Karen Mezzi

The effect of indacaterol/glycopyrronium versus tiotropium or salmeterol/fluticasone on the prevention of clinically important deterioration in COPD

Background Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients. Methods Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George’s Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1. Results Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P<0.0001). With D2, IND/GLY significantly reduced the risk of first, but not sustained, CID versus TIO (0.80 [0.64 to 0.99], P=0.0359 and 0.85 [0.66, 1.10], P=0.2208) and both first and sustained CID versus SFC (0.73 [0.61, 0.88], P=0.001 and 0.72 [0.58, 0.90], P=0.0036). Conclusion These data confirm the utility of the CID endpoint as a means of monitoring COPD worsening in patients with moderate-to-severe COPD. Using the CID measure, we demonstrated that dual bronchodilation with IND/GLY significantly reduced the risk of CID versus either long-acting muscarinic antagonist or long-acting β2-agonist/inhaled corticosteroid treatment, providing further evidence for the benefit of dual bronchodilation in this patient population.

Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis.

Background Indacaterol/glycopyrronium (IND/GLY) is approved for maintenance treatment of adult patients with COPD. This post hoc analysis explored the efficacy and safety of IND/GLY versus salmeterol/fluticasone (SFC) in symptomatic (Global Initiative for Chronic Obstructive Lung Disease [GOLD] B and GOLD D) patients with moderate-to-severe COPD. Patients and methods Data from LANTERN and ILLUMINATE studies were pooled and analyzed. In both studies, symptomatic COPD patients were randomized to once-daily IND/GLY 110 μg/50 μg or twice-daily SFC 50 μg/500 μg. End points were pre-dose trough forced expiratory volume in one second (FEV1), standardized area under the curve for FEV1 from 0 to 12 hours (FEV1 AUC0–12 hours), peak FEV1, peak forced vital capacity (FVC), pre-dose trough FVC, Transition Dyspnea Index (TDI) total score, St George’s Respiratory Questionnaire total score, rescue medication use and safety. Results A total of 1,263 patients were classified as either GOLD B (n=809) or GOLD D (n=454). At week 26, IND/GLY demonstrated statistically significant improvement in all lung function parameters versus SFC in patients in both the GOLD B and GOLD D subgroups. TDI total score and rescue medication use were significantly improved with IND/GLY versus SFC in the overall population and in the GOLD B (TDI total score only) and GOLD D (rescue medication only) subgroups. IND/GLY also reduced the rate of exacerbations in the pooled population. Overall safety profile was comparable with a higher incidence of pneumonia in the SFC-treated group. Conclusion In this pooled analysis, IND/GLY demonstrated superior efficacy compared with SFC in patients in the GOLD B and GOLD D subgroups and supported its use in symptomatic COPD patients.

Response to Indacaterol/Glycopyrronium (IND/GLY) by Sex in Patients with COPD: A Pooled Analysis from the IGNITE Program

ABSTRACT In this pooled analysis, we compared the effect of indacaterol/glycopyrronium (IND/GLY) by sex versus other commonly used chronic obstructive pulmonary disease (COPD) treatments and placebo. Male and female patients with moderate-to-very-severe COPD who had participated in six randomized controlled trials were included in the analysis. Baseline demographics and disease characteristics were analyzed by sex, and any differences noted. The effects of IND/GLY versus salmeterol/fluticasone (SFC), glycopyrronium, tiotropium and placebo, on lung function and the patient-reported outcomes (health status, dyspnea, rescue medication use and symptoms) were assessed by sex after 26 weeks treatment. The analysis population comprised 4719 men and 1389 women. Most baseline parameters differed significantly between men and women. Nonetheless, despite these differences in baseline characteristics, IND/GLY significantly improved lung function versus placebo (p < 0.0001) and all active comparators (p < 0.01) in men and women. Overall, IND/GLY showed better improvement in dyspnea and health status compared with all other treatments in both sex. Greater reduction of rescue medication use was observed with IND/GLY versus placebo and other treatments (all p < 0.01 expect IND/GLY versus SFC). Although some variability was observed, improvements in health status, dyspnea, rescue medication use and symptoms were generally larger in women than in men. Irrespective of sex, IND/GLY provided superior efficacy to monotherapy or SFC in both men and women. Small differences in efficacy response by sex were observed, which should be evaluated further in prospective clinical studies. Nevertheless, the benefits observed with IND/GLY confirm dual bronchodilator as the preferred therapy in patients with moderate-to-very-severe COPD regardless of sex.

