A blinded comparison of fluticasone propionate with budesonide via powder devices in adult patients with moderate-to-severe asthma: a clinical evaluation

In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma. However, controversy still remains as to whether these differences translate into clinical benefits. This 12-week, international, randomized, doubleblind, parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate (FP) 800 μg daily, administered as a powder via the Diskhaler®, and budesonide (BUD) 1600 μg daily, administered using the Turbuhaler®, in adult patients with moderate-tosevere asthma. A total of 518 patients participated in the study, 256 of whom received FP and 262 BUD. Assessment of mean morning peak expiratory flow (PEF) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 μg daily and BUD 1600 μg daily in favour of FP (p = 0.003), with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD. Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF (p = 0.04), diurnal PEF variation (p = 0.03) and percentage predicted PEF (p = 0.003), as well as forced expiratory volume (p = 0.008), forced vital capacity (p = 0.02) and PEF (p = 0.005) measured at clinic visits. The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups, with similar changes seen for the median percentage of days with symptom score < 2, rescue medication use and exacerbations of asthma. The incidence of adverse events was found to be comparable in the two treatment groups. The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP, indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline, and 0.93 for BUD (p = 0.0002 compared with FP). In summary, FP 800 μg daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 μg daily.


Introduction
The objectives of anti-asthma therapy are to abolish symptoms, prevent exacerbations and maintain normal lung function. A number of therapeutic approaches are available for the clinical management of this condition, including bronchodilators and anti-inflammatory agents. In general, a stepwise approach is recommended. Minimum therapy to maintain effective control should be used, with the level of therapy increased with increasing asthma severity. Inhaled anti-inflammatory drugs are now re- 382 Mediators of Inflammation Vol 5. 1996 commended in international guidelines for the treatment of even mild asthma, with corticosteroids being the therapy of choice. 1 may have a role in the treatment of asthma exacerbations. 3 However, while older corticosteroids such as budesomide (BUD) and beclomethasone dipropionate (BDP) generally do not produce clinically significant systemic adverse effects at low doses, they may suppress the hypothalamic-pituitary:adrenal (HPA) axis function at higher doses. [4][5][6] There is therefore a clear need for new inhaled corticosteroids with a high topical potency combined with a reduced potential for systemic effects. Fluticasone propionate (FP) is a topical corticosteroid which has been shown in vitro ( Table  1) to be more potent than either BDP or BUD, with the advantage of a lower oral bioavail-ability7 -11 This is significant, as up to 80% of any inhaled dose may be swallowed and possibly absorbed into the circulation, increasing the potential for systemic adverse effects. 4 However, there has been some criticism as to the relevance of in vitro data being used to predict improved clinical benefit when treating patients with asthma. Clinical experience to date has shown that at equal doses, FP is more effective than either BDP or BUD for the treatment of moderate-to-severe asthma in adults 12a3 and to have an approximate 2:1 potency ratio com- 14 pared with other inhaled corticosteroids. 17 This double-blind study was designed to show equivalent efficacy and compare the tolerability of FP at a relatively high dose of 800 lag daily administered as a powder in adults with moderate-to-severe asthma, versus BUD 1 600 bg daily, an established treatment in this indication.

Study design
This was an international, double-blind, doubledummy, parallel-group study, with a treatment duration of 12 weeks preceded by a 2-week run-in period. Study visits took place at the start of the run-in and treatment periods, and after 4, haler (R) Patients received their usual inhaled steroid during the run-in period and switched to the study drug at the start of the treatment period.
Salbutamol was used throughout the study as rescue medication. All concomitant asthma medication (except oral corticosteroids and short-acting 2 agonists other than salbutamol) were permitted, provided they had been taken at a constant dosage for 4 weeks prior to visit 1 and during run-in. Any changes in concomitant therapy were documented.
The study was conducted to Good Clinical Practice in accordance with the Declaration of Helsinki (Hong Kong Amendment 1989), and approved by local ethics committees. Patients gave written or witnessed oral consent to participate.

