Clinical Burden of Chronic Obstructive Pulmonary Disease in Patients with Suboptimal Peak Inspiratory Flow.

Introduction: Many patients with chronic obstructive pulmonary disease (COPD) may derive inadequate benefit from dry powder inhalers (DPIs) because of suboptimal peak inspiratory flow (sPIF). Objectives: To assess the clinical burden of COPD by characterizing the clinical characteristics of participants with sPIF against medium-low resistance DPIs versus those with optimal PIF (oPIF) from two phase 3 clinical trials. Methods: Baseline data were collected from two randomized, controlled, phase 3 trials (NCT03095456; NCT02518139) in participants with moderate-to-severe COPD. oPIF (60 L/min) against the medium-low resistance DPIs was used as the threshold for defining the PIF subgroups (<60 L/min (sPIF) vs ≥60 L/min (oPIF)). Results: Most participants included in this analysis were White (92%) and male (63%); the mean (range) age was 65 (43-87) years. Participants with sPIF had significantly greater dyspnea than those with oPIF as measured using the modified Medical Research Council scoring (mean (95% CI): 2.1 (2.0-2.2) vs 1.6 (1.4-1.7); P < 0.001) and baseline dyspnea index (mean (95% CI): 5.1 (4.9-5.4) vs 6.1 (5.8-6.3); P < 0.001). Based on COPD Assessment Test scores, participants with sPIF had a higher COPD symptom burden than those with oPIF (mean (95% CI): 21.5 (19.7-23.3) vs 19.5 (18.6-20.4); P = 0.05). Conclusion: In these trials, participants with COPD who had sPIF against the medium-low resistance DPIs had more dyspnea and worse health status than those with oPIF. These results demonstrate that sPIF is associated with a higher clinical burden as measured by patient-reported outcomes.

Effects of CB1R inverse agonist, INV-202, in patients with features of metabolic syndrome. A randomized, placebo-controlled, double-blind phase 1b study.

AIMS: To evaluate the clinical safety, tolerability, and pharmacokinetic and pharmacodynamic profile of the novel cannabinoid receptor-1 (CB1R) inverse agonist, INV-202, in adults with features of metabolic syndrome. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, placebo-controlled, 28-day repeat-dose (INV-202 [25 mg] or placebo, once-daily oral tablet), parallel-group study in 37 participants aged 18 to 65 years (46% female, mean age 55 years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1 kg/m2 ) with features of metabolic syndrome and glucose intolerance. An oral glucose tolerance test (OGTT) was performed at baseline and at the end of the study. Lipid profiles, weight, waist circumference and biomarkers were assessed weekly. Statistical comparisons were performed post hoc. RESULTS: INV-202 was well tolerated with no serious or severe treatment-emergent adverse events; the most common events related to known effects of CB1R blockade in the gastrointestinal tract. INV-202 produced a significant mean weight loss of 3.5 kg (3.3% compared with placebo participants who gained a mean 0.6 kg [0.5%]). INV-202 also exhibited significant reductions in waist circumference and BMI (P ≤ 0.03). There was no significant difference in OGTT 0- to 3-hour area under the curve for INV-202 versus placebo: least squares mean 29.38 versus 30.25 h*mmol/L, with an INV-202: placebo ratio of 97.1% (95% confidence interval 90.2, 105.6; P = 0.43). CONCLUSIONS: INV-202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long-term assessment of cardiometabolic effects.

Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy.

Objective: This study assessed the efficacy of INV-202, a novel peripherally restricted cannabinoid type-1 receptor (CB1R) inverse agonist, in a streptozotocin-induced type-1 diabetes nephropathy mouse model. Methods: Diabetes was induced in 8-week-old C57BL6/J male mice via intraperitoneal injection of streptozotocin (45 mg/kg/day for 5 days); nondiabetic controls received citrate buffer. Diabetic mice were randomized to 3 groups based on blood glucose, polyuria, and albuminuria, and administered daily oral doses for 28-days of INV-202 at 0.3 or 3 mg/kg or vehicle. Results: INV-202 did not affect body weight but decreased kidney weight compared with the vehicle group. While polyuria was unaffected by INV-202 treatment, urinary urea (control 30.77 ± 14.93; vehicle 189.81 ± 31.49; INV-202 (0.3 mg/kg) 127.76 ± 20; INV-202 (3 mg/kg) 93.70 ± 24.97 mg/24h) and albumin (control 3.06 ± 0.38; vehicle 850.08 ± 170.50; INV-202 (0.3 mg/kg) 290.65 ± 88.70; INV-202 (3 mg/kg) 111.29 ± 33.47 µg/24h) excretion both decreased compared with vehicle-treated diabetic mice. Compared with the vehicle group, there was a significant improvement in the urinary albumin to creatinine ratio across INV-202 groups. Regardless of the dose, INV-202 significantly reduced angiotensin II excretion in diabetic mice. The treatment also decreased Agtr1a renal expression in a dose-dependent manner. Compared with nondiabetic controls, the glomerular filtration rate was increased in the vehicle group and significantly decreased by INV-202 at 3 mg/kg. While the vehicle group showed a significant loss in the mean number of podocytes per glomerulus, INV-202 treatment limited podocyte loss in a dose-dependent manner. Moreover, in both INV-202 groups, expression of genes coding for podocyte structural proteins nephrin (Nphs1), podocin (Nphs2), and podocalyxin (Pdxl) were restored to levels similar to nondiabetic controls. INV-202 partially limited the proximal tubular epithelial cell (PTEC) hyperplasia and normalized genetic markers for PTEC lesions. INV-202 also reduced expression of genes contributing to oxidative stress (Nox2, Nox4, and P47phox) and inflammation (Tnf). In addition, diabetes-induced renal fibrosis was significantly reduced by INV-202. Conclusions: INV-202 reduced glomerular injury, preserved podocyte structure and function, reduced injury to PTECs, and ultimately reduced renal fibrosis in a streptozotocin-induced diabetic nephropathy mouse model. These results suggest that INV-202 may represent a new therapeutic option in the treatment of diabetic kidney disease.

