Seretide Research Articles

Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting

Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting β2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND+GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with low-exacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year. Assuming equal efficacy, a cost-minimisation analysis compared IND/GLY vs IND+GLY using model inputs from the double-blind, randomised SHINE trial. The double-blind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS-related pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA). IND/GLY was cost-saving vs IND+GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY. IND/GLY is cost-minimising vs IND+GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk.

Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients

Fluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL). Three 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged ≥40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0-24 h weighted mean FEV(1) (wmFEV(1)) on Day 84. Safety was also assessed. In Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0-24 h wmFEV(1) was significantly greater with FF/VI than FP/SAL (Δ80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0-24 h wmFEV(1) was not significantly greater with FF/VI than FP/SAL (Δ29 mL, P = 0.267; Δ25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (Δ41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments. Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar. clinicaltrials.gov: NCT01323634; NCT01323621; NCT01706328. GlaxoSmithKline study codes: HZC113109; HZC112352; RLV116974.

Tiotropium bromide combined with seretide for elderly patients with severe persistent asthma

Objective To explore the clinical efficacy of tiotropium bromide combined with seretide in the treatment of elderly patients with severe persistent asthma.Methods 60 elderly patients with severe persistent asthma treated in our hospital were divided into a control group and an experimental group.The control group was treated with serretide,and the experimental group with tiotropium bromide and seretide.The clinical symptoms and efficacies of both groups before and after the treatment were observed and compared.Results The score of chest tightness,cough degree,heart rate,and pulse pressure were higher in the experimental group than in the control group,with statistical differences (P＜0.05).The total effective rate of the experimental group (90.00％) was significantly higher than that of the control group (50.00％),with statistical a diference (P＜0.05).Conclusions Tiotropium bromide combined with seretide in the treatment of elderly patients with severe persistent asthma is quite effective,can make the patients breathe easily improving the function of smooth muscles and respiratory muscles,and is worth being clinically generalized. Key words: Tiotropium bromide; Seretide; Severe persistency; Asthma

Appraisal of lens opacity with mometasone furoate/formoterol fumarate combination in patients with COPD or asthma

Long-term corticosteroid use may increase cataract risk. The Lens Opacities Classification System (LOCS) III ranked lens opacities as Class 1: 0.5-0.9unit; Class 2: 1.0-1.4units; or Class 3: ≥1.5units in clinical trials of combined mometasone furoate and formoterol (MF/F) administered by metered-dose inhaler (MDI). We examined retrospectively shifts in lenticular opacity in patients with chronic obstructive pulmonary disease (COPD) or asthma. We analyzed pooled LOCS III data from two COPD studies and separately analyzed LOCS III data from an asthma study. COPD subjects were randomized to twice daily MF/F 200/10μg, MF/F 400/10μg, MF 400μg, F 10μg, and placebo; asthma subjects were randomized to MF/F 200/10μg, MF/F 400/10μg, fluticasone propionate/salmeterol (FP/S) 250/50μg, and FP/S 500/50μg. Lenticular opacity changes were analyzed post hoc for proportions of subjects with LOCS III grade increases ≥0.5, ≥1.0, or ≥1.5units at weeks 26 and 52. Proportions of subjects in the COPD studies with Class 1 (≥0.5unit), 2 (≥1.0unit), or 3 (≥1.5units) increases in LOCS III at week 26 (N=1675) ranged from 15.5 to 18.6%, 3.3-6.0%, and 0.9-2.2%, respectively. At week 52 (N=1085), proportions of active-treated subjects with Class 1, 2, or 3 increases in LOCS III ranged from 26.6 to 28.9%, 6.3-10.7%, and 2.6-5.9%, respectively. Treatment differences in lenticular shifts were generally small and nonsignificant in the asthma study. No clinically relevant trends were observed in the LOCS III assessment of lenticular shifts during treatment of COPD and asthma patients, although further study may be needed to confirm the findings presented here. In these trials, MF/F effects on lens opacity were not observed. (Clinicaltrials.gov numbers: NCT00383435, NCT00383721, and NCT00379288.).

