8,ll) or BDP However, the use of high doses of inhaled corticosteroids (estimated at 20%). This is most likely due to a combination in greater numbers of patients and for longer periods has of poor gastrointestinal absorption and almost complete first-pass metabolic inactivation (9-l 1). FP therefore appears to have the potential for a greater therapeutic index Received 12 March 1997 and accepted 12 May 1997. than Bud or BDP. Although many studies have been Correspondence should be addressed to: N. C. Barnes, Respiratory performed comparing FP with Bud and BDP, controversy Medicine, London Chest Hospital, Bonner Road, London E2 9JX, exists as to the relative clinical efficacy and safety of the U.K. different inhaled steroids.

0954-6111/98/010095 + 10 $12.00/O 0 1998 w. B. SAUNDERS COMPANY LTD TABLE 1. Overview of trials comparing FP with Bud

Number of patients in Number of patients in Study design morning PEFR analysis plasma cortisol analysis and treatment Dose FP Dose Bud Method of Author (year) [refl duration Cug day- ‘> OLg day ~ ‘1 delivery Patient population FP BUD Total FP BUD Total

Williams (1995) [17] Open-label 200 400 Accuhalera (FP) Children 150 150 300 - ~ -* 4 weeks TurbuhalerO (Bud) Langdon & Open-label 200 400 MD1 (FP) MD1 (Bud) Adults/mild-to-moderate 65 57 122 61 53 114 Thompson (1994) [14] 8 weeks asthma Connolly et al. Open-label 200 400 DiskhalerO (FP) Adults/symptomatic mild 8 3 81 164 49 51 100 (1995) [15] 8 weeks Turbuhalera (Bud) asthma Langdon & Open-label 400 800 Diskhale@ (FP) Adults/mild- to-moderate 127 116 243 84 87 171 Capsey (1994) [13] 8 weeks Turbuhaler@ (Bud) asthma Backman et al. Open-label 500 1200 Accuhalera (FP) Adults/mild-to-moderate 126 133 259 120 131 251 (1996) 1161 4 weeks Turbuhaler@ (Bud) asthma Steinmetz & Open-label 500 1200 MD1 (FP) Steroid-naive with moderate 221 205 426 - - -* Trautmann (1996) [19] 6 weeks Turbuhaler@ (Bud) asthma Ringdal eb al. Double-blind 800 1600 Diskhale@ (FP) Adults/moderate-to-severe 228 238 466 217 226 443 (1996) [18] 12 weeks Turbuhaler@ (Bud) asthma

Grand totals 1000 980 1980 531 548 1079

FP=Auticasone propionate, Bud= budesonide, MDI=metered-dose inhaler. *Plasma cortisol was not measured in the Williams or Steinmetz & Trautmann studies. FLUTICASONE META-ANALYSIS 97

TAESLE 2. Summary of BUD trials: confidence intervals for treatment differences in final week mean morning peak flow

Average difference Lower 95% Upper 95% Trial (FP-BUD) confidence limit confidence limit P-value

Williams (1995) 6.7 0.5 13.0 0.036 Langdon & Thompson (1994) 1.8 - 18.0 21.6 0.8 Connolly et al. (1995) 6.3 - 9.5 22.1 0.4 Langdon & Capsey (1994) 20.8 6.6 34.9 0.005 Backman et al. (1996) 8.5 - 3.4 20.4 0.16 Steinmetz & Trautmann (1996) 16.5 6.1 26.4 0.001 Ringdal et al. (1996) 15.3 6.6 24.1

TABLE 3. Summary of BUD trials: confidence intervals for treatment ratio of final visit plasma cortisollbaseline plasma cortisol

Average ratio Lower 95% Upper 95% Trial (FP/BUD) confidence limit confidence limit P-value

Langdon & Thompson (1994) 0.95 0.80 1.14 0.6 Connolly et al. (1995) 0.99 0.86 1.14 0.9 Langdon & Capsey (1994) 1.00 0.89 1.13 0.9 Backman et al. (1996) 1.30 1.14 1.48

