- Email: [email protected]
fluticasone combination is more effective than fluticasone plus oral montelukast in asthma
Vol. 97 (2003) 234 ^241
The salmeterol/£uticasone combination is more e¡ective than £uticasone plus oral montelukast in asthma N. RINGDAL*, A. ELIRAZw, P. PRUZINECz, H-H.WEBER}, P.G.H. MULDERz, M. AKVELD8 AND E.D. BATEMAN**, ON BEHALF OF AN INTERNATIONAL STUDYGROUP *Strandgaten 3, Molde, Norway, wKaplan Medical Centre, Rehovot, Israel, zUniversity Hospital, Bratislava, Slovak Republic, }Tulpenstrasse 1, Hannover, Germany, zDepartment of Biostatistics, Erasmus University, Rotterdam, The Netherlands, 8GlaxoSmithKline R&D, U.K. and **University of CapeTown and Groote Schuur Hospital, CapeTown, South Africa Abstract The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product (SFC) with fluticasone propionate (FP) plus oral montelukast (M) over 12 weeks in symptomatic asthma patients.The study was a multinational, randomised, double-blind, double-dummy, parallel-group design in patients aged 15 years. After a 4-week run-in during which all patients received FP100 mg twice daily, patients were randomised to inhaled SFC (50/100 mg) twice daily or inhaled FP100 mg twice daily and oral M10 mg once daily.Patients kept daily records of their peakexpiratory flow (PEF), symptom scores and use of rescue medication.Over the12-week treatment period, the adjusted increase in mean morning PEF was significantly greater in the SFC group (36 l/min) than the FP/Mgroup (19 l/min; Po0.001).Theimprovementin FEV1 was also significantlygreaterinthe SFC group (meantreatment difference 0.11l; Po0.001). SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations. Patients in the SFC group were also significantly more likely to have a rescue-free day. Both treatments were equally well tolerated.Combination therapy with FP plus salmeterol (SFC) produced significantly greaterimprovementsin lung function and asthma control than the addition of montelukastto FP. r 2002 Elsevier Science Ltd. All rights reserved. Available online at http://www.sciencedirect.com
Keywords £uticasone propionate; salmeterol; montelukast; therapy; combination drug; asthma
INTRODUCTION Worldwide, the rates of morbidity and mortality associated with asthma are increasing (1,2). Improvements to current asthma management are becoming increasingly important as more information becomes available on the e¡ects of untreated airway in£ammation on disease progression (3). National and international guidelines recommend that the goals of asthma management should be to control symptoms and prevent exacerbations, thus leading to reductions in healthcare burden and an improvement in the patient’s quality of life (4,5). It is widely accepted that inhaled corticosteroids are the most e¡ective preventative treatment Received 8 April 2002, accepted in revised form 29 August 2002 Correspondence should be addressed to: Martijn Akveld, GlaxoSmithKline, Grange Road, Rathfarnham, Dublin16, Ireland. Fax: +3531 4955 225; E-mail address: [email protected]
for asthma, as they are the most potent and e¡ective anti-in£ammatory medication available (6). For those patients who remain symptomatic on inhaled corticosteroids, addition of a long-acting beta-agonist such as salmeterol has been shown to produce greater improvements in lung function and symptom control than at least doubling the dose of inhaled corticosteroid (7^10). It is now well established that the combination of long-acting beta-agonists and inhaled corticosteroids is very e¡ective in treating both components of asthma, in£ammation and smooth muscle dysfunction (11). The addition of a leukotriene receptor antagonist to therapy has been proposed in current European datasheets as an alternative treatment strategy in those patients inadequately controlled on inhaled corticosteroids (12), but their role has not been clari¢ed in treatment guidelines (5,13). Leukotriene receptor antagonists have
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
a bronchodilator e¡ect and limited anti-in£ammatory activity (14). There is a modest increase in patients’ lung function and daytime asthma symptom score when montelukast is added to inhaled corticosteroid therapy (15). This study compares the clinical e¡ect of the addition of either salmeterol or montelukast to treatment with an inhaled corticosteroid, £uticasone propionate (FP), in adults with asthma who are symptomatic despite treatment with inhaled corticosteroids. A recent study performed in the U.S.A. has con¢rmed that salmeterol/ £uticasone propionate combination (SFC) is superior to therapy with FP plus montelukast (16). The aim of the current study was to con¢rm these ¢ndings in a geographical area with di¡erent clinical practices, to provide guidance to clinicians for the selection of the most e¡ective and safest therapeutic approach for patients who are receiving inhaled corticosteroids and who require additional therapy. Duplication of clinical trial ¢ndings is a good clinical research practice, to ensure that ¢ndings are reproducible and not spurious.
MATERIAL AND METHODS Study subjects Asthmatic patients aged15 years or older who were willing to give written informed consent were considered for entry into the run-in period. Patients were required to have received inhaled corticosteroids (400 ^1000 mg/ day of inhaled beclomethasone dipropionate, budesonide or £unisolide or 200 ^500 mg/day of inhaled FP) for at least 4 weeks before the study. Patients were also required to have a documented history of reversible airways obstruction and a 15% increase from baseline in forced expiratory volume in 1second (FEV1) following inhalation of up to 800 mg of salbutamol. Patients who had changed their regular asthma medication, had a respiratory tract infection or required hospitalisation for an acute exacerbation of asthma in 4 weeks before entry were excluded. Patients were also excluded if they had taken oral, depot or parenteral corticosteroids in the preceding 4 weeks or on X2 occasions in the preceding 12 weeks. Patients with a smoking history greater than10 pack years were also excluded, as were pregnant or lactating women, or those likely to become pregnant during the study. Patients were required to be able to understand and complete a daily record card (DRC) and measure their peak expiratory £ow (PEF) using a miniWright peak £ow meter. At the end of the run-in period, patients were required to meet all of the following additional criteria to demonstrate that they were symptomatic and their asthma uncontrolled: K
A mean morning PEF recorded on the DRC during the last 7 consecutive days of 450% and o85% of the
K
235
value measured in the clinic following the administration of salbutamol 400 mg. A cumulative symptom score (day and night) of X8 during the last 7 consecutive days of the run-in, and symptoms on at least 4 of the last 7 days of the run-in.
Patients with an FEV1 of r50% of the predicted normal value were excluded to avoid selection of patients that were too severe and at risk of early withdrawal for safety reasons.
Study design This was a multinational, multicentre, randomised, double-blind, double-dummy, parallel-group study carried out in114 centres in19 countries.The study was approved by the appropriate regulatory authority and local ethics committee for each centre and was conducted in accordance with the Declaration of Helsinki. A 4 -week run-in period was followed by 12 weeks’ treatment and a 2week follow-up. Patients discontinued all existing corticosteroids, long-acting beta-agonists, leukotriene antagonists and inhaled short-acting beta-agonists on entry into the 4 -week run-in period and were initiated on FP 100 mg twice daily via a DiskusTM inhaler (DiskusTM is a trademark of the GlaxoSmithKline group of companies). At the end of the run-in, eligible patients were randomised using patient allocation for clinical trials (PACT) software to receive either FP100 mg twice daily via a DiskusTM inhaler and oral montelukast 10mg once daily or salmeterol/FP combination (SFC)(50/100 mg strength) twice daily via a DiskusTM inhaler plus matching oral placebo once daily. The FP and SFC DiskusTM inhalers were identical in shape and colour to ensure blinding of the study. During the study, short-acting bronchodilators were replaced by salbutamol for rescue relief as required. Other regular existing asthma medication could be continued throughout the study provided the dose remained constant. The use of oral, parenteral or depot corticosteroids was not allowed during the study, except where documented for the treatment of exacerbations.
Assessments At the screening visit, DRCs were issued to each patient to record the following information: the highest of three morning and the highest of three evening PEF readings, the number of times salbutamol was administered for symptomatic relief, daytime symptom score on a 6 -point scale (0 = no symptoms; 5 = symptoms so severe that the patient is unable to work or perform normal daily activities), night-time symptom score on a 5-point scale (0 = no symptoms; 4 = symptoms so severe that the patient is unable to sleep) and changes in asthma medication.