Lung deposition of inhaled once-daily long-acting muscarinic antagonists via standard jet nebulizer or dry powder inhaler, measured using functional respiratory imaging, in patients with chronic obstructive pulmonary disease.

BACKGROUND: Data for bronchodilator deposition via nebulizers and dry powder inhalers (DPIs) in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD) are limited. We used functional respiratory imaging (FRI) to determine deposition patterns for revefenacin solution via a PARI LC® Sprint® nebulizer and tiotropium powder via HandiHaler® DPI. METHODS: Ten patients with COPD, of whom 9 had severe airflow obstruction, were selected from FLUIDDA's database. The study did not enroll patients. Drug deposition in the extrathoracic and intrathoracic regions, including the central and peripheral airways was simulated by FRI. The percentage of delivered dose and central-to-peripheral (C/P) deposition ratio for nebulizer and DPI were evaluated. RESULTS: Mean ±â€„standard deviation (SD) age was 64.7 ±â€„7.1 years, height was 168.8 ±â€„8.5 cm, and percent predicted forced expiratory volume in 1 s was 40.8 ±â€„12.3%; 50% of patients were men. At optimal inhalation flow, intrathoracic and peripheral deposition was three-fold higher for revefenacin via nebulizer than tiotropium via HandiHaler (mean ±â€„SD 34.6 ±â€„8.53% versus 10.9 ±â€„5.67% and 18.2 ±â€„4.30% versus 5.8 ±â€„2.73% of delivered dose, respectively). Similar results were observed for suboptimal flow (mean ±â€„SD percentage of revefenacin versus tiotropium: intrathoracic, 32.1 ±â€„8.3% versus 15.1 ±â€„5.9%; peripheral; 16.6 ±â€„4.1% versus 8.4 ±â€„2.9%). The C/P deposition ratio for nebulizer was similar to DPI (mean ±â€„SD 0.915 ±â€„0.241 versus 0.812 ±â€„0.249 at optimal; 0.947 ±â€„0.253 versus 0.784 ±â€„0.219 at suboptimal flow), even though the mass median aerodynamic diameter of revefenacin was higher than tiotropium. C/P deposition ratio for revefenacin decreased after bronchodilation (0.915 ±â€„0.241 pre-bronchodilation versus 0.799 ±â€„0.192 post-bronchodilation), suggesting progressively better deposition in the peripheral region, assuming bronchodilation occurred during the nebulization process. CONCLUSIONS: These results demonstrate more efficient intrathoracic and peripheral deposition for revefenacin via standard jet nebulizer than tiotropium via HandiHaler, with similar C/P deposition ratio in patients with COPD. Nebulizers are an efficient alternative to DPIs for bronchodilator administration in patients with COPD.

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis.

BACKGROUND: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV1) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD. METHODS: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV1, St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 µg and placebo: severe and very severe airflow limitation (percent predicted FEV1 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV1) to short-acting bronchodilators, concurrent use of long-acting ß agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors. RESULTS: Revefenacin demonstrated significant improvements in FEV1 versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years. CONCLUSIONS: Revefenacin showed significantly greater improvements in FEV1 versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD. TRIAL REGISTRATION: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).

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.

Peak Inspiratory Flows: Defining Repeatability Limits and a Predictive Equation for Different Inhalers.