Extrafine Beclomethasone/formoterol compared to Fluticasone/salmeterol Combination Therapy in COPD

BackgroundThe study evaluated the efficacy of beclomethasone dipropionate/formoterol fumarate (BDP/FF) extrafine combination versus fluticasone propionate/salmeterol (FP/S) combination in COPD patients.MethodsThe trial was a 12-week multicentre, randomised, double-blind, double dummy study; 419 patients with moderate/severe COPD were randomised to BDP/FF 200/12 μg or FP/S 500/50 μg twice daily. The primary objective was to demonstrate the equivalence between treatments in terms of Transition Dyspnoea Index (TDI) score and the superiority of BDP/FF in terms of change from pre-dose in the first 30 minutes in forced expiratory volume in the first second (FEV1). Secondary endpoints included lung function, symptom scores, symptom-free days and use of rescue medication, St. George’s Respiratory Questionnaire, six minute walking test and COPD exacerbations.ResultsBDP/FF was equivalent to FP/S in terms of TDI score and superior in terms of FEV1 change from pre-dose (p < 0.001). There were no significant differences between treatments in secondary outcome measures, confirming overall comparability in terms of efficacy and tolerability. Moreover, a clinically relevant improvement (>4 units) in SGRQ was detected in the BDP/FF group only.ConclusionBDP/FF extrafine combination provides COPD patients with an equivalent improvement of dyspnoea and a faster bronchodilation in comparison to FP/S.Trial registrationClinicalTrials.gov: NCT01245569

The combined effects of pulmonary rehabilitation and bronchial dilation drugs on patients with advanced pulmonary disease

Objective To evaluate the effects of pulmonary rehabilitation combined with the inhalation of Seretide and tiotropium bromide on pulmonary function and the quality of life of patients with advanced chronic obstructive pulmonary disease (COPD).Methods Seventy-two patients with advanced COPD were randomly divided into a rehabilitation group (n =36) and a control group (n =36).The patients in both groups were administrated Seretide (a combination of fluticasone and salmeterol xinafoate) and tiotropium bromide by inhalation for 8 weeks.Meanwhile,the patients in the rehabilitation group received breathing and upper and lower limb muscle strength exercises.Pulmonary function was tested on admission,at the beginning of the training,and after training for 2,4 and 8 weeks.The COPD assessment test (CAT) was also used to evaluate the patients' quality of life.Results There was no significant improvement in the average CAT score of the control group at any time from baseline to 8 weeks.The average CAT scores in the rehabilitation group after training for 2,4 and 8 weeks were all significantly lower than that of the same group at baseline.The average FEV1％ Pre score of the control group at 4 weeks was significantly higher than at baseline.At 2 weeks,the average FEV1％ FVC and MVV scores of the rehabilitation group had improved significantly compared against the baseline averages of the same group.At 4 and 8 weeks,pulmonary function in the rehabilitation group had improved significantly.At 8 weeks,pulmonary function and the CAT scores in the rehabilitation group were significantly better than those of the control group.Conclusion There is an advantage in combining pulmonary rehabilitation and the inhalation of Seretide and tiotropium bromide for improving pulmonary function,clinical symptoms and the quality of life of patients with advanced COPD. Key words: Pulmonary rehabilitation; Obstructive pulmonary disease; Seretide; Tiotropium bromide

Comparison of the effects of budesonide/formoterol maintenance and reliever therapy with fluticasone/salmeterol fixed-dose treatment on airway inflammation and small airway impairment in patients who need to step-up from inhaled corticosteroid monotherapy

BackgroundIf asthma patients fail to achieve symptom control using a medium dose of inhaled corticosteroid (ICS) alone, adding a long-acting β2 agonist (LABA) is the preferred treatment. We aimed to compare the effect of two widely available ICS/LABA combinations in these patients in real-life conditions: budesonide/formoterol (BUD/FM; Symbicort®) for maintenance and reliever therapy (SMART) and a fixed dose of fluticasone propionate/salmeterol (FP/SM). MethodsInadequately controlled asthma patients treated with a medium dose of ICS alone, with an Asthma Control Questionnaire (ACQ) score >0.75 and using a short-acting β2-agonist (SABA) 2–6 occasions/week, were enrolled. Patients were randomized into two groups and treated with two inhalation twice-daily BUD/FM 160/4.5 μg plus as-needed BUD/FM (SMART group, n = 15) or one inhalation twice-daily FP/SM 250/50 μg plus as-needed procaterol (FP/SM group, n = 15) for 8 weeks. ResultsBoth groups showed significant improvement in airway inflammation, pulmonary functions and symptoms from baseline. The SMART group showed significant improvement in the fraction of nitric oxide, ACQ score, rescue medication use and small airway parameter R5–R20 measured by impulse oscillometry compared with the FP/SM group. ConclusionFor stepping up treatment from ICS alone to an ICS/LABA combination, SMART is preferable for controlling asthma symptoms by suppressing airway inflammation and improving small airway impairment compared with a fixed dose of FP/SM. It may be achieved by the property of BUD/FM itself and as-needed use, but the degree of each contribution must be investigated further.