236
Patients returned to the clinic after 4, 8 and 12 weeks of treatment. Lung function (FEV1) was measured at all clinic visits. The incidence and severity of exacerbations of asthma were recorded. Exacerbations were classi¢ed as mild (a deterioration in asthma requiring a clinically relevant increase in salbutamol use de¢ned as more than three additional inhalations per 24 -h period with respect to baseline for 42 consecutive days), moderate (requiring oral corticosteroids and/or antibiotics) or severe (requiring a hospitalisation). Patient assessment of satisfaction with treatment was recorded at the end of the run-in and the end of the treatment period on a 5-point scale ranging from very satis¢ed to very dissatis¢ed. Physician assessment of the e¡ectiveness of study treatment was recorded at the end of the treatment period on a 5-point scale ranging from very e¡ective to very ine¡ective. Compliance with the study treatment was assessed by recording the number of doses remaining in the DiskusTM inhaler and by counting the number of tablets returned to the clinic by the patient. The safety and tolerability of the study treatments was monitored by recording adverse events at each clinic visit and by monitoring the number of patient withdrawals. The patient’s oropharynx was examined at each clinic visit during the treatment period and swabs taken if candidiasis was suspected.
Statistical analysis The primary e⁄cacy variable was the mean morning PEF recorded on the DRC. The population used for analysis was de¢ned as all randomised patients with at least 1 day recorded on the DRC, but excluding those who were incorrectly randomised because they failed major inclusion criteria (the reduced ITT population).The two major criteria for exclusion were that patients did not demonstrate the required peak £ow reversibility or had too few symptoms during the run-in. Safety was assessed in the safety population, de¢ned as all randomised patients who took study medication. Assuming a standard deviation of PEF values of 50 l/min in the population studied and the requirement for 90% power, it was calculated that 470 evaluable patients would be required to detect a di¡erence between treatments of 15 l/min at the 5% level of signi¢cance. PEF measurements were analysed using repeated measures mixed model ANOVA. PEF data throughout the study were aggregated for each patient into six 14 -day periods; those periods with less than 8 valid scoring days were considered missing in the analyses. For symptom score and salbutamol use, daily symptom-free and rescue-free scores were used. In all ef¢cacy analyses, the average value over the run-in period was used as a baseline covariate. Other covariates included 14 -day period (a within-subjects factor with six
RESPIRATORY MEDICINE
levels), treatment, gender, age, height and country (between subjects). In the PEF analyses, the country e¡ect (with 19 levels) was considered random, whereas in the symptom-free and rescue-free analyses it was considered ¢xed. The between-period correlation (for repeated PEF data) and the day-to-day correlation (for repeated symptom-free and rescue-free data) were assumed to have a ¢rst order autoregressive structure. Clinic FEV1 was also analysed by mixed model ANOVA, with the baseline measurement as covariate. Symptom score and salbutamol use (rescue medication) were analysed using generalised linear modelling after dichotomisation of the daily scores as symptomfree (y/n) and rescue-free (y/n), respectively.The binomial distribution with logit link and the generalised estimating equation method (17) for repeated data were used. The logit link implies that the e¡ect of treatment on the probabilities of having a symptom-free or rescue-free day is expressed by means of an odds ratio of SFC relative to FP plus montelukast. Comparison between treatment groups of the number of patients who withdrew or had exacerbations of asthma was done using a chi-square test. The time to ¢rst exacerbation was analysed using Kaplan^Meier survival analysis with the log rank test. For the assessment of patient and physician satisfaction with treatment, comparisons were based on the response obtained at the end of treatment using the Wilcoxon rank sum test. All the above non-parametric tests were performed strati¢ed by (and hence adjusted for) country.
RESULTS Patient characteristics A total of 1168 patients were enrolled into the study, of whom 806 were randomised to study medication. One patient did not receive study medication, so 805 patients were included in the safety population (used for the adverse event tables). Three hundred and sixty two patients were withdrawn from the study before randomisation, mainly because of failing the criteria for entry into the treatment period. During the statistical analysis, a further 81 patients were excluded due to not meeting the pre-randomisation eligibility criteria to arrive at the reduced ITT population of 725 patients (356 in the SFC and 369 in the FP plus montelukast group).The demographic and baseline clinical characteristics of each treatment group are outlined in Table 1. The treatment groups were well matched for sex, age and lung function. The compliance with study medication was high in both groups; 96% of patients in both treatment groups returned the correct number of doses in the DiskusTM inhaler and 97% in both groups returned the right number of tablets according to the protocol requirements.
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
237
TABLE 1. Patient characteristics (reduced intent-to-treat population)
Patients, n: Sex, n (%) Male Female Mean age, years (range) Current smoker (%) Ex-smoker (%) Mean number of pack years (range) Mean % predicted FEV1 (SD): Reversibility, % change from baseline (SD)
SFC
FP plus montelukast
356
369
164 (46%) 192 (54%) 43 (15^75) 6.2% 20.8% 5 (0^10) 75.8% (15.3%) 27.4% (13.5%)
165 (45%) 204 (55%) 43 (14^79) 6.2% 24.4% 5(0^10) 74.3% (16.1%) 27.0% (12.6%)
FEV1 = forced expiratory volume in1second;FP = £uticasone propionate; SD = standard deviation; SFC = salmeterol/£uticasone propionate.
SFC FP + montelukast
Mean morning PEF (L/min)
420 410 400
P<0.05
390 380 370 360 0
1-2
3-4
5-6 9-10 7-8 Treatment week
11-12
1-12
FIG. 1. Mean morning peak expiratory £ow (PEF) at baseline and during 12 weeks’ treatment with either salmeterol/£uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice dailyplus oralmontelukast10 mg once daily.Error bars show standard error of the mean.
E⁄cacy PEF Mean baseline morning PEF was similar in the two treatment groups: 371and 367 l/min for the SFC group and FP plus montelukast group, respectively. Mean morning PEF increased from baseline in both treatment groups during the study period (Fig.1).The adjusted mean increase from baseline in the SFC group was 36 l/min over the 12-week period and19 l/min in the FP plus montelukast group.The di¡erence was 17 l/min (95% CI 12^22 l/min; Po0.05) which did not signi¢cantly change over the 2-weekly intervals throughout the treatment period (P=0.39; Fig. 1; Table 2). In both treatment groups, the improvement in mean morning PEF from baseline was evident 1 week after starting treatment (Fig. 2). The onset of improvement was, however, signi¢cantly faster in the SFC group with a signi¢cant di¡erence already recorded 24 h after starting treatment (mean treatment di¡erence 16.9 l/
min; 95% CI 1.9^32 l/min; P=0.03).The results for the primary e⁄cacy variable were supported by those for the secondary e⁄cacy variables. The increase from baseline in evening PEF over the 12-week treatment period was signi¢cantly greater in the SFC group, with an adjusted mean improvement of 29 l/min compared with 14 l/min in the FP plus montelukast group (Table 2).The di¡erence was 15 l/min (95% CI 11^20 l/min; Po0.05). There was some evidence that this di¡erence increased in time from 12 l/min in the ¢rst two-weekly interval to18 l/min in the sixth two-weekly interval.
Clinic FEV1 In both treatment groups, there was an improvement in FEV1 from baseline during the study period. At baseline, the mean FEV1 value in the SFC group was 2.47 l, which increased to 2.73 l at the end of 12 weeks (Table 2). This was signi¢cantly greater (Po0.05) than the FEV1 increase
238
RESPIRATORY MEDICINE
TABLE 2. E⁄cacy variables at baseline and during treatmentin patients who received salmeterol/£uticasone propionate combination (SFC; 50/100mg) twice daily or £uticasone propionate (FP) 100mg twice daily plus montelukast 10mg once daily for 12 weeks. analysis of reduced intent-to-treat population Variable
SFC
Mean morning PEF (l/min) (SEM) Mean evening PEF (l/min) (SEM) Clinic FEV1 (L) (SEM) Median % symptom-free days Median % symptom-free nights Median % rescue-free days Median % rescue-free nights
FP plus montelukast
Baseline
Weeks1^12
Baseline
Weeks1^12
370.8 7 5.1 385.7 7 5.3 2.47 7 0.04 7.1 32.1 23.5 53.6
407.7 7 2.2 416.5 7 2.2 2.73 7 0.03 50.0 78.6 71.4 92.9
367.3 7 4.9 380.3 7 4.9 2.41 70.04 7.0 30.3 20.7 56.7
388.2 7 2.1 395.5 7 2.1 2.58 7 0.03 38.5 71.4 66.7 85.7
Odds ratio
P value
F F F 1.32 1.28 1.29 1.15
0.0001 0.0001 0.0001 0.017 0.033 0.03 0.26
P-values are based on mixed model analysis of variance or generalised linear model. SEM = standard error ofthe mean;FEV1 = forced expiratory volume in1second,PEF= peak expiratory £ow.