Patients
Patients were aged 18 to 75 years, with a documented clinical history of reversible airways obstruction treated with inhaled steroids at a constant dosage for 4 weeks prior to study entry (BDP or BUD at 800-1 600 bg/day or FP at 400-800 bg/day). All patients were required to have: (i) a forced expiratory volume in 1 s (FEV1) of between 45% and 90% of the predicted value; (ii) a clear response to bronchodilator therapy, defined as a mean morning peak expiratory flow (PEF) over the last 7 days of the run-in period of < 90% of the response obtained following administration of salbutamol 400 lag or 800 btg at the start of the treatment period; (iii) required two or more doses of a bronchodilator, or to have had asthma symptoms (total score of > 2) on at least four of the last 7 days of the run-in period.
Patients were excluded from the study if their reversible airways obstruction was unstable; if they had received oral corticosteroids; had a respiratory tract infection or been admitted to withheld use of a short-acting bronchodilator hospital for respiratory disease during the 4 for 4 h, and a long-acting bronchodilator or weeks prior to study entry; or if they had theophylline for 12 h before attending the required 16 or more doses of rescue salbutamol clinic. All adverse events were recorded, and during the last 6 days of the run-in period, serum cortisol measurements were taken at Patients with concomitant disease which might baseline and at the end of the study. have interfered with assessment of study medication, hypersensitivity to inhaled corticosteroids, evidence of alcohol or drug abuse, and pregnant or lactating women were also excluded from participation.

Efficacy assessments
Statistical analysis For calculation of sample size, treatment groups were considered equivalent if the 95% confidence interval (CI) for the difference between treatments was < 15 1/min. Assuming a standard deviation of 30-45 1/min, as seen in The primary efficacy variable was morning previous studies, 260 evaluable patients per PEE measured every day at weeks 1-12, with treatment group were required to ensure a secondary variables of evening PEF, day-and power of at least 80%. It was anticipated that a night-time symptom severity, symptomatic maximum number of 700 patients, recruited bronchodilator use, clinical lung function meafrom approximately 50-60 centres, would be surements (PEE FEV1 and forced vital capacity required to achieve this figure. (FVC)) and exacerbation rate. Patients measured Data from the daily diary cards completed their own PEF in the morning and evening, during the run-in period were used to establish using a mini-Wright peak flow meter. PEF was baseline values. For the assessment period, data measured in the morning before taking any were analysed for weeks 1-4, 5-8, 9-12 and medication, and in the evening at least 4 h after 1-12. All efficacy data were analysed on an bronchodilator use (preferably at least 12 h after intent-to-treat basis. To be included in the analytaking a long-acting or oral 2 agonist, or sis of a variable, patients were required to have theophylline). Three measurements were taken, provided data from at least 1 day of the last and the highest one recorded in a daily diary week of the run-in period and at least 1 day of record card. the assessment period.
Symptom severity and bronchodilator use Diary card data from the treatment period were recorded by the patients each day on a were used to calculate mean morning and diary card. Day-time symptoms were rated on a evening PEE the diurnal variation in PEF (descale of 0 to 5 as follows: 0 no symptoms; fined as the mean difference between the 1 symptoms for one short period; 2 sympprevious evening and next morning values)and toms for two or more short periods; 3--symppercentage predicted PEF for both treatments toms for most of the day which did not affect over each assessment period. An analysis of daily activities; 4 symptoms for most of the covariance was performed on these variables day which did affect daily activities; 5 sympusing baseline values as a covariate. toms so severe the patient could not work or In addition, the following variables were perform normal daily activities. Night-time analysed by treatment and assessment period: symptoms were rated on a scale of 0 to 4: percentage of days with a symptom score < 2; O=no symptoms; 1 =symptoms causing the percentage of symptom-free nights; median patient to wake once or early; 2 symptoms night-time symptom score; median day-time causing the patient to wake twice or more symptom score; percentage of days and nights (including early waking); 3 symptoms causing when additional bronchodilator medication was the patient to be awake most of the night; not required; median day-and night-time rescue 4 symptoms so severe the patient did not medication requirement. These variables were sleep at all. Exacerbation of asthma was defined analysed by the Wilcoxon rank-sum test. An as requiring salbutamol more than eight times analysis of covariance was performed on the per day on more than 3 days during any 6-day measurements of PEE FEV1 and FVC taken in period, or a PEF value of < 85% of the baseline the clinic, using baseline values as a covariate.
morning value on 3 days during any 6-day All patients randomized to treatment were period, included in the safety analysis. Differences in Lung function measurements were performed .the number of exacerbations of asthma, withat the clinic at each of the five study visits