Cost-effectiveness analysis of combined inhaled corticosteroids and bronchodilators for severe and very severe COPD patients in a Teaching Hospital

BACKGROUND: This study aims at simplifying the practical patient management and offers some general indications for pharmacotherapeutic choice by the implementation of (GOLD 2004) guidelines. This study was designed to evaluate the clinical and economic consequences of Salmeterol/Fluticasone(SF), Formoterol/Budesonide(FB) and Formoterol/Fluticasone(FF) in severe and very severe COPD patients. OBJECTIVES: To find out the most cost-effective drug combination between the three combinations (SF/FB/FF) in COPD patients. METHODS: A Prospective observational Comparative study (Cost-effectiveness Analysis) in which 90 severe (30≤FEV1<50% predicted) and very severe (FEV1<30% predicted) COPD patients (OP/IP) who are prescribed with any one of the following combinations (SF/FB/FF) were selected. In our study we have divided 90 COPD patients into 3 groups (Group I, Group II & Group III) each group consisting of 30 patients. Group I was prescribed with medication SF (salmeterol/fluticasone), Group II with medication FB (formoterol/budesonide) and Group III with medication FF (formoterol/fluticasone). We used five different parameters such as Spirometry test (mean FEV1 initial & final visit), Number of symptom free days, Number of moderate & severe exacerbations and Direct, indirect & total cost to assess the cost-effectiveness of SF/FB/FF. Comparison of cost and effects was done during the period of 6 months of using SF/FB/FF. RESULTS: The average FEV1 for group I, group II and group III subjects at initial visit was 33.47%, 33.73% & 33.20% and was increased to 36.60%, 35.8% and 33.4% respectively. A 3% increment in FEV1 was reported for group I subjects (SF) and was highly significant statistically (t=-8.833, p=0.000) at 95% CI. For group II subjects (FB), a 2% increment in FEV1 was reported and was highly significant statistically (t=-9.001, p=0.000) at 95% CI. For group III subjects 0.2% increment in FEV1 was reported. The overall mean total cost for group I, group II and group III subjects during the 6 months period was found to be Rs.29725/-, Rs.32602/and Rs.37155/-. Incremental cost-effectiveness of FB vs SF was Rs.37781/per avoided exacerbation and Rs.661/per SFD. CONCLUSION: This study highlighted the favorable therapeutic performance of combined inhaled bronchodilators & corticosteroids (SF/FB/FF), thus suggesting that healthcare costs would be also affected positively. Results from our study showed that SF (Salmeterol/Fluticasone) and FB (Formoterol/Budesonide)) were the most effective strategies in the treatment of COPD, with a slight clinical superiority of SF. The FF (Formoterol/Fluticasone) strategy was not much effective (i.e. associated with less outcomes & higher costs).

A Comparison of Long-Term Anti-Inflammatory Effect of Two ICS/LABA Combination Inhalers; Fix-Dosed Maintenance Therapy with Budesonide/Formoterol and Salmeterol/Fluticasone