SFC FP + montelukast
410
SFC FP + montelukast
2.7 Mean FEV1 (L)
Mean morning PEF (L/min)
2.8
400
390
380
P<0.05 2.6 2.5 2.4
370
2.3
360 0
1
2
3 4 Treatment day
5
6
7
0
4
8 Treatment week
12
1-12
FIG. 2. Mean morning peak expiratory £ow (PEF) at baseline and during the ¢rst 7 days of treatment with either salmeterol/ £uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice daily plus oral montelukast 10 mg once daily. Error bars show standard error of the mean.
FIG. 3. Forced expiratory volume in 1s (FEV1; adjusted mean values 7 standard error of the mean) at baseline and during 12 weeks’ treatment with either salmeterol/£uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice dailyplus oralmontelukast10 mg once daily.
in the FP plus montelukast group, which rose to 2.58 l from a baseline of 2.41l (mean treatment di¡erence 0.11l; 95% CI 0.06 ^ 0.16 l; Po0.05) (Fig. 3).
group for weeks 1^12 (odds ratio 1.28; 95% CI 1.02^1.61; Po0.05).
Rescue medication use Symptom-free days and nights The percentage of symptom-free days and nights improved from baseline in both treatment groups (Table 2).The patients in the SFC group were signi¢cantly more likely to have a symptom-free day during the study period (odds ratio 1.32; 95% CI 1.05^1.65; Po0.05). The results for symptom-free nights were very similar; the chances of a symptom-free night were signi¢cantly higher in the SFC group than in the FP plus montelukast
The number of rescue-free days and nights, i.e. those days and nights when salbutamol was not used, increased from baseline in both groups during the 12-week treatment period (Table 2).The patients in the SFC group were signi¢cantly more likely to have a rescue-free day during the study period (odds ratio 1.29; 95% CI 1.02^ 1.63; P=0.03). The chances of a rescue-free night were also numerically higher in the SFC group than in the FP plus montelukast group for weeks 1^12, but this did not
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
Exacerbations of asthma The number of patients who had at least one asthma exacerbation (any severity) was signi¢cantly lower in the SFC group (34; 9.6%) than in the FP plus montelukast group (54; 14.6%; Po0.05). The percentage of patients who had at least one asthma exacerbation of either moderate or severe intensity was 4.8% in the SFC group and 8.4% in the FP plus montelukast group; this di¡erence did not reach statistical signi¢cance (P=0.07).The time to the ¢rst exacerbation was signi¢cantly longer in the SFC group than in the FP plus montelukast group (Po0.05) (Fig. 4).
Patient/physician satisfaction with treatment The percentage of patients at the end of the treatment period who were either very satis¢ed or satis¢ed with the treatment they had received was signi¢cantly higher in the SFC group (92.9%) than in the FP plus montelukast group (83.5%; Po0.05).The percentage of physicians who assessed the treatment as very e¡ective or e¡ective was also signi¢cantly higher in the SFC group (79.6%) than in the FP plus montelukast group (72.6%; Po0.05).
Eleven serious adverse events (SAEs) were reported (four in the SFC group and seven in the FP plus montelukast group) of which none were drug-related. The most common SAE was hospitalisation due to an asthma exacerbation; this occurred in one patient in the SFC group and two in the FP plus montelukast group. Signi¢cantly fewer patients withdrew from the SFC group during the treatment period (19; 5%) than from the FP plus montelukast group (37; 10%) (Po0.05). The main reason for these withdrawals was an adverse event (32 out of 56 withdrawals; 57%).
DISCUSSION The results of this study showed that SFC (salmeterol 50 mg/FP 100 mg) administered twice daily for 12 weeks was more e¡ective than FP100 mg twice daily plus montelukast 10 mg once daily for the treatment of symptomatic patients with moderate to severe asthma; SFC 100 96 Exacerbation-free (%)
reach signi¢cance (odds ratio 1.15; 95% CI 0.90 ^1.47; P=0.26).
92 88 84
Safety
80
Adverse events
76
The overall incidence of adverse events in the safety population was similar in the SFC group (44%) and the FP plus montelukast group (42%).Respiratory system events predominated during treatment, with the most frequent event in both groups being an exacerbation of asthma (Table 3). Oropharyngeal candidiasis occurred in three patients in the SFC group and one in the FP plus montelukast group.
239
SFC FP + montelukast
0
1
2
3
4 5 6 7 8 Treatment week
9 10 11 12
FIG. 4. Number of patients in each study arm who remained free of an asthma exacerbation over the 12 weeks of the study, plotted as a percentage of the number who started study treatment (Kaplan^Meier analysis).Patients received either salmeterol/£uticasone propionate combination (50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice daily plus oral montelukast10 mg once daily.
TABLE 3. Adverse events reported by more than ¢ve patients in the safety population Number of events (%)
Exacerbation of asthma Common cold Upper respiratory tract infection Headache Sore throat In£uenza Bronchitis
SFC (n=404)
FP plus montelukast (n=401)
39 (10%) 30 (7%) 15 (4%) 12 (3%) 10 (2%) 9 (2%) 4 (o1%)
50 (12%) 31 (8%) 9 (2%) 18 (4%) 3 (o1%) 10 (2%) 10 (2%)
FP = £uticasone propionate; SFC = salmeterol/£uticasone propionate.
240
produced larger improvements in lung function and symptom control and reduced the frequency and timeto-¢rst exacerbation. These results, obtained from a multicountry patient population, reproduce those of an earlier study performed in a U.S. population (16). This study was designed to assess the bene¢ts of adding either salmeterol or montelukast to patients already taking inhaled corticosteroids. Criteria for inclusion into the study ensured that patients were asthmatic (as demonstrated by their reversibility), symptomatic and required step-up therapy. The requirement for the subjects to be reversible to salbutamol may have potentially favoured the SFC group over the FP plus montelukast group. However, reversibility to short-acting bronchodilators is central in the correct diagnosis of asthma and has been used as a patient selection criterion in other large studies investigating the clinical bene¢t of adding montelukast to inhaled corticosteroid therapy (15,18). The study duration of 12 weeks was chosen as it has previously been shown to be su⁄cient to demonstrate the maximal e¡ect of both salmeterol (7,8) and montelukast (15). In the current study, the di¡erence in morning PEF between the groups of 17 l/min was close to the value perceived by patients to be of a clinical bene¢t (19). In addition, the improvement in the other endpoints achieved in the SFC group was accompanied by fewer patient withdrawals and a smaller number of asthma exacerbations. The percentage of patients with at least one exacerbation was signi¢cantly lower in the SFC group, as was the time to ¢rst exacerbation. Reduction in the frequency of asthma exacerbations is important in decreasing morbidity and mortality in asthma patients, improving their quality of life and reducing the costs associated with the disease. As with all controlled clinical trials, questions remain around the generalisability of these ¢ndings to daily practice. Patients in the current trial were selected before entering the study and had very high levels of compliance. Studies that addressed this issue using retrospective data from clinical practice found that in a real-world setting the combination of salmeterol and FP or the combination of salmeterol and inhaled corticosteroids provides superior clinical bene¢t compared to inhaled corticosteroids plus leukotriene modi¢ers. This was demonstrated by less visits to the emergency department and hospital, and less use of rescue medication by patients on the combination of salmeterol and FP or other inhaled corticosteroids (20,21). In the current study, the di¡ering e⁄cacy cannot be attributed to the di¡erences in compliance in the taking of study treatment. As mentioned before and as expected in the study setting, compliance with study medication was high in both treatment groups. In both groups, the need for an additional inhaler for rescue use remains, meaning that outside the clinical trial setting in
RESPIRATORY MEDICINE
daily practice in the montelukast group, treatment with three separate drugs is required. The use of multiple routes and daily administrations of treatment has been shown to contribute to poor compliance (22). At the end of the study, patient satisfaction with treatment was high.The number of patients who were either very satis¢ed or satis¢ed with the study medication was signi¢cantly higher in the SFC group. Similar ¢ndings have been reported in a recently published study (23). In the current study, this result is notable since the study medication was administered double-dummy, i.e. both groups used two inhalations and one tablet per day, yet patients and investigators recorded a preference for SFC. In summary, in patients symptomatic on a low dose of inhaled corticosteroids, both treatments were e¡ective, although the improvement seen with SFC was consistently better, irrespective of study endpoint measured. Both treatments were equally well tolerated. These results strengthen the ¢ndings of previously reported studies with both montelukast and za¢rlukast (15,24,25) and con¢rm that the combination of salmeterol and FP is the preferred option for patients uncontrolled on a low dose of inhaled corticosteroids.
