Dual-controller therapy, or combinations REVIEW DUAL-CONTROLLER REGIMENS I: DATA FROM RANDOMIZED, CONTROLLED CLINICAL TRIALS.

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1 DUAL-CONTROLLER REGIMENS I: DATA FROM RANDOMIZED, CONTROLLED CLINICAL TRIALS Samy Suissa, PhD ABSTRACT Dual-controller therapy, or combinations of 2 or more pharmacotherapies with complementary mechanisms of action, is often used to treat patients with persistent asthma. In particular, the use of the fluticasone propionate-salmeterol combination has been evaluated in several randomized, controlled clinical trials involving more than 1200 patients with persistent asthma. These 3 studies are examined in this article and suggest that the fluticasone propionate-salmeterol combination is more effective than (1) placebo, (2) either medication administered alone, and (3) other dual-controller regimens. (Advanced Studies in Medicine 2002;2(3):81 85) Dual-controller therapy, or combinations of 2 or more pharmacotherapies with complementary mechanisms of action, is recommended by the National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines for patients who suffer moderate persistent or severe persistent asthma. 1 In dual-controller therapy, an inhaled corticosteroid is combined with one of several classes of medication including a Correspondence to Samy Suissa, PhD, Director, Division of Clinical Epidemiology, McGill University Health Center, Royal Victoria Hospital, 697 Pine Avenue West, R4.29, Montreal, Canada H3A 1A1. long-acting β 2 agonist, a leukotriene modifier, or (less commonly) theophylline. Dual-controller regimens have been extensively researched in randomized, controlled clinical trials and, increasingly, in observational studies. In choosing among dual-controller regimens, health care providers should consider both information from controlled clinical trials and observational studies because the 2 sources provide complementary information. Controlled clinical trials, which employ strict patient selection criteria and methodologic controls, allow causal inferences to be made about the effects of a manipulation (in this case, the effects of a dual-controller regimen on clinical status of the patient). The measures of control employed in the trials, however, may render it difficult to generalize their results to routine clinical practice. Observational studies, which study patients as they use a drug in clinical practice, do not permit strong causal inferences although they do provide a gauge of the performance of a medication in real-world use. The randomized, controlled clinical trial is best suited to measure the efficacy of a medicine ie, the ability of the medicine to improve health under carefully controlled conditions. The observational study is best suited for evaluating the effectiveness of a medicine ie, the extent to which the medicine improves health in a clinical practice setting and for providing information on major asthma outcomes. This paper reviews data from randomized, controlled clinical trials on a new dual-controller therapy for asthma, the combination of the inhaled corticosteroid fluticasone propionate and the long-acting β 2 agonist salmeterol administered in a single delivery system The body of evidence from randomized, controlled clinical trials regarding the efficacy of this form of dual-controller therapy illustrates the value of systematic, well-controlled evalua- Advanced Studies in Medicine 81