The clinical usefulness of fixed-dose maintenance therapy with salmeterol/fluticasone (SFC) and budesonide/formoterol combination inhaler (BUD/FM) has been established, though evidence of the long-term anti-inflammatory effects of these 2 inhalers are limited. Patients with moderate persistent adult asthma who had received SFC 50/250μg bid with well-control status were recruited. After switching to 8-week therapy with fixed-dose BUD/FM 4 puffs (640/18μg) (phase-1), patients chose either SFC or BUD/FM. FeNO and ACT score were evaluated every 8 weeks until the end of the 52-week treatment period for both treatment groups (phase-2). In total, 103 patients were examined: BUD/FM was chosen by 34 patients (BUD/FM group), while SFC was chosen by 23 (SFC group). Thirty-six received SFC consistently from the beginning of the study (control). Patients in the BUD/FM and SFC groups showed significant improvements in ACT scores and FeNO levels in phase-1; these beneficial effects persisted for 52 weeks in the BUD/FM group. On the other hand, in the SFC group, although the FeNO level decreased from 54.3 ± 26.4 ppb to 41.9 ± 18.3 ppb in phase-1, it increased to 54.5 ± 26.2 ppb, a level similar to the baseline prior to the beginning of BUD/FM therapy, at 8 weeks in phase-2, and remained at 50-odd ppb thereafter. These results suggest that maintenance therapy with fixed-dose BUD/FM is a useful treatment option exerting an airway anti-inflammatory effect for a period as long as 1 year, even for asthmatics who could not accomplish total control with SFC.

A Prescription event monitoring (PEM) study to assess safety and health outcomes of Airtec SF (Salmeterol Fluticasone propionate combination) in Indian population

Background: Asthma management has been fraught with several challenges especially for partly or uncontrolled cases. Incremental dosage strategy with salmeterol, fluticasone propionate combination offers stable yet effective control of symptoms preventing further exacerbations. However, there is limited evidence available on the need and safety profile of this incremental dosage strategy with the combination especially in Indian settings. To examine the safety and adverse clinical outcomes of Airtec SF when prescribed in patients with well- or poorly controlled persistent asthma. Methods: Based on the principle of prescription event monitoring (PEM) for safety reporting, this study was conducted at 20 centers across India. PEM study booklets with study questionnaire were provided to capture information related to adverse “events” during the observation period of 30 days. Results: Data of 384 patients were analyzed, with a mean age 44.5 years. 39% (n=150) were newly diagnosed and 61% (n=234) being in poorly controlled asthma status (i.e., partly or uncontrolled asthma). Of them, 42% (161), 44% (n=169) and 14% (54) patients were diagnosed with mild, moderate or severe persistent asthma, respectively. These were prescribed with metered-dose inhaler (n=187) or dry powder inhaler (n=197) formulations. 56% (n=216) patients suffered from concomitant allergic rhinitis. Among newly diagnosed patients with moderate to severe asthma dosage were tapered in 5.5% (n=3) cases. Dosage consistency was well-maintained in 98.2% (n=155) among partial or uncontrolled asthmatics with moderate to severe asthma with exacerbation rate of 1.9% (n=3). Adverse events including infective pneumonitis and upper respiratory tract infection were transient with none requiring treatment withdrawal. Conclusion: Use of Airtec SF was safe and well-tolerated with a negligible rate of exacerbations in Indian population especially amongst poorly controlled asthma patients.

Comparison of the clinical efficacy of low-dose budesonide plus seretide and double dose budesonide in treatment of adults with moderate persistent asthma

目的 比较低剂量沙美特罗替卡松联用布地奈德与单用双倍量布地奈德干粉吸入剂治疗成年人中度持续性哮喘的临床疗效和不良反应.方法 选取60例成年人中度持续性哮喘患者,应用随机数字表法分为两组,每组30例,A组患者接受低剂量沙美特罗替卡松联用布地奈德干粉吸入剂,B组接受单用双倍量布地奈德干粉吸入剂,观察两组临床症状、肺功能相关指标(FEV1%,PEF%)、缓解药物的使用量.结果 相对治疗前,两组都能明显改善成年人哮喘症状、临床症状改善、缓解药物使用量减少.治疗后两组间的短效β受体激动剂使用量、FEV1占预计值百分比差异无统计学意义(t=0.243,0.132,均P＞0.05),PEF占预计值百分比差异无统计学意义(t=0.125,P＞0.05).结论 低剂量吸入布地奈德联用沙美特罗替卡松与单用双倍量布地奈德疗效相当,从布地奈德全身性副反应考虑,低剂量沙美特罗替卡松联用布地奈德是更加合理的治疗选择。