Acknowledgements The authors would like to thank the investigators who took part in this study: Prof. Z. Iankova, Dr Al. Simidchiev; Prof. K. Kissiova, Prof. M. Peneva, Dr T. Odjakova, Prof. J. Mileva, Prof.V. Dimitrov, Prof. M. Staneva, Prof. D. Popov, Dr Gugushev (Bulgaria); Dr E. Amer, Dr A. Booth, Dr N. Colman, Dr M. Gold, Dr D. Stollery, Dr G. Tellier, Dr K. Tse, Dr W. Yang (Canada); Prof. Dr V. Ahel, Dr A. Rozman, Dr A. Markovi, Dr E.Verona, Dr A. StipiP MarkoviP (Croatia); Dr M. Fuchs, Dr F. Kopriva, Dr B. Novotna, Dr Z. Parakova (Czech Republic); Prof. L. Jannus-Pruljan, Dr E. Pˇttsepp (Estonia); Dr W.Gams, Dr U. Gehling, Dr M. Jahn, DrT. Jung, Dr A. Linnho¡, Dr H.-H. Ponitz, Dr E. Scheer, Dr R. Schnorr, Dr P.-M. Stutz, Dr H. ten-Ho¡, Dr L. vonVersen, Dr W.Weede (Germany); Dr N. Galanis, Dr N. Georgatou, Dr D. Gioulekas, Prof. N. Siafakas (Greece); Dr L. Bentur, Dr R. Breuer, Dr M. Kramer, Prof. A. Rubin, Dr E. Tabachnik, Dr B. Volovitz (Israel); Dr I. Cerveri, Prof. E. Maggi, Dr A. Potena, Dr M. Vignola, Prof. M. Neri (Italy); Dr V. Duurkens, Dr E. van Hezik, Dr W. Pieters, Dr N. Schloesser, Dr H. Damste, Dr F.Vermetten (The Netherlands); Dr B. Harbo, Dr O. Haugen, Dr H.-O. Hoivik, Dr E. Ofjord, Dr O. Rysstad (Norway); Dr D.Comajova, Dr M. Hrubisko, Prof. P. Kristufek, Dr J.Ruzicka (Slovakia); Dr S. Kajba, Dr R. Kopriva, Prof. J. Sorli (Slovenia); Dr M. Abdool-Ga¡ar, Prof. P. Bardin, Dr C. Duvenage, Dr J. Killian, Dr M. Laher, Prof. U. Lalloo, Dr J. O’Brien (South Africa); Dr T. Carrillo, Dr L. Prieto, Dr J. Serra (Spain); Dr S. Boes Hansen,
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
Dr N. Funder Jorgensen, Dr C. Pedersen, Dr K.Theman, Dr J. Ziegler (Sweden); Prof. F. Erkan, Dr Z. Misirligil, Prof. A. Sayiner, Prof. N. Yildirim (Turkey); Prof. L.Yashina, Prof. Y. Feschenko (Ukraine); Dr W. Aitchison, Dr A. Bremner, Dr B. Calder, Dr G .Canning, Dr A. Cooper, Dr A. Darrah, Dr P. Dobson, Dr M. Doyle, Dr D. Ferry, Dr S. Gunn, Dr G. Hackett, Dr J. Ham, Dr P. Lee, Dr C. Lenton, Dr J.Litch¢eld, Dr R. Lloyd, Dr A.Marshall, Dr H. McGoldrick, Dr B. Penney, Dr P. Shearer, Dr D. Sheldon, Dr G. Singh (UK). The authors would like to thank Andy Michael and Richard Steadman for their valuable statistical input. This study was sponsored by GlaxoSmithKline (Study Number SAS40015).
REFERENCES 1. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma: United States 1960–1995. MMWR 1998; 47: 1–28. 2. Anderson HR, Butland BK, Strachan DP. Trends in prevalence and severity of childhood asthma. BMJ 1994; 308: 1600–1604. 3. Robertson CF, Rubinfield AR, Bowes G. Pediatric asthma deaths in Victoria. The mild are at risk. Pediatr Pulmonol 1992; 13: 95–100. 4. Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report 2. National Institutes of Health, National Heart, Lung and Blood Institute. July 1997, NIH Publication Number 97–4051. 5. British Thoracic Society. The British guidelines on asthma management. 1995 review and position statement. Thorax 1997; 52 (Suppl. 1): S1–S21. 6. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998; 102: 531–538. 7. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344: 219–224. 8. Woolcock AJ, Lundba¨ck B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroid with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481–1488. 9. Condemi JJ, Goldstein S, Kalberg C, Yancey S, Emmett A, Rickard K. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Ann Allergy Asthma Immunol 1999; 82: 383–389. 10. Van Noord JA, Schreurs AJ, Mol SJ, Mulder PG. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999; 54: 207–212. 11. Johnson M. Combination therapy for asthma: complementary effects of long-acting beta-agonists and corticosteroids. Curr Allergy Clin Immunol 2002; 15: 16–22.
241
12. Merck Sharp & Dohme Ltd. Summary of product characteristics. 27 June 2000. Available from URL: http://srs.vhn.net/eMc/documents/01100/01192/SPC.1192.html. 13. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. National Institutes of Health, National Heart, Lung and Blood Institute. 2002, Updated from: NHLBI/WHO Workshop Report: Global Strategy for Asthma Management and Prevention Issued January, 1995. NIH Publication No. 02–3659. 14. Dempsey OJ. Leukotriene receptor antagonist therapy. Postgrad Med J 2000; 76: 767–773. 15. Laviolette M, Malmstro¨m K, Lu S, et al for the Montelukast/ Beclomethasone Additivity Group. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999; 160: 1862–1868. 16. Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/ salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000; 106: 1088–1095. 17. Liang KY, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika 1986; 73: 13–22. 18. Bjermer L, Bisgaard H, Bousquet J, etal. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy Trial). Respir Med 2000; 94: 612–621. 19. Santenello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999; 14: 23–27. 20. O’Connor RD, O’Donnell JC, Pinto LA, Wiener DJ, Legorreta AP. Two-year retrospective economic evaluation of three dualcontroller therapies used in the treatment of asthma. Chest 1999; 121: 1028–1035. 21. Stempel DA, O’Donnell JC, Meyer JW. Inhaled corticosteroids plus salmeterol or montelukast: effects on resource utilization and costs. J Allergy Clin Immunol 2002; 109: 433-439. 22. Kelloway JS, Wyatt RA, Adlis SK. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994; 154: 1349–1352. 23. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomized double-blind placebo-controlled trial. Lancet 2001; 357: 2007–2011. 24. Fish JE, Israel E, Murray JJ, Emmett A, Boone R, Yancey SW, Rickard KA. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001; 120: 423–430. 25. Busse W, Nelson H, Wolfe J, Kalberg C, Yancey SW, Rickard KA. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999; 103: 1075–1080.
