Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials).

Rationale: Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. Methods: These phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trials were conducted between September 2020 and December 2022 at 250 research centers and pulmonology practices in 17 countries. Patients aged 40-80 years with moderate to severe symptomatic COPD were enrolled. Measurements and Main Results: Totals of 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% receiving concomitant long-acting muscarinic antagonists or long-acting ß2-agonists, respectively. Post-bronchodilator FEV1 percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV1 area under the curve at 0-12 hours versus placebo (ENHANCE-1, 87 ml [95% confidence interval, 55, 119]; ENHANCE-2, 94 ml [65, 124]; both P < 0.001). Ensifentrine treatment significantly improved symptoms (Evaluating Respiratory Symptoms) and quality of life (St. George's Respiratory Questionnaire) versus placebo at Week 24 in ENHANCE-1 but not in ENHANCE-2. Ensifentrine treatment reduced the rate of moderate or severe exacerbations versus placebo over 24 weeks (ENHANCE-1, rate ratio, 0.64 [0.40, 1.00]; P = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87]; P = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97]; P = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87]; P = 0.009). Adverse event rates were similar to those for placebo. Conclusions: Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies. Clinical trial registered with www. CLINICALTRIALS: gov and EudraCT (ENHANCE-1, www. CLINICALTRIALS: gov identifier NCT04535986, EudraCT identifier 2020-002086-34; ENHANCE-2, www. CLINICALTRIALS: gov identifier NCT04542057, EudraCT identifier 2020-002069-32).

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

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).

Correct use and ease-of-use of placebo ELLIPTA dry-powder inhaler in adult patients with chronic obstructive pulmonary disease.

BACKGROUND: Inhaler technique errors are common in chronic obstructive pulmonary disease (COPD) treatment, potentially leading to poor disease management. Our pooled analysis approach assessed correct use and ease-of-use of a placebo ELLIPTA dry-powder inhaler (DPI) in patients with COPD. METHODS: Adults with COPD from open-label/non-blinded studies evaluating a placebo ELLIPTA DPI and reporting outcomes of correct use (based on the ELLIPTA DPI patient information leaflet [PIL]) and/or ease-of-use were included. Correct use and ease-of use at study end were primary and secondary endpoints, respectively. Data from patients in the placebo ELLIPTA DPI arm of each study were pooled, and the intent-to-treat (ITT) population was used for all analyses. RESULTS: Four placebo ELLIPTA DPI studies, reporting correct use (n = 4) and ease-of-use (n = 2), were included in the analysis. The ITT population comprised 1232 patients (mean age 66.2 years). For the primary endpoint, 80.1% (n = 975/1217) of patients demonstrated correct use at study end (95% confidence interval [CI]: 77.8%-82.3%). For the secondary endpoint, 95.7% (n = 797/833) of patients rated placebo ELLIPTA DPI use "easy"/"very easy" at study end (95% CI: 94.1%-97.0%). Correct use and "easy"/"very easy" user ratings remained high across younger (40-64 years) and older (≥65 years) age groups. CONCLUSIONS: Across age groups, most patients used the placebo ELLIPTA DPI correctly and rated it "easy"/"very easy" to use. Consistent with the Global Initiative for Chronic Obstructive Lung Disease 2021 report, our findings emphasize that proper training and clear instructions on PILs are important for optimal inhaler use.

Efficacy of Nebulized Glycopyrrolate on Lung Hyperinflation in Patients with COPD.

INTRODUCTION: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown. METHODS: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment. RESULTS: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was - 0.323 l (- 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was - 0.446 l (- 0.741 to - 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected. CONCLUSIONS: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04155047.

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 of the Western Europe and North America Regions.