BACKGROUND: Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking. RESEARCH QUESTIONS: What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFD) and HandiHaler (Boehringer Ingelheim; PIFHH) resistances? STUDY DESIGN AND METHODS: Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFD and PIFHH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149). RESULTS: In study 0128, the mean values (SD) for PIF at zero resistance and PIFHH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIFD and PIFHH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIFD and PIFHH was small, < 5 and < 3 L/min, respectively. The repeatability limit was determined as 10 and 5 L/min for PIFD and PIFHH, respectively. Modeling the relationship between PIFD and PIFHH, after controlling for significant covariates, demonstrated that a PIFD value of 60 L/min was approximately equivalent to PIFHH of 40 L/min. INTERPRETATIONS: This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov.

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials.

BACKGROUND: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting ß-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup). METHODS: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV1). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ). RESULTS: Revefenacin produced similar improvements from baseline in trough FEV1 in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV1, 150.9 (110.3-191.6) ml and 139.2 (82.9-195.5) ml; p < 0.0001 versus placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [-3.3 (-5.4 to -1.2) and -3.4 (-6.3 to -0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup. CONCLUSIONS: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS. CLINICALTRIALS.GOV IDENTIFIERS: NCT02512510, NCT02459080, NCT02518139 The reviews of this paper are available via the supplemental material section.

Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 µg or 88 µg daily during the 52-week trial. METHODS: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 µg or 88 µg in a double-blind manner, or open-label active control tiotropium. RESULTS: Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV1). The trough FEV1 profile (least squares mean change from baseline) for revefenacin 175 µg ranged from 52.3-124.3 mL and the trough FEV1 profile for tiotropium ranged from 79.7-112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV1 was comparable in patients taking concomitant long-acting ß-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George's Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms. CONCLUSIONS: Significant sustained improvements from baseline in trough FEV1 and respiratory health outcomes were demonstrated for 175-µg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD. TRIAL REGISTRATION: NCT02518139 ; Registered 5 August 2015.

Nebulized Versus Dry Powder Long-Acting Muscarinic Antagonist Bronchodilators in Patients With COPD and Suboptimal Peak Inspiratory Flow Rate.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus®). METHODS: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler® DPI. RESULTS: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV1, 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV1 from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV1 < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3-91.9) mL in trough FEV1 and 103.5 (7.7-199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV1 in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV1 < 50% predicted populations. CONCLUSIONS: Revefenacin did not produce significant improvements in FEV1 versus tiotropium in the ITT population, but increased trough FEV1 in patients with FEV1 < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456).

Data on the safety and tolerability of revefenacin, in patients with moderate to very severe chronic obstructive pulmonary disease.

This article contains information on the experimental design and methods on how the safety and tolerability data concerning patients with moderate to very severe chronic obstructive pulmonary disease (COPD) were obtained. This is in addition to our original research article. [1] We have also provided information on the clinical laboratory tests that were conducted. Further interpretation and discussion of the data are demonstrated in the article "Revefenacin, a Once-daily, Lung-selective, Long-acting Muscarinic Antagonist for Nebulized Therapy: Safety and Tolerability Results of a 52-week Phase 3 Trial in Moderate to Very Severe Chronic Obstructive Pulmonary Disease." [1].

Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials.

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 µg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 µg (n = 23, 5.6%) and revefenacin 175 µg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 µg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 µg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 µg, and revefenacin 175 µg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 µg, revefenacin 175 µg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 µg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.

Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease.

BACKGROUND: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 µg and 175 µg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 µg and 175 µg over 52 weeks of treatment. METHODS: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 µg or 175 µg in a double-blind manner, or open-label active control tiotropium. RESULTS: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 µg, 272 [74.7%]; 175 µg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 µg (73 [21.8%]) than with 88 µg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 µg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 µg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 µg or tiotropium with a concurrent long-acting ß-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 µg. CONCLUSIONS: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.

Improvements in Lung Function with Nebulized Revefenacin in the Treatment of Patients with Moderate to Very Severe COPD: Results from Two Replicate Phase III Clinical Trials.

BACKGROUND: Revefenacin, a novel, lung-selective, long-acting muscarinic antagonist, has been developed for nebulized therapy for chronic obstructive pulmonary disease (COPD). We present the results of replicate Phase III efficacy and safety studies of revefenacin in patients with moderate to very severe COPD. METHODS: In 2 double-blind, parallel-group studies, (Study 0126 and Study 0127), patients ≥ 40 years old were randomized to revefenacin 88 µg, revefenacin 175 µg or placebo administered once daily by standard jet nebulizer for 12 weeks. The primary endpoint was 24-hour trough forced expiratory volume in 1 second (FEV1) on day 85. Secondary efficacy endpoints included overall treatment effect (OTE) on trough FEV1 and peak FEV1 (0-2 hours after first dose). Safety assessments included treatment-emergent adverse events. RESULTS: At day 85, revefenacin 88 µg and 175 µg improved trough FEV1 versus placebo in Study 0126 (by 79 mL [p=0.0003] and 146 mL [p<0.0001]) and Study 0127 (by 160 mL and 147 mL; both p<0.0001). Compared with placebo, pooled data of revefenacin 88 µg and 175 µg increased OTE trough FEV1 by 115 mL and 142 mL (both p<0.001) and increased peak FEV1 by 127 mL and 129 mL (both p<0.0001). Revefenacin 175 µg demonstrated greater improvements in FEV1 in concomitant long-acting beta2-agonist patients and in more severe patients than revefenacin 88 µg. Adverse events were minor. CONCLUSION: Revefenacin, administered once daily for 12 weeks to patients with moderate to very severe COPD, demonstrated clinically significant improvements in trough FEV1 and OTE FEV1. Revefenacin was generally well tolerated with no major safety concerns.

Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK).

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials.

OBJECTIVE: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD were randomized in two multicentre, double-blind, incomplete block crossover studies. Patients received two of six treatments in sequence (12 weeks each): placebo, umeclidinium (UMEC)/vilanterol (VI) (125/25 mcg or 62.5/25 mcg), VI (25 mcg) or UMEC (62.5 mcg or 125 mcg). Exercise endurance time (EET) and trough forced expiratory volume in 1 second (FEV1) (Week 12) were co-primary endpoints. Safety was monitored throughout. RESULTS: Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI (Week 12). Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 (UMEC/VI 125/25 mcg: 65.8 s; p = 0.005; UMEC/VI 62.5/25 mcg: 69.4 s; p = 0.003), but not in Study 417, where a placebo effect was evident. Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 (UMEC/VI 125/25 mcg: 47.5 s; p = 0.002; UMEC/VI 62.5/25 mcg: 43.7 s; p = 0.001). Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses. The incidence of adverse events was similar between treatment groups within each study. CONCLUSIONS: UMEC/VI improved lung function and EET.

Fluticasone propionate/salmeterol 250/50 µg versus salmeterol 50 µg after chronic obstructive pulmonary disease exacerbation.

BACKGROUND: Inhaled long-acting beta2 agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone. METHODS: Patients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 µg or SAL 50 µg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed. RESULTS: There was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV1 change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort. CONCLUSIONS: No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV1 ≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment. TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).

Characterization of airway inflammation in patients with COPD using fractional exhaled nitric oxide levels: a pilot study.

OBJECTIVE: To characterize fractional exhaled nitric oxide (FeNO) levels that may be indicative of Th2-mediated airway inflammation in patients with chronic obstructive pulmonary disease (COPD). METHODS: This single-visit, outpatient study was conducted in 200 patients aged 40 years and older with COPD. All patients underwent spirometry and FeNO testing. COPD severity was classified according to the Global initiative for chronic Obstructive Lung Disease (GOLD) 2010 guidelines. RESULTS: Patients who participated in the study had a mean age of 63.9 ± 11.3 years and a mean smoking history of 46 ± 29 pack years. Patients had a mean forced expiratory volume in 1 second % predicted of 53.9% ± 22.1%. The percentage of patients classified with COPD severity Stage I, II, III, and IV was 13%, 40%, 39%, and 8%, respectively. In addition, according to current procedural terminology codes, 32% of patients were classified as mixed COPD/asthma, 26% as COPD/emphysema, and 42% as all other codes. The mean FeNO level for all patients was 15.3 ± 17.2 parts per billion (ppb). Overall, 89% of patients had a FeNO <25 ppb, 8% had a FeNO 25-50 ppb, and 3% had a FeNO >50 ppb. The percentages of patients with FeNO in the intermediate or high ranges of FeNO were greatest among patients with mixed COPD/asthma (intermediate, 11.5%; high, 6.6%) compared with COPD/emphysema (intermediate, 8%; high, 0) and all other codes (intermediate, 6.3%; high, 1.3%). CONCLUSION: Increases in FeNO were identified in a subset of patients with COPD, particularly in those previously diagnosed with both COPD and asthma. Since FeNO is useful for identifying patients with airway inflammation who will have a beneficial response to treatment with an inhaled corticosteroid, these data may have important implications for the management of COPD patients.

Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.

BACKGROUND: Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD. METHODS: In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 µg plus VI 25 µg, UMEC 62·5 µg plus VI 25 µg, TIO 18 µg, and either VI 25 µg (study 1) or UMEC 125 µg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2). FINDINGS: 1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 µg plus VI 25 µg, and UMEC 62·5 µg plus VI 25 µg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 µg plus VI 25 µg, and UMEC 62·5 µg plus VI 25 µg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 µg plus VI 25 µg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 µg plus VI 25 µg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 µg plus VI 25 µg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 µg plus VI 25 µg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 µg plus VI 25 µg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 µg plus VI 25 µg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 µg monotherapy (UMEC 125 µg plus VI 25 µg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 µg plus VI 25 µg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups. INTERPRETATION: Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD. FUNDING: GlaxoSmithKline.