Hypothalamic-Pituitary-Adrenal Axis Effects of Mometasone Furoate/Formoterol Fumarate vs Fluticasone Propionate/Salmeterol Administered Through Metered-Dose Inhaler

The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products. In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 μg/10 μg, MF/F 400 μg/10 μg, fluticasone propionate/salmeterol (FP/S) 460 μg/42 μg, or placebo. Plasma cortisol concentrations were measured over 24 h on days -1 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable. Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 μg/10 μg and FP/S 460 μg/42 μg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 μg/10 μg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 μg/10 μg and FP/S 460 μg/42 μg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated. MF/F 400 μg/10 μg or FP/S 460 μg/42 μg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 μg/10 μg was similar to placebo.

P235 Dual-bronchodilation with once-daily QVA149 in patients with moderate-to-severe COPD: overview of the IGNITE program

IntroductionIn patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by monotherapy, current treatment strategies recommend the addition of a second bronchodilator with a different mechanism...

Clinical and cost effectiveness of switching asthma patients from fluticasone-salmeterol to extra-fine particle beclometasone-formoterol: a retrospective matched observational study of real-world patients

Background:Efficacy trials suggest that extra-fine particle beclometasone dipropionate-formoterol (efBDP-FOR) is comparable to fluticasone propionate-salmeterol (FP-SAL) in preventing asthma exacerbations at a clinically equivalent dosage. However, switching from FP-SAL to efBDP-FOR has not been evaluated in real-world asthma patients.Aims:The REACH (Real-world Effectiveness in Asthma therapy of Combination inHalers) study investigated the clinical and cost effectiveness of switching typical asthma patients from FP-SAL to efBDP-FOR.Methods:A retrospective matched (1:3) observational study of 1,528 asthma patients aged 18–80 years from clinical practice databases was performed. Patients remaining on FP-SAL (n=1,146) were compared with those switched to efBDP-FOR at an equivalent or lower inhaled corticosteroid (ICS) dosage (n=382). Clinical and economic outcomes were compared between groups for the year before and after the switch. Non-inferiority (at least equivalence) of efBDP-FOR was tested against FP-SAL by comparing exacerbation rates during the outcome year.Results:efBDP-FOR was non-inferior to FP-SAL (adjusted exacerbation rate ratio 1.01 (95% CI 0.74 to 1.37)). Switching to efBDP-FOR resulted in significantly better (p<0.05) odds of achieving overall asthma control (no asthma-related hospitalisations, bronchial infections, or acute oral steroids; salbutamol ≤200μg/day) and lower daily short-acting β2-agonist usage at a lower daily ICS dosage (mean −130μg/day FP equivalents; p<0.001). It also reduced mean asthma-related healthcare costs by £93.63/patient/year (p<0.001).Conclusions:Asthma patients may be switched from FP-SAL to efBDP-FOR at an equivalent or lower ICS dosage with no reduction in clinical effectiveness but a significant reduction in cost.

A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD

Fluticasone furoate/vilanterol trifenatate (FF/VI) is a once-daily inhaled corticosteroid/long-acting β₂-agonist combination in development for chronic obstructive pulmonary disease (COPD) treatment. We compared the efficacy and safety of FF/VI versus fluticasone propionate/salmeterol (FP/SAL) twice daily over 12 weeks. Moderate to very severe COPD patients received FF/VI 100/25 μg once daily in the morning (n=266) or FP/SAL 500/50 μg twice daily (n=262). The primary end-point was a change from baseline in 0-24 h weighted mean forced expiratory volume in 1 s (wmFEV₁) at 12 weeks. Additional end-points included time to 100 mL improvement from baseline on day 1 and a change from baseline in St George's Respiratory Questionnaire (SGRQ). Safety was also assessed. wmFEV₁ (mean 130 mL) was greater and time to 100 mL improvement shorter (median 16 min) with FF/VI than FP/SAL (weighted mean 108 mL, median 28 min). Health status (SGRQ total score) improved in both groups (FF/VI -4.3 units, FP/SAL -3.0 units). Differences between treatments were not statistically significant. Six patients in the FF/VI (2%) and three in the FP/SAL (1%) arm experienced serious adverse events, none of which were considered to be drug related. Improvements in lung function and health status were not significantly different between FF/VI 100/25 μg once daily and FP/SAL 500/50 μg twice daily; there was no apparent difference between the safety profiles of either therapy.