2 tion of a medication. Observational data on dual-controller therapy are considered in the article by Blaiss in this issue. 2 RANDOMIZED, CONTROLLED CLINICAL TRIALS WITH A NEW DUAL-CONTROLLER REGIMEN The effects of the fluticasone propionate-salmeterol combination have been evaluated in several randomized, controlled clinical trials involving more than 1200 patients with persistent asthma. These studies, examples of which are described below, demonstrate the fluticasone propionate-salmeterol combination to be more effective than (1) placebo, (2) either medication administered alone, and (3) other dual-controller regimens. DUAL THERAPY VERSUS SINGLE THERAPY OR PLACEBO Three trials addressed the effectiveness of this dual therapy against single therapy or placebo. Kavuru et al compared the efficacy of fluticasone propionate-salmeterol (100 mcg/50 mcg bid) with that of fluticasone propionate alone (100 mcg bid), salmeterol alone (50 mcg bid), or placebo in a 12-week, randomized, double-blind, parallel-group clinical trial conducted in 356 patients with asthma. 3 Patients were enrolled if they were not adequately controlled on their current asthma therapy, and they were stratified at baseline according to their asthma therapy: 70% of patients were using low-dose inhaled corticosteroids at study entry, and 30% were using salmeterol alone at study entry. The primary endpoint in this study was pulmonary function as measured by morning predose forced expiratory volume in 1 second (FEV 1 ). The results demonstrate: Improvements in pulmonary function as measured by morning predose FEV 1 were significantly greater with the fluticasone propionatesalmeterol combination than with either medication administered alone. At the last study visit, patients receiving the fluticasone propionate-salmeterol combination showed a 25% improvement in morning predose FEV 1 compared with 15%, 5%, and 1% improvements with fluticasone propionate alone, salmeterol alone, and placebo, respectively (Figure 1). The percentage of patients withdrawn from the study because of worsening asthma was lower with the fluticasone propionate-salmeterol combination (3%) compared with fluticasone propionate alone (11%), salmeterol alone (35%), or placebo (49%). A similar pattern of results was observed for secondary measures of efficacy including morning and evening peak expiratory flow rate (PEF), percentage of days with no use of rescue albuterol, percentage of days with no symptoms, and percentage of nights with no awakenings (Table). These data were corroborated and extended by the results of a 12-week, randomized, double-blind, parallel-group clinical trial study assessing the effects of a 250-mcg bid dose of fluticasone propionate combined with 50 mcg bid salmeterol compared with fluticasone propionate alone (250 mcg bid), salmeterol alone (50 mcg bid), or placebo among 349 patients with asthma. 4 Patients had mean baseline FEV 1 s ranging from 66% to 69% of predicted values and were not optimally controlled on inhaled corticosteroid therapy. The primary endpoint in this study was pulmonary Figure 1. Mean Change from Baseline in Morning Predose FEV 1 at the Last Study Visit (Kavuru et al) Data from reference Vol. 2, No. 3 January 2002

3 function as measured by morning predose FEV 1. The results show: Improvements in pulmonary function as measured by morning predose FEV 1 were significantly greater with the fluticasone propionate-salmeterol combination compared with the other treatments. At the last study visit, patients receiving the fluticasone propionate-salmeterol combination showed a 23% improvement in morning predose FEV 1 compared with 13%, 4%, and -5% changes in the groups receiving fluticasone propionate alone, salmeterol alone, or placebo (Figure 2). The percentage of patients withdrawn from the study because of worsening asthma was lower with the fluticasone propionate-salmeterol combination (4%) compared with fluticasone propionate alone (22%), salmeterol alone (38%), or placebo (62%). A third randomized, controlled clinical trial employing the 500-mcg bid dose of fluticasone propionate combined with a 50-mcg bid dose of salmeterol demonstrated the superiority of the combination to fluticasone propionate administered alone. 5 This 12-week study enrolled 503 patients with mean baseline FEV 1 ranging from 71% to 72% of predicted values. The primary endpoint in this study was morning PEF over weeks 1 through 12. The results show that at each treatment week on which PEF was measured (ie, weeks 1, 2, 3, 4, 8, and 12), the increase from baseline in mean morning PEF was significantly greater with the fluticasone propionate-salmeterol combination than with fluticasone propionate alone. DUAL THERAPIES AND LEUKOTRIENE MODIFIERS The fluticasone propionate-salmeterol combination has also been compared with the leukotriene modifier montelukast administered either in combination with fluticasone propionate 6 or alone. 7 In the first study, a 12-week, randomized, doubleblind, parallel-group study conducted in 447 patients with asthma, the combination of fluticasone propionate and salmeterol (100 mcg/50 mcg bid) was significantly more effective than the combination of fluticasone propionate 100 mcg bid and montelukast 10 mg qd at improving, compared with baseline, Morning PEF over weeks 1 through 12 (24.9 L/min versus 13.0 L/min; P<0.05); Evening PEF over weeks 1 through 12 (19 L/min versus 10 L/min; P<0.001); and Table 1. Baseline and Change-from-Baseline Values for Secondary Efficacy Parameters Fluticasone-Salmeterol Combination Fluticasone Salmeterol Placebo (n=87) (n=85) (n=86) (n=77) Morning PEF (L/min) Baseline Change from baseline at the last visit 53* Evening PEF (L/min) Baseline Change from baseline at the last visit 35* % days with no rescue albuterol use Baseline Change from baseline 30* % days with no symptoms Baseline Change from baseline 23* % nights with no awakenings Baseline Change from baseline 5* *P<0.05 versus placebo. P<0.05 versus fluticasone propionate. P<0.05 versus salmeterol. Data from patients who did not withdraw during follow-up for worsening asthma (reference 3). Advanced Studies in Medicine 83