To evaluate further the efficacy and safety of FP relative the drugs in healthy volunteers or at equal doses were not to Bud and BDP in patients with asthma, we have per- included formed a meta-analysis of all studies (as of December 1995) in adults and children where FP was used at half the microgram dose (or less) of Bud or BDP and morning peak EFFICACY expiratory flow rate (PEFR) was an outcome measure. In vitro and initial clinical studies have indicated a 2: 1 potency In all trials, mean morning PEFR was recorded daily by the ratio of FP to Bud and BDP (11-13) and FP is recom- subjects on a diary card during both the run-in phase and mended for use at half the dose of Bud and BDP in national the treatment phase. Measurements recorded on the 7 days and international guidelines (3). immediately prior to administration of the first dose of study medication were combined and divided by the number of days for which data were available for that 7-day Methods period to obtain a baseline measurement. To calculate the mean morning PEFR for the treatment SELECTION OF STUDIES phase, the end of treatment was determined from the protocol, and the last week was nominally described as The meta-analysis included seven studies evaluating the ending 3 days before the last day of the protocol. This safety and efficacy of FP vs Bud (13-19) and seven studies ensured that missing values towards the end of the study, vs BDP (12,20&25). Criteria for inclusion were studies of FP often due to administrative reasons, did not result in vs Bud or BDP in which FP was used at half or less of the substantial missing data. Three days was chosen arbitrarily dose of Bud or BDP, in which daily morning peak expir- as the minimum necessary, whilst maintaining as long a atory flow rate (PEFR) was an outcome measure and which period of treatment exposure as possible. Morning PEFR were reported by December 1995. One further study com- values recorded on this day and the previous 6 days were paring FP vs BDP in China was known to have completed then pooled and divided by the number of days for which patient entry, but the data were not reported or available. data were available. This value was then used as the mean The objective of the analysis was to evaluate all the data morning PEFR at the end of therapy. It was necessary to available to support or refute the hypothesis that FP at half use this method to determine mean morning PEFR as it the dose (or less) is as effective as Bud and BDP when used was found that many subjects did not complete their diaries to treat patients with asthma. Therefore, studies comparing in full for their final week of treatment. Furthermore, in TABLE 4. Overview of trials comparing FP with BDP

Number of patients in Number of patients in Study design morning PEFR analysis plasma cortisol analysis and treatment Dose FP Dose BDP Method of Author (year) [refl duration Cug day- ‘1 OLg day- ‘1 delivery Patient population FP BDP Total FP BDP Total

Dahl et al (1993) [12] Double-blind 200 400 MD1 Adults/mild-to-moderate 123 121 244 114 116 230 4 weeks asthma Leblanc et al. (1994) [23] Double-blind 200 400 MD1 Adults/mild-to-moderate 121 126 247 108 114 222 4 weeks asthma Gustafsson et al. (1993) [21] Double-blind 200 400 MD1 Children 173 171 344 182 181 363 6 weeks Pauwels et al. (1995) [25] Double-blind, 500 1000 MD1 Adults 147 151 298 154 159 313 crossover 6 months Lundback et al. (1993) [22] Double-blind 500 1000 Diskhaler@/MDI Adults/moderate asthma 141 153 294 165 170 335 6 weeks (FP) MD1 NW Bootsma et al. (1995) [24] Double-blind, 750 1500 MD1 Adults 7 14 21 7 13 20 crossover 6 weeks Barnes et al. (1993) [20] Double-blind 1000 2000 MD1 Adults/severe asthma 68 68 136 56 60 116 6 weeks

Grand totals 780 804 1584 786 813 1599

FP, fluticaspne propionate, BDP, beclomethasone dipropionate, MDI, metered-dose inhaler. FLLJTICASONE META-ANALYSIS 99

TABLE 5. Summary of BDP trials: confidence intervals for treatment differences in final week mean morning peak flow

Average difference Lower 95% Upper 95% Trial (FP-BDP) confidence limit confidence limit P-value

Dahlet al (1993) 2.1 +8.9 13.1 0.7 Leblanc et al. (1994) 3.2 - 6.4 12.7 0.5 Gustafsson et al. (1993) 5.2 - 2.3 12.6 0.2 Pauwels et al. (1995) 5.9 - 6.0 17.9 0.3 Lundback et al. (1993) 0.7 - 9.3 10.7 0.9 Bootsma et al. (1995) 8.6 - 23.3 40.5 0.6 Barnes et al. (1993) - 5.4 - 24.4 13.6 0.6 Pooled 3.2 - 0.9 7.4 0.13

TABLE 6. Summary of BDP Trials: confidence intervals for treatment ratio of final visit plasma cortisol/baseline plasma cortisol

Average ratio Lower 95% Upper 95% Trial (FPIBDP) confidence limit confidence limit P-value