Efficacy of Indacaterol/Glycopyrronium in Patients with COPD Who Have Increased Dyspnea with Daily Activities

Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 µg compared with placebo, once-daily tiotropium 18 µg, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 µg. In this analysis, a Baseline Dyspnea Index (BDI) score ≤7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p<0.05) and SFC (0.97 units; p<0.05), and significantly increased the likelihood of a patient achieving a 1-unit improvement in TDI compared with tiotropium (odds ratio [OR] 1.87; p<0.05). IND/GLY also significantly improved trough forced expiratory volume in 1 second (FEV1) compared with tiotropium and SFC (p<0.001 and p<0.0001, respectively), and significantly reduced rescue medication use compared with tiotropium (p<0.001). Conclusions: Our analysis indicates that IND/GLY provides additional improvements in dyspnea and lung function compared with tiotropium and SFC in dyspneic patients.

P60 Effect of Indacaterol/Glycopyrronium (IND/GLY) on patient-reported outcomes in men and women with COPD: a pooled analysis from the ignite programme

Introduction Literatures, although limited, suggest differences in the manifestations of COPD in terms of symptoms and health-related quality of life between men and women. Moreover, a pooled analysis of 6 randomised trials from the IGNITE programme showed a lower baseline dyspnoea index (greater dyspnoea) and higher baseline St. George’s Respiratory Questionnaire (SGRQ) total scores (worse health related quality of life) in women compared with men1. Here, we report the treatment impact in patient-reported outcomes (PROs) in men and women by further investigating data from the aforementioned pooled analysis. Methods Six trials of 24 to 62 weeks duration (ENLIGHTEN, SHINE, ILLUMINATE, ARISE, SPARK and LANTERN) from the IGNITE programme were included. Effects of IND/GLY on PROs, such as transition dyspnoea index (TDI) and SGRQ total scores, symptoms scores via electronic diary and rescue medication use, were assessed, compared with salmeterol/fluticasone (SFC), glycopyrronium (GLY), tiotropium (TIO) and placebo (PBO) in both men and women with moderate to very severe COPD. Results Data from 6108 patients were pooled and analysed (men, n = 4719; women, n = 1389). Overall, IND/GLY showed better improvement in dyspnoea and health status at Week 26 compared with other treatments. Although, there was some variability, the effect size was generally larger in women compared with men (Table). In addition, a higher percentage of women than men treated with IND/GLY achieved the minimal clinically important difference (MCID) from baseline in TDI and SGRQ total scores versus other comparators. Similarly, there was a greater reduction of rescue medication use in women than in men that received IND/GLY versus other treatments (Table). The reduction of symptom scores in the e-Diary with IND/GLY was comparable in both genders (Table). Conclusions IND/GLY demonstrated superior improvement in dyspnoea and health status in both men and women with COPD compared with SFC, GLY, TIO and PBO. Furthermore, the efficacy of IND/GLY in terms of PROs was found to be better in women than in men and IND/GLY could be considered as a start-up treatment vs monotherapy for women with COPD. If confirmed in further studies these data may support gender differences in PROs response to bronchodilator therapy. Reference Fucile S, et al. Am J Respir Crit Care Med 2016;193:A6781. Abstract P60 Table 1 Effects of IND/GLY on PROs in men and women compared with other comparators at Week 26 Parameters IND/GLY vs SFC IND/GLY vs GLY IND/GLY vs TIO IND/GLY vs PBO Men Women Men Women Men Women Men Women TDI total scores 0.46(0.06, 0.85)* 0.65(−0.12, 1.43) 0.23(−0.23, 0.68) 1.31(0.52, 2.10)† 0.51(0.05, 0.97)* 1.39(0.63, 2.15)‡ 0.66(0.05, 1.26)* 2.51(1.52, 3.51)τ SGRQ total scores −0.93(−2.53, 0.66) −1.93(−4.92, 1.06) −1.36(−2.57, −0.14)* −2.83(−4.91, −0.75)† −2.51(−3.72, −1.31)τ −1.83(−3.90, 0.24) −2.27(−4.59, 0.06) −6.82(−10.6, −3.01)‡ Symptom scores (total) via e-diary −0.37(−0.82, 0.09) 0.06(−0.60, 0.73) −0.34(−0.60, −0.08)† −0.40(−0.82, 0.02) −0.39(−0.65, −0.13)† −0.62(−1.05, −0.19)† −0.22(−0.79, 0.35) −0.31(−1.30, 0.68) Rescue medication use −0.14(−0.45, 0.17) −0.03(−0.74, 0.67) −0.66(−0.89, −0.43)τ −1.22(−1.66, −0.78)τ −0.53(−0.76, −0.30)τ −1.13(−1.56, −0.69)τ −0.66(−1.03, −0.29)‡ −1.12(−1.84, −0.40)† pp < 0.05; †p < 0.01; ‡p < 0.001; τp < 0.0001; data presented as LSM (95% confidence interval); e-diary, electronic diary; IND/GLY, indacaterol/glycopyrronium (110/50 µg once daily); LSM, least square mean; PBO, placebo; PRO, patient-reported outcome; SFC, salmeterol/fluticasone (50/500 µg twice daily); SGRQ, St. George’s Respiratory Questionnaire; TDI, transition dyspnoea index; TIO, tiotropium (18 µg once daily)

