InforMing the PAthway of COPD Treatment (IMPACT Trial) Single-Inhaler Triple Therapy (Fluticasone Furoate/Umeclidinium/Vilanterol) Versus Fluticasone Furoate/Vilanterol and Umeclidinium/Vilanterol in Patients With COPD: Analysis o the Western Europe and North America Regions

Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airflow limitation and progressive respiratory symptoms.1 Global public health trends estimate that the COPD burden will continue to rise, with COPD deaths estimated to increase to 4.4% of all deaths in Europe and 6.3% in the World Health Organization-defined region of the Americas by 2060.2 There are differences in the COPD burden in different regions reflecting variations in etiology,3,4 disease severity,5 symptoms,6 medication use,7 and health care systems and utilization.7 These differences may help inform therapeutic strategies to optimize therapeutic approaches to reducing symptoms and exacerbation risk.1 In the global InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates and improved lung function and health-related quality of life versus FF/VI or UMEC/VI dual therapy in patients ≥40 years of age with symptomatic COPD and a history of exacerbations.8 Within trial populations, regional differences such as patient characteristics, treatment patterns, access to care and cultural/socioeconomic factors may dictate treatment choices and influence disease severity and progression in particular geographical locations. For example, a meta-analysis conducted in 2015 comprising 123 studies between 1990 and 2010 found that the overall prevalence of COPD as well as the rate of increase was higher in the Americas (including both North and South America) compared with Europe.9 Furthermore, a cross-sectional study assessing the burden of COPD symptoms in the United States and Europe found variations between patients across countries who had experienced at least 1 symptom of COPD.10 In Europe, patients with more frequent symptoms were more likely to experience worsening of symptoms and unexpected hospitalization. Whereas in the United States, patients with more frequent symptoms were not only more likely to experience worsening of symptoms but also longer lasting symptoms and a longer length of exacerbations.10 A further difference was that treatment adherence was higher in the United States than Europe, however, adherence was consistent across patients in Europe when assessed by modified Global initiative for chronic Obstructive Lung Disease (GOLD) 2014 groups11 but varied in the United States with adherence highest in the GOLD Group C and lowest in Group A.10 Therefore, it is important to evaluate how overall population results pertain to patients treated in particular regions. As IMPACT is one of the largest trials conducted in patients with COPD to date, we have the unique opportunity to analyze study outcomes in patients enrolled in Western Europe and North America, the 2 main regions from an enrollment perspective

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

This is the final version. Available from Elsevier via the DOI in this record. Data sharing: Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).GlaxoSmithKleinGlaxoSmithKlei

Optimizing Dietary Restriction for Genetic Epistasis Analysis and Gene Discovery in C. elegans

Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases. Lifespan extension due to DR is conserved across a wide range of species. Recent research has focused upon genetically tractable model organisms such as C. elegans to uncover the genetic mechanisms that regulate the response to DR, in the hope that this information will provide insight into the mammalian response and yield potential therapeutic targets. However, no consensus exists as to the best protocol to apply DR to C. elegans and potential key regulators of DR are protocol-specific. Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies. The food intake that maximizes longevity varies for different genotypes and informative epistasis analysis with another intervention is only achievable at this ‘optimal DR’ level. Importantly therefore, the degree of restriction imposed using our method can easily be adjusted to determine the genotype-specific optimum DR level. We used this protocol to test two previously identified master regulators of DR in the worm. In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity

A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 &micro;g on health-related quality of life in patients with COPD