Dahl et al. (1993) 0.99 0.90 1.09 0.051 Leblanc et al. (1994) 1.13 1.03 1.23 0.012 Gustafsson et al. (1993) 0‘99 0.91 1.08 0.9 Pauwels et al. (1995) 0.99 0.88 1.10 0.8 Lundback et al. (1993) 0.98 0.91 1.06 0.7 Bootsma et al. (1995) 1.21 1.00 1.46 0.06 Barnes et al. (1993) 1.25 1.02 1.54 0.030 Pooled 1.03 0.99 1.07 0.13

several subjects, morning PEFR values were recorded after STATISTICAL ANALYSIS the end of the treatment period. Therefore, this enabled the mean difference in improvement in morning PEFR on To perform the meta-analysis on the mean morning PEFR, therapy between FP and Bud or BDP to be calculated in a each separate trial was analysed with all patients included standard way for each trial. and using a common model involving centre, baseline and For each patient, the time to 10% improvement was treatment factors [SA@ Proc GLM (PC Version 6.08)]. determined as the day at which the diary card morning Similarly, in the meta-analysis for the plasma cortisol, PEFR reached 10% or more of the mean baseline value. each separate trial was analysed using the logarithm of the Exacerbations of asthma were collected from the diary ‘end-treatment’ plasma cortisol as the response variable cards, and the overall percentage of patients in each trial with centre, logged baseline and treatment factors included with exacerbations was calculated. in the model. Results are given as ratios following back transformation. As the analysis includes all worldwide studies performed SYSTEMIC ACTIVITY at a ratio of at least 1:2, a fixed-effect model was used for the meta-analysis. Morning serum cortisol levels (8810 am) were used as a A pooled weighted mean of all the separate estimates of measure of systemic activity. Serum cortisols were the treatment differences from each individual trial was measured in 12 of the 14 trials included in this meta- calculated using the inverse variance from each trial as analysis. For each of these studies, the ratio between the weights. mean serum cortisol level (nmol l- ‘) at baseline (a day The common variance estimate of the pooled treatment prior to taking treatment) and at the end of therapy (last difference was computed from the inverse sum of the square day of treatment) was determined for both study drugs and root of the above weights. This pooled variance was then the mean difference between cortisol ratios on FP and Bud used to calculate the confidence limits of the pooled mean or BDP was compared. treatment difference (ratio). (26). 100 N. C. BARNESETAL.

Study FP Bud Bud better i FP better Williams 200 400 Diskus Turbuhaler Langdon & 200 400 Thompson MD1 MD1 Connolly 200 400 etal. Diskhaler Turbuhaler Langdon & 400 800 Capsey Diskushaler Turbuhaler

Backman 500 1200 ef al. Diskus Turbuhaler

Steinmetz & 500 1200 Trautmann MD1 Turbuhaler Ringdal 800 1600 et al. Diskhaler Turbuhaler

Pooled

II,I,I,,,/I/,,,l,,I,lI/I,lll,,l,,,/l//I,l,,I,I,II,/,,/1l,,,,l,,,/ -25 -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 Difference in PEFR (1 mine’) FP - Bud FIG. 1. Difference with 95% confidence interval in mean improvement in morning peak expiratory flow rate (PEFR) for fluticasone propionate (FP) and budesonide (Bud). MDI, metered-dose inhaler.