P235 DUAL-BRONCHODILATION WITH ONCE-DAILY QVA149 IN PATIENTS WITH MODERATE-TO-SEVERE COPD: OVERVIEW OF THE IGNITE PROGRAM

Introduction In 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 of action. Once-daily QVA149 is a dual bronchodilator combining the long-acting β2-agonist indacaterol (IND) and long-acting muscarinic antagonist glycopyrronium (GLY). The IGNITE program comprises a series of randomised controlled trials that investigate the efficacy and safety of QVA149 in patients with moderate-to-severe COPD. Methods This overview includes data from 4 multicentre, double-bind, randomised controlled trials evaluating the effect of QVA149 110/50 μg versus IND 150 μg, GLY 50 μg, tiotropium (TIO) 18 μg (open-label in the SHINE and SPARK studies; blinded in the BLAZE study), salmeterol/fluticasone (SFC) 50/500 μg, and placebo (PBO) in patients with moderate-to-very severe COPD. Outcomes reported here are lung function, transitional dyspnoea index (TDI), health status (via the St George’s Respiratory Questionnaire [SGRQ]), and exacerbations over 6 weeks (BLAZE), 26 weeks (SHINE, ILLUMINATE), and 64 weeks (SPARK). Results Data from 5138 patients were included in this overview. QVA149 provided statistically significant and clinically meaningful bronchodilation (p < 0.001) that was sustained throughout the treatment periods versus all comparators in all studies. QVA149 provided superior benefits versus TIO, SFC, and PBO with respect to TDI score in BLAZE and ILLUMINATE studies. At Week 64, QVA149 significantly improved SGRQ score (p≤0.001) and significantly lowered the rate of all exacerbations compared with GLY and TIO in the SPARK study (Table). In addition, QVA149 reduced the rate of all exacerbations by 31% and significantly delayed the time to first exacerbation versus SFC in the ILLUMINATE trial. Conclusion The results from the IGNITE trials demonstrate that superior improvements in lung function with once-daily QVA149 translate into meaningful therapeutic outcomes for patients with COPD as demonstrated by improved lung function, dyspnoea, health status, and reduced exacerbations. Abstract P235 Table 1. IGNITE data overview Treatment differences (QVA149 vs comparator) Parameters Study (N) PBO IND GLY TIO SFC Lung function SPARK(2224) Trough FEV1, mL - - 70*** 60*** - SHINE (2144) 200*** 70*** 90*** 80*** - FEV1 AUC0−12h, mL 330*** 130*** 130*** 120*** - ILLUMINATE (523) - - - - 140*** BLAZE (247) FEV1 AUC0−4h, mL 250*** - - 90*** - Dyspnoea TDI score 1.37*** - - 0.49* - ILLUMINATE - - - - 0.76** Health status SPARK SGRQ score - - −2.07*** −2.69*** - Rate reduction of exacerbations, % Moderate-to-severe - - 12 RR 0.88* 10 RR 0.90 - All - - 15RR 0.85*** 14RR 0.86** - ILLUMINATE Moderate-to-severe - - - - 20 RR 0.80 All - - - - 31RR 0.69 * p<0.05;** p<0.01; *** p≤0.001; †free combination; GLY=glycopyrronium; IND=indacaterol; PBO=placebo; SFC=salmeterol/fluticasone; RR=rate ratio;TIO=tiotropium