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease.

Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F). To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD). We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers. Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component. Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs. A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials. Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.

Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus Other Combination Products: the DIFFUSE Study

The efficacy of inhaled products is affected by the degree, and potentially the site, of drug particle deposition in the lungs. Lung deposition correlates with the fine particle fraction (FPF; the proportion of dose containing particles <5 μm in aerodynamic diameter). This in vitro study (defining fluticasone propionate/formoterol particulate size [DIFFUSE]) examined the effects of inhalation flow rate on the FPF of the fluticasone propionate/formoterol (FP/FORM) pMDI aerosol compared with three other inhaled corticosteroids/long-acting β2-agonist (ICS/LABA) combination therapies administered by either DPI or pMDI [fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (BUD/FORM) and beclometasone dipropionate/formoterol (BDP/FORM)]. Aerodynamic particle size distribution was determined for each product using an 8-stage Andersen Cascade Impactor at two inhalation flow rates: 28.3 and 60.0 L/min. Fine particle dose (mass of dose <5.0 μm) and FPF were calculated as a percentage of the labeled dose for the LABA and ICS of each product at both flow rates. FP/FORM suspension aerosol provided a high and consistent FPF of approximately 40% for the ICS and LABA components at both flow rates. At 28.3 L/min, the FPF of each component of FP/FORM (41.2% and 39.2%) was greater than that of FP/SAL DPI (12.5% and 11.3%), BUD/FORM DPI (8.2% and 6.6%) and BDP/FORM pMDI (28.5% and 26.0%). At 60.0 L/min, the FPFs of the FP/FORM components (43.7% and 42.1%) were greater than those of FP/SAL (17.8% and 14.8%) and BUD/FORM (35.0% and 30.1%), and similar to those of BDP/FORM (43.0% and 39.5%). The FP/FORM suspension aerosol produced a high and consistent FPF of approximately 40% across both flow rates. The consistent FPF in vitro may be predictive of FP/FORM providing more consistent drug dosing in vivo, helping to counteract variable lung dose due to variation in inspiratory flow rate among patients and between a patient’s day-to-day or successive inhalation maneuvers.

Montelukast improves air trapping, not airway remodeling, in patients with moderate-to-severe asthma: a pilot study

Background Evidence has demonstrated that the distal lung, which includes airways of &lt;2 mm in diameter and lung parenchyma, constitutes an important component of asthma pathology. Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators and bronchoconstrictors involved in the asthmatic process. Guidelines recommend the leukotriene-modifying agents for asthma treatment. We hypothesized that a leukotriene receptor antagonist with an inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) combination would improve small airways function in moderate-to-severe asthmatics evaluated by physiological tests and high-resolution computed tomography (HRCT) analysis. This study was performed at a tertiary university hospital in Beijing. Methods This was a randomized, double-blind, parallel study performed in 38 patients with moderate-to-severe asthma treated with salmeterol/fluticasone (SFC) plus montelukast (SFC+M) or SFC plus placebo over 24 weeks. Small airway function was assessed by physiological studies and HRCT image analysis. Results Montelukast significantly improved air trapping as expressed by the residual volume (RV)/total lung capacity (TLC). Over 24 weeks of treatment, RV/TLC was improved by (15.41±6.67)% in patients receiving SFC+M while RV/TLC was decreased by (8.57±10.26)% in patients receiving SFC alone, the difference between the two groups was significant (P=0.02). There was a trend towards a significant difference in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) in the SFC+M group compared to that in the SFC group ((17.87±8.17)% vs. (12.28±9.20)%, P=0.056). There was no significant change in percentage wall area (WA%) after 24 weeks of add-on treatment with montelukast. Patients receiving SFC+M showed significant improvement in the ratio of CT-determined values at full expiration to those at full inspiration (E/I ratio) (0.894±0.005 vs. 0.871±0.003, P=0.002). Conclusion We have shown, using lung function tests and HRCT image technique, that add-on therapy with montelukast improves distal lung function reflected by air trapping, but not airway wall thickness in moderate-to-severe asthma. (ClinicalTrials.gov number, NCT00699062)