Efficacy
Morning and evening PEF improved over baseline values in both treatment groups during the course of the trial. For morning PEE greater improvements were seen on FP than on BUD (Fig. 1), resulting in statistically significant differences favouring FP at each assessment interval (p=O.O007, weeks 1-4 and 5-8; p 0.002 weeks 9-12) and over the whole 12-week treatment period (p= 0.003, Table 3). The overall improvement in mean morning PEF (baseline vs weeks 1-12)was 20.9 1 (Table 3). Patient diary card data revealed an improvement in symptoms experienced by the patientsover the course of the trial, with comparable stability in median day-and night-time symptom scores in both treatment groups. At baseline, patients in both treatment groups had a symptom score < 2 on only approximately 30% of days. Between weeks 9 and 12, however, this had increased to 95% with FP and 89% with BUD (Table 4). Similarly, the percentage of symptom-free nights improved from 28% at baseline to 80% between weeks 9 and 12 for FP, and 33% at baseline to 85% between weeks 9 and 12 for BUD (Table 4). There were no statistically significant differences between groups after controlling for centre. For all measures of symptom severity, the largest improvement occurred during the first 4 weeks of treatment in both treatment groups.
The improvement in asthma symptoms of patients receiving therapy was also reflected in a decrease in patients' additional day-and nighttime bronchodilator use. For the percentage of days with no additional bronchodilator use, there was a statistically significant difference in favour of FP over the period 9-12 weeks (  ments were seen over the course of the trial in both patient groups; this decrease, was most marked during the first 4 weeks of treatment (Table 5).
There were no significant differences in the total number of patients reporting exacerbations of asthma (as defined in the protocol) between the two groups. In all, 41 (16.0%) patients on FP and 51 (19.5%) of those who received BUD experienced exacerbations of asthma during the course of the trial.  The range of minimum and maximum values for percentage of symptom-free nights at baseline was 0-88%. All other ranges were 0-100%. BUD budesonide; FP fluticasone propionate. The range of minimum and maximum values for percentage of days with no additional bronchodilator use at baseline was 0-88% in the fluticasone propionate (FP) group and 0-70% in the budesonide (BUD) group. The range for percentage of nights with no additional bronchodilator use at baseline was 0-88% in both groups. All other ranges were 0-100%. bly related to study medication. The most common adverse events of any severity occurring during therapy are summarized in Table 6.
There were no significant intergroup differences in frequency. Mean serum cortisol levels, measured over the 12-week treatment period, increased by 12.2 nmol/1 from baseline in patients treated with FP compared with a decrease of -4.9 nmol/1 from baseline on BUD. In patients who did not take prednisolone during the trial (91% of patients on FP; 90% on BUD) the difference between FP and BUD was more marked (an increase of 13.5 nmol/1 for FP compared with a decrease of-8.0 nmol/l for BUD). Analysis of log-transformed values revealed a statistically significant difference between the two treatment groups favouring FP (p 0.0002). The adjusted geometric mean ratio was 1.03 for FP and 0.93 for BUD (p 0.0002). Most common is defined as experienced by >4% of patients in each treatment group. Some patients reported more than one adverse event. BUD budesonide; FP fluticasone propionate.
There was, however, a statistically significant interaction between the baseline serum cortisol values and treatments (p =0.0004). Suppression of the HPA axis of clinical concern was seen in six patients (2.3%) on FP compared with eleven (4.2%) of those who received BUD. However, this difference did not attain statistical significance.