The salmeterol/£uticasone combination is more e¡ective than £uticasone plus oral montelukast in asthma N. RINGDAL*, A. ELIRAZw, P. PRUZINECz, H-H.WEBER}, P.G.H. MULDERz, M. AKVELD8 AND E.D. BATEMAN**, ON BEHALF OF AN INTERNATIONAL STUDYGROUP *Strandgaten 3, Molde, Norway, wKaplan Medical Centre, Rehovot, Israel, zUniversity Hospital, Bratislava, Slovak Republic, }Tulpenstrasse 1, Hannover, Germany, zDepartment of Biostatistics, Erasmus University, Rotterdam, The Netherlands, 8GlaxoSmithKline R&D, U.K. and **University of CapeTown and Groote Schuur Hospital, CapeTown, South Africa Abstract The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product (SFC) with fluticasone propionate (FP) plus oral montelukast (M) over 12 weeks in symptomatic asthma patients.The study was a multinational, randomised, double-blind, double-dummy, parallel-group design in patients aged 15 years. After a 4-week run-in during which all patients received FP100 mg twice daily, patients were randomised to inhaled SFC (50/100 mg) twice daily or inhaled FP100 mg twice daily and oral M10 mg once daily.Patients kept daily records of their peakexpiratory flow (PEF), symptom scores and use of rescue medication.Over the12-week treatment period, the adjusted increase in mean morning PEF was significantly greater in the SFC group (36 l/min) than the FP/Mgroup (19 l/min; Po0.001).Theimprovementin FEV1 was also significantlygreaterinthe SFC group (meantreatment difference 0.11l; Po0.001). SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations. Patients in the SFC group were also significantly more likely to have a rescue-free day. Both treatments were equally well tolerated.Combination therapy with FP plus salmeterol (SFC) produced significantly greaterimprovementsin lung function and asthma control than the addition of montelukastto FP. r 2002 Elsevier Science Ltd. All rights reserved. Available online at http://www.sciencedirect.com
Keywords £uticasone propionate; salmeterol; montelukast; therapy; combination drug; asthma
INTRODUCTION Worldwide, the rates of morbidity and mortality associated with asthma are increasing (1,2). Improvements to current asthma management are becoming increasingly important as more information becomes available on the e¡ects of untreated airway in£ammation on disease progression (3). National and international guidelines recommend that the goals of asthma management should be to control symptoms and prevent exacerbations, thus leading to reductions in healthcare burden and an improvement in the patient’s quality of life (4,5). It is widely accepted that inhaled corticosteroids are the most e¡ective preventative treatment Received 8 April 2002, accepted in revised form 29 August 2002 Correspondence should be addressed to: Martijn Akveld, GlaxoSmithKline, Grange Road, Rathfarnham, Dublin16, Ireland. Fax: +3531 4955 225; E-mail address: [email protected]
for asthma, as they are the most potent and e¡ective anti-in£ammatory medication available (6). For those patients who remain symptomatic on inhaled corticosteroids, addition of a long-acting beta-agonist such as salmeterol has been shown to produce greater improvements in lung function and symptom control than at least doubling the dose of inhaled corticosteroid (7^10). It is now well established that the combination of long-acting beta-agonists and inhaled corticosteroids is very e¡ective in treating both components of asthma, in£ammation and smooth muscle dysfunction (11). The addition of a leukotriene receptor antagonist to therapy has been proposed in current European datasheets as an alternative treatment strategy in those patients inadequately controlled on inhaled corticosteroids (12), but their role has not been clari¢ed in treatment guidelines (5,13). Leukotriene receptor antagonists have
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
a bronchodilator e¡ect and limited anti-in£ammatory activity (14). There is a modest increase in patients’ lung function and daytime asthma symptom score when montelukast is added to inhaled corticosteroid therapy (15). This study compares the clinical e¡ect of the addition of either salmeterol or montelukast to treatment with an inhaled corticosteroid, £uticasone propionate (FP), in adults with asthma who are symptomatic despite treatment with inhaled corticosteroids. A recent study performed in the U.S.A. has con¢rmed that salmeterol/ £uticasone propionate combination (SFC) is superior to therapy with FP plus montelukast (16). The aim of the current study was to con¢rm these ¢ndings in a geographical area with di¡erent clinical practices, to provide guidance to clinicians for the selection of the most e¡ective and safest therapeutic approach for patients who are receiving inhaled corticosteroids and who require additional therapy. Duplication of clinical trial ¢ndings is a good clinical research practice, to ensure that ¢ndings are reproducible and not spurious.
MATERIAL AND METHODS Study subjects Asthmatic patients aged15 years or older who were willing to give written informed consent were considered for entry into the run-in period. Patients were required to have received inhaled corticosteroids (400 ^1000 mg/ day of inhaled beclomethasone dipropionate, budesonide or £unisolide or 200 ^500 mg/day of inhaled FP) for at least 4 weeks before the study. Patients were also required to have a documented history of reversible airways obstruction and a 15% increase from baseline in forced expiratory volume in 1second (FEV1) following inhalation of up to 800 mg of salbutamol. Patients who had changed their regular asthma medication, had a respiratory tract infection or required hospitalisation for an acute exacerbation of asthma in 4 weeks before entry were excluded. Patients were also excluded if they had taken oral, depot or parenteral corticosteroids in the preceding 4 weeks or on X2 occasions in the preceding 12 weeks. Patients with a smoking history greater than10 pack years were also excluded, as were pregnant or lactating women, or those likely to become pregnant during the study. Patients were required to be able to understand and complete a daily record card (DRC) and measure their peak expiratory £ow (PEF) using a miniWright peak £ow meter. At the end of the run-in period, patients were required to meet all of the following additional criteria to demonstrate that they were symptomatic and their asthma uncontrolled: K
A mean morning PEF recorded on the DRC during the last 7 consecutive days of 450% and o85% of the
K
235
value measured in the clinic following the administration of salbutamol 400 mg. A cumulative symptom score (day and night) of X8 during the last 7 consecutive days of the run-in, and symptoms on at least 4 of the last 7 days of the run-in.
Patients with an FEV1 of r50% of the predicted normal value were excluded to avoid selection of patients that were too severe and at risk of early withdrawal for safety reasons.
Study design This was a multinational, multicentre, randomised, double-blind, double-dummy, parallel-group study carried out in114 centres in19 countries.The study was approved by the appropriate regulatory authority and local ethics committee for each centre and was conducted in accordance with the Declaration of Helsinki. A 4 -week run-in period was followed by 12 weeks’ treatment and a 2week follow-up. Patients discontinued all existing corticosteroids, long-acting beta-agonists, leukotriene antagonists and inhaled short-acting beta-agonists on entry into the 4 -week run-in period and were initiated on FP 100 mg twice daily via a DiskusTM inhaler (DiskusTM is a trademark of the GlaxoSmithKline group of companies). At the end of the run-in, eligible patients were randomised using patient allocation for clinical trials (PACT) software to receive either FP100 mg twice daily via a DiskusTM inhaler and oral montelukast 10mg once daily or salmeterol/FP combination (SFC)(50/100 mg strength) twice daily via a DiskusTM inhaler plus matching oral placebo once daily. The FP and SFC DiskusTM inhalers were identical in shape and colour to ensure blinding of the study. During the study, short-acting bronchodilators were replaced by salbutamol for rescue relief as required. Other regular existing asthma medication could be continued throughout the study provided the dose remained constant. The use of oral, parenteral or depot corticosteroids was not allowed during the study, except where documented for the treatment of exacerbations.
Assessments At the screening visit, DRCs were issued to each patient to record the following information: the highest of three morning and the highest of three evening PEF readings, the number of times salbutamol was administered for symptomatic relief, daytime symptom score on a 6 -point scale (0 = no symptoms; 5 = symptoms so severe that the patient is unable to work or perform normal daily activities), night-time symptom score on a 5-point scale (0 = no symptoms; 4 = symptoms so severe that the patient is unable to sleep) and changes in asthma medication.