4 Morning postdose FEV 1 (0.34 L versus 0.20 L; P<0.001). Consistent with these data, results of the second randomized, double-blind, 12-week study conducted in 423 patients with asthma demonstrate that combination therapy with fluticasone propionate and salmeterol (100 mcg/50 mcg bid) resulted in significantly greater improvement than administration of montelukast (10 mg qd) alone in several parameters including morning predose FEV 1, morning and evening PEF, and percentages of symptom-free days, rescue medication-free days, and nights with no awakenings. 7 The authors suggested that using combination therapy to target the 2 main pathophysiologic components of asthma (ie, inflammation and bronchoconstriction) is more effective for maintenance treatment than is treatment with a singlemediator agent such as montelukast. DUAL THERAPY VERSUS HIGHER-DOSE INHALED CORTICOSTEROIDS Several studies have shown that the fluticasone propionate-salmeterol combination is more effective in controlling lung function and asthma symptoms than an inhaled corticosteroid alone administered at a 2- fold higher dose than the fluticasone propionate in the combination The results of these studies were recently supplemented by findings of a randomized, double-blind, parallel-group study comparing the efficacy of the fluticasone propionate-salmeterol combination (100 mcg/50 mcg) with that of the inhaled corticosteroid budesonide administered at a 4-fold higher dose (ie, 400 mcg) than the fluticasone propionate in the combination. 11 Patients (n=349) received either the fluticasone propionate-salmeterol combination (100 mcg/50 mcg bid) or budesonide (400 mcg bid) for 12 weeks. At the end of treatment, patients in the combination-therapy group compared with the budesonide group showed significantly greater improvement in both morning PEF (difference of 11 L/min) and evening PEF (difference of 11 L/min). The onset of significant improvement in PEF with the combination versus budesonide was evident within the first 7 days of initiation of therapy. The authors suggested that the ability to control asthma with a 4-fold lower microgram corticosteroid dose with the combination regimen may help to improve safety of asthma treatment by minimizing exposure to the systemic effects of inhaled corticosteroids. CONCLUSIONS These data show that the fluticasone propionatesalmeterol combination is more effective than placebo, either medication administered alone, and other combination-therapy and monotherapy regimens in improving lung function and reducing respiratory symptoms in asthma. The cross-study consistency of the data from this extensive number of trials lends credence to the findings. Considered in the context of data from observational studies showing the real-world utility of combination therapy involving fluticasone propionate and salmeterol, 2 the results of these randomized, controlled clinical trials become compelling. Further studies with follow-up longer than 12 weeks could provide additional information on the long-term effectiveness of this regimen. Observational studies could also assess the impact of this regimen on major outcomes such as emergency department visits, hospitalizations, and even death due to asthma. Figure 2. Mean Change from Baseline in Morning Predose FEV 1 at the Last Study Visit (Shapiro et al) Data from reference Vol. 2, No. 3 January 2002

5 REFERENCES 1. National Asthma Education and Prevention Program. Guidelines for the Diagnosis and Management of Asthma. US Dept of Health and Human Services, National Institutes of Health; Bethesda, MD: NIH publication Blaiss MS. Dual-controller regimens II: Observational data. Adv Stud Med. 2002;2(3): Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, doubleblind, placebo-controlled trial. J Allergy Clin Immunol. 2000;105: Shapiro G, Lumry W, Wolfe J, et al. Combined salmeterol 50 mcg and fluticasone propionate 250 mcg in the Diskus device for the treatment of asthma. Am J Respir Crit Care Med. 2000;161: Aubier M, Pieters WR, Schlösser NJJ, et al. Salmeterol/fluticasone propionate in combination in a Diskus inhaler is effective and safe in the treatment of steroid-dependent asthma. Respir Med. 1999;93: 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: Calhoun WJ, Nelson HS, Nathan RA, et al. Comparison of fluticasone propionate-salmeterol combination therapy and montelukast in patients who are symptomatic on shorting acting β2 agonists alone. Am J Respir Crit Care Med. 2001;164: Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;344: Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy Asthma Immunol. 1999;82: van Noord JA, Schreurs AJM, Mol SJM, et al. Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax. 1999;54: Johansson G, McIvor RA, D-Ambrosio FP, et al. Comparison of salmeterol/fluticasone propionate combination with budesonide in patients with mild-to-moderate asthma. Clin Drug Invest. 2001;21: Advanced Studies in Medicine 85