Discussion
FP 800#g daily was found to be more effective than BUD 1 600 bg daily for the treatment of moderate-to-severe asthma in adults, with the primary efficacy variable of morning PEF showing a statistically significant advantage for FP over BUD. During the 12 weeks of treatment, morning PEF increased by 20.9 1/min in patients treated with FP compared with only 12.4 1/min on BUD. For purposes of comparison, an improvement of 20.0 1/min on therapy is gene.rally considered to be of clinical significance. 6 Analysis of evening PEF, diurnal variation and percentage predicted PEE as well as FEV1, FVC and PEF measured at the clinic, confirms these findings, with statistically significant differences in favour of FP for all parameters.
International asthma treatment guidelines recommending inhaled corticosteroids as first-line therapy are likely to lead to an increased use of these agents in asthma. 1'2 A stepwise approach, which increases the dose with increasing severity of symptoms is recommended, meaning that some patients with moderate asthma may receive inhaled corticosteroids at higher dosages than are currently given as maintenance. Once symptoms resolve and lung function improves, the dose is then typically reduced to the minimum required to maintain control. In practice, however, many physicians initiate therapy at a high dose, which is then reduced once symptoms have been adequately controlled to establish the optimum maintenance dose.
Inhaled corticosteroids such as BDP and BUD are generally well tolerated at maintenance doses. However, studies have shown that high doses of these agents are associated with an increased risk of systemic adverse effects, possibly including suppression of the HPA axis, osteoporosis and growth retardation. [4][5][6] Such findings clearly indicate the need for inhaled corticosteroids which combine high topical potency with higher safety margins for systemic adverse effects for the treatment of symptomatic patients who are currently taking high doses of these drugs. The results of this study indicate that FP, as predicted by its potent in vitro profile, may offer this advantage.
The improvements in lung function seen during treatment with FP in this trial are consistent with the results of previous studies which have shown FP to be at least as effective as BUD or BDP, even when administered at half the dosage. 12-17 FP therefore appears to be at least twice as potent as these older inhaled corticosteroids in vivo, confirming in vitro data7 -11 Secondary efficacy variables of day-and nighttime symptom score, additional bronchodilator use and exacerbations of asthma showed similar improvements in both treatment groups. Again, these results are consistent with those of previous studies. [12][13][14][15][16][17] Both patient groups experienced an improvement in their asthma symptoms and required less additional bronchodilator therapy. Night-time symptom severity and bronchodilator use were particularly improved. This is of clinical significance as both are possible factors which have a major effect on patient quality-of-life, although this was not formally studied in this trial.
The overall incidence and type of adverse events reported on therapy were found to be comparable in both treatment groups and only a minority of those adverse events reported were actually considered to be related to therapy in any way.
The potential for the two treatments to cause systemic effects was evaluated by measurement of serum cortisol levels. FP produced an increase in mean morning serum cortisol levels, whilst treatment with BUD decreased serum cortisol levels. The clinical importance of this is uncertain. Clinically relevant suppression of the HPA axis was seen in only 2.3% of patients treated with FP compared with 4.2% of those who received BUD during this trial.
In summary, the results of this study show that FP 800 pg daily is more effective than BUD 1 600 g daily for the treatment of adults with moderate-to-severe asthma. Superior improvements were seen in PEF with FP, even at half the dose of BUD. In contrast to BUD, FP at this relatively high dose had less effect on HPA axis function as measured by serum cortisol levels, indicating a superior efficacy:safety ratio. These findings support the use of FP in adult patients who require inhaled corticosteroids to further improve their asthma control.