236
Patients returned to the clinic after 4, 8 and 12 weeks of treatment. Lung function (FEV1) was measured at all clinic visits. The incidence and severity of exacerbations of asthma were recorded. Exacerbations were classi¢ed as mild (a deterioration in asthma requiring a clinically relevant increase in salbutamol use de¢ned as more than three additional inhalations per 24 -h period with respect to baseline for 42 consecutive days), moderate (requiring oral corticosteroids and/or antibiotics) or severe (requiring a hospitalisation). Patient assessment of satisfaction with treatment was recorded at the end of the run-in and the end of the treatment period on a 5-point scale ranging from very satis¢ed to very dissatis¢ed. Physician assessment of the e¡ectiveness of study treatment was recorded at the end of the treatment period on a 5-point scale ranging from very e¡ective to very ine¡ective. Compliance with the study treatment was assessed by recording the number of doses remaining in the DiskusTM inhaler and by counting the number of tablets returned to the clinic by the patient. The safety and tolerability of the study treatments was monitored by recording adverse events at each clinic visit and by monitoring the number of patient withdrawals. The patient’s oropharynx was examined at each clinic visit during the treatment period and swabs taken if candidiasis was suspected.
Statistical analysis The primary e⁄cacy variable was the mean morning PEF recorded on the DRC. The population used for analysis was de¢ned as all randomised patients with at least 1 day recorded on the DRC, but excluding those who were incorrectly randomised because they failed major inclusion criteria (the reduced ITT population).The two major criteria for exclusion were that patients did not demonstrate the required peak £ow reversibility or had too few symptoms during the run-in. Safety was assessed in the safety population, de¢ned as all randomised patients who took study medication. Assuming a standard deviation of PEF values of 50 l/min in the population studied and the requirement for 90% power, it was calculated that 470 evaluable patients would be required to detect a di¡erence between treatments of 15 l/min at the 5% level of signi¢cance. PEF measurements were analysed using repeated measures mixed model ANOVA. PEF data throughout the study were aggregated for each patient into six 14 -day periods; those periods with less than 8 valid scoring days were considered missing in the analyses. For symptom score and salbutamol use, daily symptom-free and rescue-free scores were used. In all ef¢cacy analyses, the average value over the run-in period was used as a baseline covariate. Other covariates included 14 -day period (a within-subjects factor with six
RESPIRATORY MEDICINE
levels), treatment, gender, age, height and country (between subjects). In the PEF analyses, the country e¡ect (with 19 levels) was considered random, whereas in the symptom-free and rescue-free analyses it was considered ¢xed. The between-period correlation (for repeated PEF data) and the day-to-day correlation (for repeated symptom-free and rescue-free data) were assumed to have a ¢rst order autoregressive structure. Clinic FEV1 was also analysed by mixed model ANOVA, with the baseline measurement as covariate. Symptom score and salbutamol use (rescue medication) were analysed using generalised linear modelling after dichotomisation of the daily scores as symptomfree (y/n) and rescue-free (y/n), respectively.The binomial distribution with logit link and the generalised estimating equation method (17) for repeated data were used. The logit link implies that the e¡ect of treatment on the probabilities of having a symptom-free or rescue-free day is expressed by means of an odds ratio of SFC relative to FP plus montelukast. Comparison between treatment groups of the number of patients who withdrew or had exacerbations of asthma was done using a chi-square test. The time to ¢rst exacerbation was analysed using Kaplan^Meier survival analysis with the log rank test. For the assessment of patient and physician satisfaction with treatment, comparisons were based on the response obtained at the end of treatment using the Wilcoxon rank sum test. All the above non-parametric tests were performed strati¢ed by (and hence adjusted for) country.
RESULTS Patient characteristics A total of 1168 patients were enrolled into the study, of whom 806 were randomised to study medication. One patient did not receive study medication, so 805 patients were included in the safety population (used for the adverse event tables). Three hundred and sixty two patients were withdrawn from the study before randomisation, mainly because of failing the criteria for entry into the treatment period. During the statistical analysis, a further 81 patients were excluded due to not meeting the pre-randomisation eligibility criteria to arrive at the reduced ITT population of 725 patients (356 in the SFC and 369 in the FP plus montelukast group).The demographic and baseline clinical characteristics of each treatment group are outlined in Table 1. The treatment groups were well matched for sex, age and lung function. The compliance with study medication was high in both groups; 96% of patients in both treatment groups returned the correct number of doses in the DiskusTM inhaler and 97% in both groups returned the right number of tablets according to the protocol requirements.
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
237
TABLE 1. Patient characteristics (reduced intent-to-treat population)
Patients, n: Sex, n (%) Male Female Mean age, years (range) Current smoker (%) Ex-smoker (%) Mean number of pack years (range) Mean % predicted FEV1 (SD): Reversibility, % change from baseline (SD)
SFC
FP plus montelukast
356
369
164 (46%) 192 (54%) 43 (15^75) 6.2% 20.8% 5 (0^10) 75.8% (15.3%) 27.4% (13.5%)
165 (45%) 204 (55%) 43 (14^79) 6.2% 24.4% 5(0^10) 74.3% (16.1%) 27.0% (12.6%)
FEV1 = forced expiratory volume in1second;FP = £uticasone propionate; SD = standard deviation; SFC = salmeterol/£uticasone propionate.
SFC FP + montelukast
Mean morning PEF (L/min)
420 410 400
P<0.05
390 380 370 360 0
1-2
3-4
5-6 9-10 7-8 Treatment week
11-12
1-12
FIG. 1. Mean morning peak expiratory £ow (PEF) at baseline and during 12 weeks’ treatment with either salmeterol/£uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice dailyplus oralmontelukast10 mg once daily.Error bars show standard error of the mean.
E⁄cacy PEF Mean baseline morning PEF was similar in the two treatment groups: 371and 367 l/min for the SFC group and FP plus montelukast group, respectively. Mean morning PEF increased from baseline in both treatment groups during the study period (Fig.1).The adjusted mean increase from baseline in the SFC group was 36 l/min over the 12-week period and19 l/min in the FP plus montelukast group.The di¡erence was 17 l/min (95% CI 12^22 l/min; Po0.05) which did not signi¢cantly change over the 2-weekly intervals throughout the treatment period (P=0.39; Fig. 1; Table 2). In both treatment groups, the improvement in mean morning PEF from baseline was evident 1 week after starting treatment (Fig. 2). The onset of improvement was, however, signi¢cantly faster in the SFC group with a signi¢cant di¡erence already recorded 24 h after starting treatment (mean treatment di¡erence 16.9 l/
min; 95% CI 1.9^32 l/min; P=0.03).The results for the primary e⁄cacy variable were supported by those for the secondary e⁄cacy variables. The increase from baseline in evening PEF over the 12-week treatment period was signi¢cantly greater in the SFC group, with an adjusted mean improvement of 29 l/min compared with 14 l/min in the FP plus montelukast group (Table 2).The di¡erence was 15 l/min (95% CI 11^20 l/min; Po0.05). There was some evidence that this di¡erence increased in time from 12 l/min in the ¢rst two-weekly interval to18 l/min in the sixth two-weekly interval.
Clinic FEV1 In both treatment groups, there was an improvement in FEV1 from baseline during the study period. At baseline, the mean FEV1 value in the SFC group was 2.47 l, which increased to 2.73 l at the end of 12 weeks (Table 2). This was signi¢cantly greater (Po0.05) than the FEV1 increase
238
RESPIRATORY MEDICINE
TABLE 2. E⁄cacy variables at baseline and during treatmentin patients who received salmeterol/£uticasone propionate combination (SFC; 50/100mg) twice daily or £uticasone propionate (FP) 100mg twice daily plus montelukast 10mg once daily for 12 weeks. analysis of reduced intent-to-treat population Variable
SFC
Mean morning PEF (l/min) (SEM) Mean evening PEF (l/min) (SEM) Clinic FEV1 (L) (SEM) Median % symptom-free days Median % symptom-free nights Median % rescue-free days Median % rescue-free nights
FP plus montelukast
Baseline
Weeks1^12
Baseline
Weeks1^12
370.8 7 5.1 385.7 7 5.3 2.47 7 0.04 7.1 32.1 23.5 53.6
407.7 7 2.2 416.5 7 2.2 2.73 7 0.03 50.0 78.6 71.4 92.9
367.3 7 4.9 380.3 7 4.9 2.41 70.04 7.0 30.3 20.7 56.7
388.2 7 2.1 395.5 7 2.1 2.58 7 0.03 38.5 71.4 66.7 85.7
Odds ratio
P value
F F F 1.32 1.28 1.29 1.15
0.0001 0.0001 0.0001 0.017 0.033 0.03 0.26
P-values are based on mixed model analysis of variance or generalised linear model. SEM = standard error ofthe mean;FEV1 = forced expiratory volume in1second,PEF= peak expiratory £ow.