No evidence was found for any heterogeneity among the from baseline favoured FP, attaining statistical significance estimates of morning PEFR or cortisol. in four of the seven trials (Fig. 1). The pooled analysis across all seven studies also significantly favoured FP, with a mean difference in improvement in morning PEFR Results on therapy between FP and Bud of + 11 1 min- ’ (95% confidence interval +7 to + 15). DEMOGRAPHICS Studies included in this analysis encompassed all severities of asthma in adult and paediatric patients, except for FP vs BDP patients on regular oral steroids. Seven studies compared There were no statistically significant differences in doses of FP 200-8OOpg day- ’ with Bud 400~16OO~g improvement in morning PEFR between FP at half the day - ’ administered via powder and metered-dose inhaler dose compared with BDP in any of the seven trials (Fig. 2). delivery systems. A total of 1980 patients recorded efficacy The pooled analysis showed a non-significant trend in data in these trials, 1000 of whom were treated with FP and favour of FP with a mean difference in improvement 980 with Bud. Individual study details are summarized in in morning PEFR on therapy between FP and BDP of Tables l-3. Seven studies compared FP 200-1000 pg day - ’ +3 1 min-’ (950/ o confidence interval - 0.9 to +7). with BDP 400-2000,~~g day-‘. A total of 1584 patients recorded efficacy data in these trials, 780 of whom were treated with FP and 804 with BDP. Individual study details SAFETY are summarised in Tables 4-6. Two studies involved children, one with Bud and one with BDP. The remaining FP vs BUD 12 studies were carried out in adults, covering all asthma severities up to moderate severe, and employed a variety of Mean changes in serum cortisol levels on therapy were powder and aerosol delivery devices. All studies were determined in five studies comparing FP at half the dose (or controlled, with eight being blinded and six open-label. less) with Bud. As would be expected, no significant inter- group differences in serum cortisols were detected at low doses. However, significant differences in favour of FP were EFFICACY apparent at higher dose levels (FP 2 500 pg day ~ 1 and Bud 2 1200 pg day - ‘) (Fig. 3). The pooled analysis across all FP vs BUD five studies also revealed a significant difference in co&sol In all studies comparing FP at half the dose (or less) with ratios favouring FP (ratio = 1.09 nmol 1~ ‘; 95% confidence Bud, mean improvements in morning PEFR on therapy interval 1.03-1.15). FLUTICASONE META-ANALYSIS 101

I I Study FP BDP BDP better i FP better

I Dahl et ai 200 400 I , MD1 MD1 I I I Leblanc ei ul. 200 400 I i: MD1 MD1 , I I I Gustafsson 200 400 I et Ml. MD1 MD1 I I Pauwels ei cii 500 1000 I I MD1 MD1 /I I 1000 II Lundback 500 I- I, ei al. DH/MDI MD1 I

I Bootsma et ul. 750 1500 I I MD1 MD1 II I I 1 Barnes et ai. 1000 2000 I I MD1 MD1 I Pooled +--H

-25 -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 Difference in morning PEFR (1 mu-‘) FP - BDP FIG. 2. Difference with 95% confidence interval in mean improvement in morning peak expiratory flow rate (PEFR) for fluticasone propionate (FP) and beclomethasone dipropionate (BDP). MDI, metered-dose inhaler; DH; Diskhaler.

I Study FP Bud Bud less effect i FP less effect on cortisol , on cortisol

I Langdon & 200 400 I I Thompson MD1 MD1 I

Connolly 200 400 et al. Diskhaler Turbuhaler ,+-j---i

Langdon & 400 800 Capsey. Diskhaler Turbuhaler

Backman 500 1200 I- et al. Diskus Turbuhaler Ringdal 800 1600 et al. Diskhaler Turbuhaler

Pooled ( I-F I I I I / I I / I / I I I I I I I I 1 I, I I / I I ,/I, I I I I,,, 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Mean ratio of plasma cortisols (nmol-l) FP/Bud FIG. 3. Difference with 95% confidence interval in the ratio of mean serum cortisol level at baseline and at the end of therapy between fluticasone propionate (FP) and budesonide (Bud). MDI, metered-dose inhaler.

FP vs BDP however, the pooled analysis across all seven studies showed no significant difference in cortisol ratios Mean changes in serum cortisol levels did not differ signifi- (ratio= 1.03 nmol l- i; 95% confidence interval 0.99-1.07). cantly between treatments in the studies comparing FP at Exacerbations of asthma were also collected for patients half the dose with BDP below 1OOOpg day-’ (Fig. 4). At in these studies. These results showed that exacerbations higher doses, a difference in favour of FP was apparent, occurred for between 4 and 10% of patients. No apparent 102 N. C. BARNES ET AL

I Study FP BDP BDI’ less effect I FP less effect on cortisol I on cortisol Dahl ei ai. 200 400 I! MD1 MD1 I I