BACKGROUND: The InforMing the Pathway of COPD Treatment (IMPACT) trial demonstrated lower moderate/severe exacerbation rates with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. Since IMPACT was a global study, post-hoc analyses were conducted by geographic region to investigate potential differences in overall findings. METHODS: IMPACT was a 52-week, randomized, double-blind trial. Patients with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25µg, FF/VI 100/25µg, or UMEC/VI 62.5/25µg. Endpoints assessed in the overall, Western Europe and North America populations included on-treatment moderate/severe exacerbation (rates and time-to-first), trough forced expiratory volume in 1 second and St George's Respiratory Questionnaire (SGRQ) total score. Safety was assessed. RESULTS: Overall, 10,355 patients were enrolled, 3164 from Western Europe, 2639 from North America. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in Western Europe (rate ratios 0.82 [95%CI 0.74-0.91], P<.001 and 0.76 [0.67-0.87], P<.001) and in North America (0.87 [0.77-0.97], P=.014 and 0.69 [0.60-0.80], P<.001). FF/UMEC/VI reduced time-to-first moderate/severe exacerbation and improved lung function versus FF/VI and UMEC/VI in both regions, and improved SGRQ total score in Western Europe, but not North America. Safety profiles were generally similar between treatment groups/regions; the inhaled corticosteroid class effect of increased pneumonia incidence was seen in North America but not Western Europe. CONCLUSION: Consistent with intent-to-treat results, FF/UMEC/VI reduced moderate/severe exacerbation rate and risk and improved lung function in Western Europe and North America; however, between-regions differences were seen for SGRQ total score and pneumonia incidence. CLINICAL TRIAL REGISTRATION: NCT02164513.

Safety and Efficacy of Revefenacin and Formoterol in Sequence and Combination via a Standard Jet Nebulizer in Patients with Chronic Obstructive Pulmonary Disease: A Phase 3b, Randomized, 42-Day Study.

Although no nebulized, dual mechanism, long-acting bronchodilator is currently marketed, with the approval of once-daily long-acting muscarinic antagonist (LAMA) revefenacinefenacin, it is theoretically possible to deliver a LAMA and long-acting beta2-agonist via standard jet nebulizer. The primary and secondary objectives of our study were to characterize the safety profile of revefenacin administered sequentially before or in combination with formoterol, via standard jet nebulizer in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, 42-day trial (NCT03573817), patients received revenacin 175 µg (n=63) or placebo (n=59), followed by formoterol 20 µg in the morning and formoterol alone in the evening formoterol 21 days via standard jet nebulizer (sequential administration). For another 21 days, revefenacin/placebo and formoterol, were administered as mixed solutions via single nebulization in the morning (combined administration), and formoterol alone in the evening. The adverse events' (AEs) incidence was higher in the placebo + formoterol arms (11%-12%) than in the revefenacin + formoterol arms (5%-8%). The most common AEs were worsening/exacerbation of COPD, cough, and dizziness. There were no serious AEs or deaths reported in any arm. The least squares mean in trough forced expiratory volume in 1 second (FEV1) versus baseline was higher in the revefenacin + formoterol arms (116-157 mL) than in the placebo + formoterol arms (35-53 mL). Revefenacin had a safety profile similar to formoterol alone when delivered sequentially or combined. Trough FEV1 was similar when revefenacin was delivered sequentially or combined with formoterol, with revefenacin providing an additional 81-104 mL improvements over formoterol alone.

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.

Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting ß2-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 µg and FF MDI 9.6 µg, and two of either BFF MDI 160/9.6 µg, BFF MDI 80/9.6 µg, or BD MDI 320 µg 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 µg (least squares mean differences 186-221 mL; all p<0.0001), and BFF MDI 320/9.6 µg demonstrated a significant improvement versus FF MDI 9.6 µg (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 µg 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 µg is an appropriate dose to take forward into Phase III studies in patients with COPD.

A randomised, phase III trial of once-daily fluticasone furoate/vilanterol 100/25 µg versus once-daily vilanterol 25 µg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD.

BACKGROUND: The contribution of fluticasone furoate (FF) on lung function in the FF/vilanterol (VI) 100/25 µg combination has been demonstrated numerically, but not statistically. METHODS: This multicentre, randomised, double-blind, controlled trial (GlaxoSmithKline study number 200820; clinicaltrials.gov NCT02105974) enrolled ≥40-year-old patients with chronic obstructive pulmonary disease (COPD), a ≥10-pack-year smoking history, a post-bronchodilator forced expiratory volume in 1 s (FEV1) 30-70% of the predicted value, a FEV1/forced vital capacity ratio of ≤0.70, ≥1 COPD exacerbation in the previous 12 months requiring corticosteroids, antibiotics and/or hospitalisation, and current COPD symptoms. Participants received FF/VI 100/25 µg or VI 25 µg once daily. The primary endpoint was the change from baseline in trough FEV1 at day 84. FINDINGS: 1620 patients were randomised and received at least one dose of FF/VI 100/25 µg (n = 806) or VI 25 µg (n = 814). At day 84, the FF/VI 100/25 µg group showed an adjusted mean treatment difference of 34 mL over VI 25 µg in change from baseline trough FEV1 (95% confidence interval [CI] 14-55; p = 0.001). There was no significant difference between the groups in the percentage of rescue medication-free 24-h periods. The FF/VI 100/25 µg group demonstrated a 42% risk reduction compared with the VI 25 µg group in time to first moderate/severe COPD exacerbation (95% CI 22-57; nominal p < 0.001). The incidence of on-treatment adverse events was similar between the groups. INTERPRETATION: The contribution of FF in the FF/VI 100/25 µg combination on lung function in COPD was statistically significant. FUNDING: GlaxoSmithKline.