SFC FP + montelukast
410
SFC FP + montelukast
2.7 Mean FEV1 (L)
Mean morning PEF (L/min)
2.8
400
390
380
P<0.05 2.6 2.5 2.4
370
2.3
360 0
1
2
3 4 Treatment day
5
6
7
0
4
8 Treatment week
12
1-12
FIG. 2. Mean morning peak expiratory £ow (PEF) at baseline and during the ¢rst 7 days of treatment with either salmeterol/ £uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice daily plus oral montelukast 10 mg once daily. Error bars show standard error of the mean.
FIG. 3. Forced expiratory volume in 1s (FEV1; adjusted mean values 7 standard error of the mean) at baseline and during 12 weeks’ treatment with either salmeterol/£uticasone propionate combination (SFC; 50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice dailyplus oralmontelukast10 mg once daily.
in the FP plus montelukast group, which rose to 2.58 l from a baseline of 2.41l (mean treatment di¡erence 0.11l; 95% CI 0.06 ^ 0.16 l; Po0.05) (Fig. 3).
group for weeks 1^12 (odds ratio 1.28; 95% CI 1.02^1.61; Po0.05).
Rescue medication use Symptom-free days and nights The percentage of symptom-free days and nights improved from baseline in both treatment groups (Table 2).The patients in the SFC group were signi¢cantly more likely to have a symptom-free day during the study period (odds ratio 1.32; 95% CI 1.05^1.65; Po0.05). The results for symptom-free nights were very similar; the chances of a symptom-free night were signi¢cantly higher in the SFC group than in the FP plus montelukast
The number of rescue-free days and nights, i.e. those days and nights when salbutamol was not used, increased from baseline in both groups during the 12-week treatment period (Table 2).The patients in the SFC group were signi¢cantly more likely to have a rescue-free day during the study period (odds ratio 1.29; 95% CI 1.02^ 1.63; P=0.03). The chances of a rescue-free night were also numerically higher in the SFC group than in the FP plus montelukast group for weeks 1^12, but this did not
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
Exacerbations of asthma The number of patients who had at least one asthma exacerbation (any severity) was signi¢cantly lower in the SFC group (34; 9.6%) than in the FP plus montelukast group (54; 14.6%; Po0.05). The percentage of patients who had at least one asthma exacerbation of either moderate or severe intensity was 4.8% in the SFC group and 8.4% in the FP plus montelukast group; this di¡erence did not reach statistical signi¢cance (P=0.07).The time to the ¢rst exacerbation was signi¢cantly longer in the SFC group than in the FP plus montelukast group (Po0.05) (Fig. 4).
Patient/physician satisfaction with treatment The percentage of patients at the end of the treatment period who were either very satis¢ed or satis¢ed with the treatment they had received was signi¢cantly higher in the SFC group (92.9%) than in the FP plus montelukast group (83.5%; Po0.05).The percentage of physicians who assessed the treatment as very e¡ective or e¡ective was also signi¢cantly higher in the SFC group (79.6%) than in the FP plus montelukast group (72.6%; Po0.05).
Eleven serious adverse events (SAEs) were reported (four in the SFC group and seven in the FP plus montelukast group) of which none were drug-related. The most common SAE was hospitalisation due to an asthma exacerbation; this occurred in one patient in the SFC group and two in the FP plus montelukast group. Signi¢cantly fewer patients withdrew from the SFC group during the treatment period (19; 5%) than from the FP plus montelukast group (37; 10%) (Po0.05). The main reason for these withdrawals was an adverse event (32 out of 56 withdrawals; 57%).
DISCUSSION The results of this study showed that SFC (salmeterol 50 mg/FP 100 mg) administered twice daily for 12 weeks was more e¡ective than FP100 mg twice daily plus montelukast 10 mg once daily for the treatment of symptomatic patients with moderate to severe asthma; SFC 100 96 Exacerbation-free (%)
reach signi¢cance (odds ratio 1.15; 95% CI 0.90 ^1.47; P=0.26).
92 88 84
Safety
80
Adverse events
76
The overall incidence of adverse events in the safety population was similar in the SFC group (44%) and the FP plus montelukast group (42%).Respiratory system events predominated during treatment, with the most frequent event in both groups being an exacerbation of asthma (Table 3). Oropharyngeal candidiasis occurred in three patients in the SFC group and one in the FP plus montelukast group.
239
SFC FP + montelukast
0
1
2
3
4 5 6 7 8 Treatment week
9 10 11 12
FIG. 4. Number of patients in each study arm who remained free of an asthma exacerbation over the 12 weeks of the study, plotted as a percentage of the number who started study treatment (Kaplan^Meier analysis).Patients received either salmeterol/£uticasone propionate combination (50/100 mg twice daily) or £uticasone propionate (FP) 100 mg twice daily plus oral montelukast10 mg once daily.
TABLE 3. Adverse events reported by more than ¢ve patients in the safety population Number of events (%)
Exacerbation of asthma Common cold Upper respiratory tract infection Headache Sore throat In£uenza Bronchitis
SFC (n=404)
FP plus montelukast (n=401)
39 (10%) 30 (7%) 15 (4%) 12 (3%) 10 (2%) 9 (2%) 4 (o1%)
50 (12%) 31 (8%) 9 (2%) 18 (4%) 3 (o1%) 10 (2%) 10 (2%)
FP = £uticasone propionate; SFC = salmeterol/£uticasone propionate.
240
produced larger improvements in lung function and symptom control and reduced the frequency and timeto-¢rst exacerbation. These results, obtained from a multicountry patient population, reproduce those of an earlier study performed in a U.S. population (16). This study was designed to assess the bene¢ts of adding either salmeterol or montelukast to patients already taking inhaled corticosteroids. Criteria for inclusion into the study ensured that patients were asthmatic (as demonstrated by their reversibility), symptomatic and required step-up therapy. The requirement for the subjects to be reversible to salbutamol may have potentially favoured the SFC group over the FP plus montelukast group. However, reversibility to short-acting bronchodilators is central in the correct diagnosis of asthma and has been used as a patient selection criterion in other large studies investigating the clinical bene¢t of adding montelukast to inhaled corticosteroid therapy (15,18). The study duration of 12 weeks was chosen as it has previously been shown to be su⁄cient to demonstrate the maximal e¡ect of both salmeterol (7,8) and montelukast (15). In the current study, the di¡erence in morning PEF between the groups of 17 l/min was close to the value perceived by patients to be of a clinical bene¢t (19). In addition, the improvement in the other endpoints achieved in the SFC group was accompanied by fewer patient withdrawals and a smaller number of asthma exacerbations. The percentage of patients with at least one exacerbation was signi¢cantly lower in the SFC group, as was the time to ¢rst exacerbation. Reduction in the frequency of asthma exacerbations is important in decreasing morbidity and mortality in asthma patients, improving their quality of life and reducing the costs associated with the disease. As with all controlled clinical trials, questions remain around the generalisability of these ¢ndings to daily practice. Patients in the current trial were selected before entering the study and had very high levels of compliance. Studies that addressed this issue using retrospective data from clinical practice found that in a real-world setting the combination of salmeterol and FP or the combination of salmeterol and inhaled corticosteroids provides superior clinical bene¢t compared to inhaled corticosteroids plus leukotriene modi¢ers. This was demonstrated by less visits to the emergency department and hospital, and less use of rescue medication by patients on the combination of salmeterol and FP or other inhaled corticosteroids (20,21). In the current study, the di¡ering e⁄cacy cannot be attributed to the di¡erences in compliance in the taking of study treatment. As mentioned before and as expected in the study setting, compliance with study medication was high in both treatment groups. In both groups, the need for an additional inhaler for rescue use remains, meaning that outside the clinical trial setting in
RESPIRATORY MEDICINE
daily practice in the montelukast group, treatment with three separate drugs is required. The use of multiple routes and daily administrations of treatment has been shown to contribute to poor compliance (22). At the end of the study, patient satisfaction with treatment was high.The number of patients who were either very satis¢ed or satis¢ed with the study medication was signi¢cantly higher in the SFC group. Similar ¢ndings have been reported in a recently published study (23). In the current study, this result is notable since the study medication was administered double-dummy, i.e. both groups used two inhalations and one tablet per day, yet patients and investigators recorded a preference for SFC. In summary, in patients symptomatic on a low dose of inhaled corticosteroids, both treatments were e¡ective, although the improvement seen with SFC was consistently better, irrespective of study endpoint measured. Both treatments were equally well tolerated. These results strengthen the ¢ndings of previously reported studies with both montelukast and za¢rlukast (15,24,25) and con¢rm that the combination of salmeterol and FP is the preferred option for patients uncontrolled on a low dose of inhaled corticosteroids.