L&lam ei ul. 200 400 MD1 MD1

Gustafsson 200 400 et al. MD1 MD1

Pauwels et al. 500 1000 MD1 MD1

Lundback 500 1000 It---& et al. DH/MDI MD1 I

Bootsma etaJ. 750 1500 MD1 MD1 i- Barnes ef al. 1000 2000 MD1 MD1

Pooled

0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Mean ratio of plasma cortisols (nmol-‘) FP/BDP FIG. 4. Difference with 95% confidence interval in the ratio of mean serum cortisol level at baseline and at the end of therapy between fluticasone propionate (FP) and beclomethason dipropionate (BDP). MDI, metered-dose inhaler. differences were seen for the percentage of patients suffer- be less affected by doses of inhaled corticosteroid in patients ing from an exacerbation, irrespective of their treatment, with normal lifestyle functioning than those in rested suggesting a similar effect on asthma control. normal volunteers. The pathophysiological pulmonary changes associated with asthma may result in clinically relevant differences in the pattern of drug distribution and Discussion absorption in the lung between asthmatic patients and normal subjects, and such differences could explain FP KS BUD alterations in the degree or rate of systemic drug absorption The results of this meta-analysis indicate that FP at half the (30). Finally, in patients with asthma, differences in the dose (or less) is more effective for the treatment of asthma respiratory fraction between delivery devices may not than Bud, irrespective of delivery system, as indicated by account for the variation in efficacy and systemic activity improvements in morning PEFR. This analysis also rein- seen in normal subjects (31). forces the findings of some individual studies (13-19) which have been used to claim a 2:l potency ratio compared with FP KS BDP Bud. The pooled analysis in mean changes in serum cortisol levels favoured FP over Bud, although, as might be antici- Comparisons between FP at half the dose and BDP showed pated, significant differences between these two cortico- that both treatments were equally as effective in terms of steroids were only seen at higher dose levels. Limitations of changes in PEFR. Mean changes in serum cortisol levels the analysis focus on the fact that some of the studies were showed that at doses 275Opg day- ’ (and also at one of open-label, because of difficulty in obtaining placebo the lower doses), differences between FP and BDP were just devices for Bud. However, it is noteworthy that the double statistically significant. However, no overall difference was blind, double-dummy study significantly favoured FP, both observed between these two drugs in the pooled analysis. in terms of efficacy and safety, and reflected the pooled analysis result. The results of this meta-analysis, therefore, contrast with Summary some reports which have suggested that FP has greater systemic activity than Bud in normal volunteers (27729) While results of the individual studies generally revealed no highlighting the difficulties with extrapolating findings from significant differences in plasma cortisol levels between FP normal subjects to patients with clinical disease. There are a YS Bud, and also FP vs BDP, at low doses, differences in number of possible explanations for these different findings. favour of FP at higher dose levels were detected. This may Hypothalamic-pituitary-adrenal (HPA) axis function may have important implications for patient management, as FLUTICASONE META-ANALYSIS 103 the major concern with currently available drugs of this adult asthmatics: a comparison using dry-powder class is the apparent increased risk of systemic effects, such inhaler devices. Br J Clin Res 1994; 5: 85-89. as suppression of the HPA axis and effects on bone 14. Langdon CG, Thompson J, on behalf of a UK study metabolism, at high doses (4-6). group. A multicentre study to compare the efficacy and The meta-analyses demonstrate that FP across a dose safety of inhaled fluticasone propionate and budeso- range of 200-8OOpg day -I is more effective than Bud nide via metered-dose inhalers in adults with mild-to- 400-16OOpg day-’ and across a dose range of 200-1000 pug moderate asthma. Br J Clin Res 1994; 5: 73-84. day ~ ’ as effective as BDP 400&2OOO~g day ~ ’ for the 15. Connolly A, on behalf of a UK Study Group. A treatment of asthma. FP is also less likely to suppress mean comparison of fluticasone propionate 100 pug twice morning serum cortisol levels than Bud, particularly/ daily with budesonide 200,ug twice daily via their moderate to severe asthma where higher dosages of inhaled respective powder devices in the treatment of mild corticosteroids are required. Therefore, the results of this asthma. Eur J Clin Res 1995; 7: 15-29. meta-analysis confirm that FP at half the clinically recom- 16. Backman R, Pickering CA, Baumgarten C, Huskisson mended dose of Bud or BDP is an effective treatment SC. Fluticasone propionate Diskus@ 25Opg bd com- option for asthma of all severities in both adult and pared with budesonide Turbohaler@ 600 pg bd in adult paediatric patients. Therefore, FP provides the potential for asthmatics. JACI 1996, 97: A267. an improved therapeutic efficacy to safety ratio compared 17. Williams J. Efficacy and ease of use of the fluticasone with Bud and BDP. propionate multi-dose powder inhaler compared with the budesonide reservoir powder device in asth- matic children. Euu Respiv J 1995; 8 (Suppl. 19): 469s References P2313. 18. Ringdal N, Swinburn P, Backman R et al. A blinded 1. National Heart, Lung and Blood Institute. 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