Mega-Trials for Blockbusters

THECONDUCTOFVERYLARGE,SIMPLETRIALS(MEGA-TRIALS) isuncommonand faces several challenges, inparticularcostanddifficulty inpatient recruitment.However, thesechallengescanbeovercomewhen interventions are widely used by hundreds of thousands of individuals and when there is a potential profit to accommodate the trial cost. Accordingly,every licensed interventionwithannualsales that exceed $1 billion, ie, a blockbuster, should have at least 1 trial performed with at least 10 000 patients randomized to the intervention of interest and as many randomized either to placebo (if deemed to be a reasonable choice) or to another active intervention that is the least expensive effective intervention available. The comparison drug can be a generic drug with a well-established effectiveness and safety profile. Adata-intensivemega-trialof20 000randomizedparticipants with 4 years of follow-up costs an estimated $420 million, but streamlining the design, monitoring, data collection, and outcomes could save 90% of that cost. For a blockbuster with $2 billion annual sales, 1-month sales ($167 million) would suffice to conduct a mega-trial of 80 000 participants. The one outcome that should routinely be collected is death. For 80% power to detect a 10% relative risk reduction, sufficient follow-up is needed to achieve a 13.2% death rate in the control group with 10 000 participants per study group, or 3.3% with 40 000 participants per group. Furthermore, information also could be collected on major clinical end points that have not been adequately studied in previous trials of the blockbuster. How many interventions would be affected if such a rule were to be applied? In 2011, sixty different drug products had sales exceeding $1 billion in the United States alone; of those, 24 exceeded $2 billion in sales. More than 100 drugs have exceeded $1 billion in US annual sales at least once. The number is substantially larger if global markets are considered. Sales of the top 100 blockbusters globally accounted for $285 billion in 2009, exceeding 35% of the global pharmaceutical market. Because blockbusters typically maintain top sales for almost a decade, less than 1% of profits could fund an efficient mega-trials agenda. Blockbusterdrugsareeventuallyusedbymillionsofpatients. Typically there is evidence from randomized trials suggesting that thesedrugsareeffective—at least for someendpoints (not necessarilythemostseriousones), forsomefollow-up(notnecessarily longenough),and insomespecificcircumstances(not necessarily representing what happens in real life). The supportingrandomizedtrials typically includeonlya fewhundred participants (as in the case of testosterone [AndroGel] or modafinil [Provigil]) or, in the best case, a few thousand participants,oftenwithrelativelyshort-termfollow-upandareconducted among populations selected to avoid patients with comorbid conditions and those who take some other drugs. Of the 24 top blockbusters of 2011, only clopidogrel has had a randomized trial with more than 10 000 participants allocated to the experimental group—COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) randomized 22 961 participants to clopidogrel and 22 891 to placebo. Rosuvastatin also came close to this threshold but not quite— JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized 8901 patients to rosuvastatin and 8901 to placebo. A few other blockbuster drugs have been studied in trials of 5000 to 10 000 patients (eg, tiotropium in the UPLIFT [Understanding Long-term Impacts on Function With Tiotropium] trial [n=5993] and fluticasone salmeterol in the 4-group TORCH [Towards a Revolution in COPD Health] trial [n=6112]), but such sample sizes coupled with modest follow-up cannot offer definitive evidence for risk of death. Fewof therandomizedtrials supporting theevidence legacy ofblockbustershave includeddeathasaprimaryoutcome.Evidenceofother seriousclinical events is alsooften limited, even though the conditions targeted for these therapies are serious, and for most of them death is the most important outcome for decision-making. Both COMMIT and JUPITER documented asignificantreductioninmortality(relativerisks,0.93[P=.03] and0.80[P=.02],respectively).Perhapsthisdocumentedbenefithascontributedtotheeventualmarketsuccessoftheseproducts. The UPLIFT and TORCH trials came close, but did not passnominalstatisticalsignificanceforreducedmortality(relativerisks,0.89[P=.08]and0.83[P=.052],respectively).Conversely, for some popular agents, such as erythropoietin, significantexcesses inmortalityhavebeendocumented inspe-

Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol–fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study

QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0-12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249. Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0-12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100-0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively). Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients. Novartis Pharma AG.