Thomas M Siler,1 Alison C Donald,2 Dianne O&rsquo;Dell,2,3 Alison Church,2 William A Fahy4 1Midwest Chest Consultants, PC, St Charles, MO, 2GSK, Research Triangle Park, NC, USA; 3Pearl Therapeutics, Inc., Durham, NC, USA; 4GSK, Respiratory Medicines Development Centre, Stockley Park, Middlesex, UK Background: The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting &beta;2-agonist vilanterol (VI) has been shown to provide significant improvements in lung function compared with UMEC, VI, or placebo (PBO) in patients with chronic obstructive pulmonary disease (COPD). This study was specifically designed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population. Methods: This was a 12-week multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Eligible patients were randomized 1:1 to receive once-daily UMEC/VI 62.5/25&nbsp;&micro;g (via ELLIPTA&reg; dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George&rsquo;s Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1&ndash;12 and trough forced expiratory volume in 1 second on day 84. Adverse events were also assessed. Results: A total of 496 patients were included in the intent-to-treat population in the UMEC/VI (n=248) and PBO (n=248) treatment groups. UMEC/VI 62.5/25 &micro;g provided a significant and clinically meaningful improvement in SGRQ total score at day 84 versus PBO (difference between treatments in SGRQ total score change from baseline: -4.03 [95% confidence interval {CI}: -6.28, -1.79]; P&lt;0.001). UMEC/VI 62.5/25 &micro;g resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P&lt;0.001). UMEC/VI 62.5/25 &micro;g provided a significant and clinically meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO (122 mL [95% CI: 71, 172]; P&lt;0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 &micro;g and PBO groups, respectively). Conclusion: The results of this study demonstrate that treatment with UMEC/VI 62.5/25 &micro;g provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD. Keywords: COPD, umeclidinium, vilanterol, health-related quality of life, SGRQ, long-acting bronchodilato

Once-daily indacaterol 75 &micro;g in moderate- to-severe COPD: results of a Phase IV study assessing time until patients&rsquo; perceived onset of effect

Thomas M Siler,1 Craig F LaForce,2 Farid Kianifard,3 James Williams,3 Selwyn Spangenthal4 1Midwest Chest Consultants, St Charles, MO, USA; 2North Carolina Clinical Research, Raleigh, NC, USA; 3Novartis Pharmaceuticals, East Hanover, NJ, USA; 4Charlotte Lung and Health Center, Charlotte, NC, USA Background: Indacaterol 75 &micro;g once daily is a long-acting &beta;2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients&#39; perception of onset of effect with a single dose. Methods: In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 &micro;g or placebo via a dry powder inhaler device. The primary variable was time until patient&rsquo;s perception of onset of effect, using a simple self-administered (nonvalidated) questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1) and change in percent predicted FEV1 from predose to postdose (determined 60&ndash;75 minutes postdose). Results: The least-squares mean time to patient&rsquo;s perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient&#39;s perception. In addition, no statistically significant differences between treatments were observed for patient&#39;s global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (P&lt;0.0001). There was little or no association between patient&rsquo;s perception of time to onset of effect and change in FEV1, or change in percent predicted FEV1. Both treatments were well tolerated. Conclusion: A single dose of indacaterol 75 &micro;g did not separate from placebo in terms of patient perception of onset, although there was an improvement in FEV1 for indacaterol compared with placebo. Development and use of a validated questionnaire may be needed to address the inconsistency in evaluating this patient-related outcome. Keywords: bronchodilator, long-acting, perceived onset of action, single dos

Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD

Edward M Kerwin,1 Thomas M Siler,2 Samir Arora,3 Patrick Darken,4 Earl St Rose,4 Colin Reisner4,5 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Midwest Chest Consultants, St Charles, MO, USA; 3Aventiv Research, Columbus, OH, USA; 4Pearl &ndash; a member of the AstraZeneca Group, Morristown, NJ, USA; 5AstraZeneca, Gaithersburg, MD, USA Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting &beta;2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 &mu;g and FF MDI 9.6 &mu;g, and two of either BFF MDI 160/9.6 &mu;g, BFF MDI 80/9.6 &mu;g, or BD MDI 320 &mu;g twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 &mu;g (least squares mean differences 186&ndash;221 mL; all p&lt;0.0001), and BFF MDI 320/9.6 &mu;g demonstrated a significant improvement versus FF MDI 9.6&nbsp;&mu;g (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 &mu;g for all lung function, dyspnea, and rescue medication use secondary efficacy endpoints. All BFF MDI doses were well tolerated, and the safety profile was not substantially different from the monocomponents. There was no evidence of clinically meaningful pharmacokinetic interactions when budesonide and formoterol were formulated together in BFF MDI. Conclusion: The findings presented here confirm that BFF MDI 320/9.6 &mu;g is an appropriate dose to take forward into Phase III studies in patients with COPD. Keywords: BFF MDI, COPD, fixed-dose combination, inhaled corticosteroid, long-acting &beta;2-agonist, single-inhaler triple therap