Acknowledgements The authors would like to thank the investigators who took part in this study: Prof. Z. Iankova, Dr Al. Simidchiev; Prof. K. Kissiova, Prof. M. Peneva, Dr T. Odjakova, Prof. J. Mileva, Prof.V. Dimitrov, Prof. M. Staneva, Prof. D. Popov, Dr Gugushev (Bulgaria); Dr E. Amer, Dr A. Booth, Dr N. Colman, Dr M. Gold, Dr D. Stollery, Dr G. Tellier, Dr K. Tse, Dr W. Yang (Canada); Prof. Dr V. Ahel, Dr A. Rozman, Dr A. Markovi, Dr E.Verona, Dr A. StipiP MarkoviP (Croatia); Dr M. Fuchs, Dr F. Kopriva, Dr B. Novotna, Dr Z. Parakova (Czech Republic); Prof. L. Jannus-Pruljan, Dr E. Pˇttsepp (Estonia); Dr W.Gams, Dr U. Gehling, Dr M. Jahn, DrT. Jung, Dr A. Linnho¡, Dr H.-H. Ponitz, Dr E. Scheer, Dr R. Schnorr, Dr P.-M. Stutz, Dr H. ten-Ho¡, Dr L. vonVersen, Dr W.Weede (Germany); Dr N. Galanis, Dr N. Georgatou, Dr D. Gioulekas, Prof. N. Siafakas (Greece); Dr L. Bentur, Dr R. Breuer, Dr M. Kramer, Prof. A. Rubin, Dr E. Tabachnik, Dr B. Volovitz (Israel); Dr I. Cerveri, Prof. E. Maggi, Dr A. Potena, Dr M. Vignola, Prof. M. Neri (Italy); Dr V. Duurkens, Dr E. van Hezik, Dr W. Pieters, Dr N. Schloesser, Dr H. Damste, Dr F.Vermetten (The Netherlands); Dr B. Harbo, Dr O. Haugen, Dr H.-O. Hoivik, Dr E. Ofjord, Dr O. Rysstad (Norway); Dr D.Comajova, Dr M. Hrubisko, Prof. P. Kristufek, Dr J.Ruzicka (Slovakia); Dr S. Kajba, Dr R. Kopriva, Prof. J. Sorli (Slovenia); Dr M. Abdool-Ga¡ar, Prof. P. Bardin, Dr C. Duvenage, Dr J. Killian, Dr M. Laher, Prof. U. Lalloo, Dr J. O’Brien (South Africa); Dr T. Carrillo, Dr L. Prieto, Dr J. Serra (Spain); Dr S. Boes Hansen,
FLUTICASONE AND SALMETEROLOR MONTELUKAST IN ASTHMA
Dr N. Funder Jorgensen, Dr C. Pedersen, Dr K.Theman, Dr J. Ziegler (Sweden); Prof. F. Erkan, Dr Z. Misirligil, Prof. A. Sayiner, Prof. N. Yildirim (Turkey); Prof. L.Yashina, Prof. Y. Feschenko (Ukraine); Dr W. Aitchison, Dr A. Bremner, Dr B. Calder, Dr G .Canning, Dr A. Cooper, Dr A. Darrah, Dr P. Dobson, Dr M. Doyle, Dr D. Ferry, Dr S. Gunn, Dr G. Hackett, Dr J. Ham, Dr P. Lee, Dr C. Lenton, Dr J.Litch¢eld, Dr R. Lloyd, Dr A.Marshall, Dr H. McGoldrick, Dr B. Penney, Dr P. Shearer, Dr D. Sheldon, Dr G. Singh (UK). The authors would like to thank Andy Michael and Richard Steadman for their valuable statistical input. This study was sponsored by GlaxoSmithKline (Study Number SAS40015).
REFERENCES 1. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma: United States 1960–1995. MMWR 1998; 47: 1–28. 2. Anderson HR, Butland BK, Strachan DP. Trends in prevalence and severity of childhood asthma. BMJ 1994; 308: 1600–1604. 3. Robertson CF, Rubinfield AR, Bowes G. Pediatric asthma deaths in Victoria. The mild are at risk. Pediatr Pulmonol 1992; 13: 95–100. 4. Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report 2. National Institutes of Health, National Heart, Lung and Blood Institute. July 1997, NIH Publication Number 97–4051. 5. British Thoracic Society. The British guidelines on asthma management. 1995 review and position statement. Thorax 1997; 52 (Suppl. 1): S1–S21. 6. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998; 102: 531–538. 7. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344: 219–224. 8. Woolcock AJ, Lundba¨ck B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroid with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153: 1481–1488. 9. Condemi JJ, Goldstein S, Kalberg C, Yancey S, Emmett A, Rickard K. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group. Ann Allergy Asthma Immunol 1999; 82: 383–389. 10. Van Noord JA, Schreurs AJ, Mol SJ, Mulder PG. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 1999; 54: 207–212. 11. Johnson M. Combination therapy for asthma: complementary effects of long-acting beta-agonists and corticosteroids. Curr Allergy Clin Immunol 2002; 15: 16–22.
241
12. Merck Sharp & Dohme Ltd. Summary of product characteristics. 27 June 2000. Available from URL: http://srs.vhn.net/eMc/documents/01100/01192/SPC.1192.html. 13. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. National Institutes of Health, National Heart, Lung and Blood Institute. 2002, Updated from: NHLBI/WHO Workshop Report: Global Strategy for Asthma Management and Prevention Issued January, 1995. NIH Publication No. 02–3659. 14. Dempsey OJ. Leukotriene receptor antagonist therapy. Postgrad Med J 2000; 76: 767–773. 15. Laviolette M, Malmstro¨m K, Lu S, et al for the Montelukast/ Beclomethasone Additivity Group. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999; 160: 1862–1868. 16. Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/ salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000; 106: 1088–1095. 17. Liang KY, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika 1986; 73: 13–22. 18. Bjermer L, Bisgaard H, Bousquet J, etal. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy Trial). Respir Med 2000; 94: 612–621. 19. Santenello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J 1999; 14: 23–27. 20. O’Connor RD, O’Donnell JC, Pinto LA, Wiener DJ, Legorreta AP. Two-year retrospective economic evaluation of three dualcontroller therapies used in the treatment of asthma. Chest 1999; 121: 1028–1035. 21. Stempel DA, O’Donnell JC, Meyer JW. Inhaled corticosteroids plus salmeterol or montelukast: effects on resource utilization and costs. J Allergy Clin Immunol 2002; 109: 433-439. 22. Kelloway JS, Wyatt RA, Adlis SK. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994; 154: 1349–1352. 23. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomized double-blind placebo-controlled trial. Lancet 2001; 357: 2007–2011. 24. Fish JE, Israel E, Murray JJ, Emmett A, Boone R, Yancey SW, Rickard KA. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001; 120: 423–430. 25. Busse W, Nelson H, Wolfe J, Kalberg C, Yancey SW, Rickard KA. Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma. J Allergy Clin Immunol 1999; 103: 1075–1080.