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD.

BACKGROUND: Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. METHODS: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 µg, FF MDI 9.6 µg, or placebo MDI (all twice daily), or tiotropium 18 µg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. RESULTS: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). CONCLUSIONS: We conclude that GFF MDI 18/9.6 µg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

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

BACKGROUND: The combination of the inhaled muscarinic antagonist umeclidinium (UMEC) with the long-acting ß2-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 µg (via ELLIPTA(®) dry powder inhaler) or PBO for 12 weeks. The primary endpoint was St George's Respiratory Questionnaire (SGRQ) total score at day 84. Secondary efficacy endpoints included rescue albuterol use (puffs/day) over weeks 1-12 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 µg 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<0.001). UMEC/VI 62.5/25 µg resulted in a statistically significant reduction in rescue albuterol use versus PBO (-0.7 puffs/day [95% CI: -1.1, -0.4]; P<0.001). UMEC/VI 62.5/25 µg 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<0.001). The incidence of adverse events was similar between treatments (32% and 30% of patients in the UMEC/VI 62.5/25 µg and PBO groups, respectively). CONCLUSION: The results of this study demonstrate that treatment with UMEC/VI 62.5/25 µg provides clinically important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD.

Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study.

Long-acting bronchodilators including muscarinic antagonists are central to the management of patients with COPD. The Glycopyrrolate Effect on syMptoms and lung function (GEM2) study assessed the efficacy and safety of twice-daily glycopyrrolate 15.6 µg in patients with moderate-to-severe airflow limitation. This 12-week multicenter, double-blind study randomized (1:1) patients to glycopyrrolate 15.6 µg twice daily (b.i.d.) or placebo both delivered via the NeohalerTM device. The primary objective was superiority of glycopyrrolate compared with placebo for forced expiratory volume in 1 second (FEV1) standardized area under curve (AUC) between 0 and 12 hours post dosing (FEV1 AUC0-12h)at week 12. Other outcomes included additional spirometry parameters, health status using St George's Respiratory Questionnaire (SGRQ), dyspnea via Transition Dyspnea Index (TDI), rescue medication use and COPD symptoms reported by patients via the electronic diary. Safety was also assessed. Of the 432 patients randomized (glycopyrrolate, n=216; placebo, n=216), 96% completed the planned treatment phase. The study met its primary objective (superiority of glycopyrrolate compared with placebo for FEV1 AUC0-12h).Compared with placebo, glycopyrrolate showed significant improvements in lung function parameters (p<0.001). Health status (SGRQ total score and COPD assessment test), rescue medication use and daily total COPD symptom scores were significantly improved with glycopyrrolate versus placebo over 12 weeks. Improvements in dyspnea were observed with glycopyrrolate and placebo although the treatment difference was not statistically significant. Overall, differences in the incidences of adverse events and serious adverse events between the groups were not considered clinically meaningful. No deaths were reported. Twice-daily glycopyrrolate 15.6 µg showed statistically significant and clinically meaningful improvements compared with placebo in lung function, COPD symptoms, health status, and rescue medication usage in COPD patients with moderate-to-severe airflow limitation. CLINICAL TRIAL REGISTRATION: NCT01715298.

Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies.

Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease (COPD). In two 12-week, double-blind, parallel-group studies, patients with COPD were randomized 1:1:1 to once-daily umeclidinium (UMEC; 62.5 µg and 125 µg) or placebo (PBO), added to twice-daily fluticasone propionate/salmeterol (FP/SAL; 250/50 µg). In both studies, the primary efficacy measure was trough forced expiratory volume in 1 second (FEV1) at Day 85. Secondary endpoints were weighted-mean (WM) FEV1 over 0-6 hours post-dose (Day 84) and rescue albuterol use. Health-related quality of life outcomes (St. George's Respiratory Questionnaire [SGRQ] and COPD assessment test [CAT]) were also examined. Safety was assessed throughout. Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 (Day 85: 0.127-0.148 L) versus PBO+FP/SAL. Similarly, both UMEC+FP/SAL doses provided statistically-significant improvements in 0-6 hours post-dose WM FEV1 versus PBO+FP/SAL (Day 84: 0.144-0.165 L). Rescue use over Weeks 1-12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL (Study 1, 0.3 puffs/day [both doses]; Study 2, 0.5 puffs/day [UMEC 125+FP/SAL]). Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL (except for Day 84 Study 2). In Study 1, no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL; however, in Study 2, statistically significant improvements were observed with UMEC 62.5+FP/SAL (Day 28) and UMEC 125+FP/SAL (Days 28 and 84) versus PBO+FP/SAL. The incidence of on-treatment adverse events across all treatment groups was 37-41% in Study 1 and 36-38% in Study 2. Overall, these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD.

Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies.

OBJECTIVE: The aim of these studies (NCT01957163; NCT02119286) was to evaluate the efficacy and safety of umeclidinium (UMEC 62.5 µg and 125 µg) added to fluticasone furoate/vilanterol (FF/VI, 100/25 µg) in chronic obstructive pulmonary disease (COPD). METHODS: These were 12-week, double-blind, placebo-controlled, parallel-group, multicenter studies. Eligible patients were randomized 1:1:1 to treatment with once-daily blinded UMEC 62.5 µg (delivering 55 µg), UMEC 125 µg (delivering 113 µg) or placebo (PBO) added to open-label FF/VI (delivering 92/22 µg; N = 1238 [intent-to-treat population]). The primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 85; the secondary endpoint was 0-6 h post-dose weighted mean (WM) FEV1 at Day 84. Health-related quality of life was reported using St George's respiratory questionnaire (SGRQ). Adverse events (AEs) were also assessed. RESULTS: In both studies, trough FEV1 was significantly improved with UMEC + FF/VI (62.5 µg and 125 µg) versus PBO + FF/VI (range: 0.111-0.128 L, all p < 0.001 [Day 85]), as was 0-6 h post-dose WM FEV1 (range: 0.135-0.153 L, all p < 0.001 [Day 84]). SGRQ results were inconsistent, with statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI in one study only and with UMEC 62.5 µg only (difference in SGRQ total score from baseline between treatments: -2.16, p < 0.05). Across all treatment groups, the overall incidences of AEs were similar (30-39%), as were cardiovascular AEs of special interest (<1-3%) and pneumonia AEs (0-1%). CONCLUSION: Overall, the addition of UMEC to FF/VI therapy resulted in significant improvements in lung function compared with PBO + FF/VI in patients with COPD, with similar safety profiles, though SGRQ results were inconsistent. CLINICAL RELEVANCE: The results from these two studies demonstrate that the addition of umeclidinium (62.5 µg and 125 µg) to FF/VI (100/25 µg) provides statistically significant and clinically meaningful improvements in lung function compared with placebo + FF/VI in patients with COPD. Statistically significant improvements in quality of life with UMEC + FF/VI versus placebo + FF/VI were reported in one study only. Safety profiles were consistent across all treatment groups in both studies. These studies support the use of triple therapy in COPD, providing physicians with an alternative treatment option.

Once-daily indacaterol 75 µg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients' perceived onset of effect.

BACKGROUND: Indacaterol 75 µg once daily is a long-acting ß2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients' 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 µg or placebo via a dry powder inhaler device. The primary variable was time until patient'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 60-75 minutes postdose). RESULTS: The least-squares mean time to patient'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's perception. In addition, no statistically significant differences between treatments were observed for patient'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<0.0001). There was little or no association between patient'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 µg 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.

Bronchodilator efficacy and safety of indacaterol 150 µg once daily in patients with COPD: an analysis of pooled data.

BACKGROUND: Indacaterol is an inhaled, once-daily long-acting ß(2)-agonist bronchodilator for regular use in patients with chronic obstructive pulmonary disease (COPD). As indacaterol is the first once-daily ß(2)-agonist to be developed, it is relevant to evaluate its bronchodilator efficacy, safety, and tolerability. METHODS: Data were pooled from three randomized, double-blind, clinical studies in patients with moderate-to-severe COPD treated with indacaterol 150 µg qd (n = 627) or placebo (n = 1021). Bronchodilator efficacy was assessed as trough (24-hour post-dose) forced expiratory volume in 1 second (FEV(1)) after 12 weeks (primary endpoint in individual studies) and FEV(1) measured serially post-dose. Rescue use of albuterol was monitored. RESULTS: At week 12, indacaterol increased trough FEV(1) by 160 mL compared with placebo (P < 0.001), exceeding the 120 mL level prespecified as clinically important. FEV(1) during the first 12-hour post-dose at week 12 averaged 210 mL higher with indacaterol than with placebo (P < 0.001). Patients receiving indacaterol recorded 53% of days without use of rescue albuterol, compared with 38% of days in the placebo group (P < 0.001). Adverse events (mostly mild or moderate) were reported for 52% and 46% of patients receiving indacaterol and placebo, respectively, and serious adverse events for 4% and 5%. Worsening of COPD was the most frequent adverse event (10% indacaterol; 15% placebo). Indacaterol had little effect on pulse or blood pressure or measures of systemic ß(2)-adrenoceptor activity (blood glucose, serum potassium, and corrected QT interval). CONCLUSION: Indacaterol was an effective bronchodilator and was well tolerated, with a good safety profile over 12 weeks of treatment. It should prove a useful treatment for patients with moderate-to-severe COPD.

Efficacy and safety of indacaterol 150 microg once-daily in COPD: a double-blind, randomised, 12-week study.

BACKGROUND: Indacaterol is a novel, once-daily (o.d.) inhaled, long-acting beta2-agonist in development for chronic obstructive pulmonary disease (COPD). This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD. METHODS: Efficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (primary endpoint) and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms). Safety was assessed by adverse events (AEs), mean serum potassium and blood glucose, QTc (Fridericia), and vital signs. RESULTS: Patients were randomised (n = 416, mean age 63 years) to receive either indacaterol 150 microg o.d. (n = 211) or placebo (n = 205) via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM +/- SEM) at Week 12 was 1.48 +/- 0.018 L for indacaterol and 1.35 +/- 0.019 L for placebo, a clinically relevant difference of 130 +/- 24 mL (p < 0.001). Trough FEV1 after one dose was significantly higher with indacaterol than placebo (p < 0.001). Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM +/- SEM) of 190 +/- 28 (p < 0.001) and 160 +/- 28 mL (p < 0.001), respectively. Standardised AUC measurements for FEV1 (between 5 min and 4 h, 5 min and 1 h, and 1 and 4 h post-dose) at Week 12 were all significantly greater with indacaterol than placebo (p < 0.001), with LSM (+/- SEM) differences of 170 +/- 24, 180 +/- 24, and 170 +/- 24 mL, respectively. Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5% (p < 0.001) and was also associated with significantly reduced use of rescue medication (p < 0.001). The overall rates of AEs were comparable between the groups (indacaterol 49.3%, placebo 46.8%), with the most common AEs being COPD worsening (indacaterol 8.5%, placebo 12.2%) and cough (indacaterol 6.2%, placebo 7.3%). One patient died in the placebo group. Serum potassium and blood glucose levels did not differ significantly between the two groups, and no patient had QTc >500 ms. CONCLUSIONS: Indacaterol 150 microg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo. TRIAL REGISTRATION: NCT00624286.

The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor-alpha is overexpressed and has been suggested to play a pathogenic role. OBJECTIVES: To determine if infliximab, an anti-TNF-alpha antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate to severe COPD received infliximab (3 mg/kg [n = 78] or 5 mg/kg [n = 79]) or placebo (n = 77) at Weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status, and safety were assessed through Week 44. MEASUREMENTS AND MAIN RESULTS: Infliximab was generally well tolerated, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV(1), 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 1 of 77 placebo-treated subjects. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued the study agent due to adverse events (20-27%) than did placebo-treated subjects (9%). CONCLUSIONS: Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.