Implementing Digital Technologies in Clinical Trials: Lessons Learned.

Multiple digital health technologies have been evaluated across clinical development programs, including external, wearable, implantable, and ingestible devices and sensors, along with digital mobile health applications (apps) that are accessible via users' personal electronic devices (e.g., smartphones, tablets, and computers). Several of these technologies have been incorporated into our ongoing neurology and respiratory clinical development programs. Based on our experience, one of the greatest potential benefits of digital health technologies is the ability to collect objective and/or biological data continuously or at regular intervals outside of office visits during a patient's normal daily activities to provide additional efficacy and safety information, versus data capture from traditional episodic, time point-based office visits. Many challenges encountered with digital health technologies can be successfully addressed by providing the appropriate training to staff and patients, ensuring availability of appropriate infrastructure support, and conducting pilot studies before scaling up to larger trials. Overall, our experience with digital health technologies demonstrated their potential to increase the amount of objective data collected in clinical trials, expand patient access to trials, and facilitate further improvement of clinical outcomes.

Impact of baseline clinical features on outcomes of nebulized glycopyrrolate therapy in COPD.

Inhaled bronchodilators are central for the treatment of chronic obstructive pulmonary disease (COPD), as they can provide symptom relief and reduce the frequency and severity of exacerbations while improving health status and exercise tolerance. In 2017, glycopyrrolate (GLY) delivered via the eFlow® closed system (CS) nebulizer (nebulized GLY; 25 µg twice daily), was approved by the US Food and Drug Administration for maintenance treatment of moderate-to-very-severe COPD. This approval was based largely on results from the replicate, placebo-controlled, Phase III clinical trials- GOLDEN 3 and 4. In this review, we summarize key findings from secondary analyses of the GOLDEN 3 and 4 studies, and provide a comprehensive overview that may assist both pulmonologists and primary-care providers in their treatment decisions. Comorbidities are common among patients with COPD in clinical practice and may impact bronchodilator efficacy. This review highlights outcomes among subpopulations of patients with comorbidities (e.g., anxiety/depression, cardiovascular disease), and their impact on the efficacy of nebulized GLY. In addition, the efficacy and safety of nebulized GLY across various demographics (e.g., age, gender) and baseline disease characteristics (e.g., disease severity, rescue medication use) are discussed. Real-world outcomes with nebulized GLY, including device satisfaction, healthcare resource utilization, and exacerbations, are also presented. These secondary analyses and real-world data complement the primary results with nebulized GLY from Phase III studies and support the need for the inclusion of patients representative of real-world clinical practice in RCTs. In addition, these data suggest that RCTs for COPD therapies should be complemented with real-world observational studies.

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.

Effect of SGRQ-Defined Chronic Bronchitis at Baseline on Treatment Outcomes in Patients with COPD Receiving Nebulized Glycopyrrolate.

BACKGROUND: Chronic bronchitis (CB) is one of the conditions that contribute to chronic obstructive pulmonary disease (COPD). Despite its widespread prevalence among patients with COPD and overall negative impact on treatment outcomes, the effect of CB on the efficacy of bronchodilator therapy has not been evaluated. The objective of this post hoc analysis is to assess the effect of nebulized glycopyrrolate (GLY) on lung function and health-related quality of life outcomes in patients with St George's Respiratory Questionnaire (SGRQ)-defined CB at baseline. METHODS: Pooled data from the replicate, 12-week GOLDEN 3 and 4 studies (N=861) were grouped by CB status at baseline. The endpoints reported are changes from baseline in trough forced expiratory volume in 1 second (FEV1), SGRQ and EXAcerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (EXACT-RS) scores. Safety of GLY was evaluated by monitoring the incidence of adverse events (AEs). RESULTS: Following 12 weeks of treatment, GLY 25 µg twice-daily (BID) resulted in placebo-adjusted improvements from baseline in FEV1 of 77.1 mL and 124.4 mL in the CB and non-CB groups, respectively (p<0.0001 vs placebo in both groups). Significant improvements in SGRQ total scores were observed with GLY 25 µg BID compared with placebo, regardless of baseline CB status. Although EXACT-RS improvements were noted in both CB and non-CB groups, significant improvements were observed only in the CB group. GLY 25 µg BID was generally well tolerated through 12 weeks of treatment, with a low incidence of AEs. CONCLUSION: Treatment with nebulized GLY 25 µg BID for 12 weeks resulted in significant improvements in lung function and SGRQ total scores, compared with placebo. Significant improvements in EXACT-RS total scores were observed only in the CB group. Together, these results support the use of GLY 25 µg BID in patients with COPD, regardless of their CB status.

Impact of Comorbidity Prevalence and Cardiovascular Disease Status on the Efficacy and Safety of Nebulized Glycopyrrolate in Patients with COPD.

PURPOSE: Patients with COPD often have multiple coexisting comorbidities, affecting quality of life, morbidity and mortality. However, the prevalence and impact of comorbidities on the efficacy of bronchodilators in COPD is poorly understood. PATIENTS AND METHODS: In this post hoc analysis, pooled data from the 12-week, placebo-controlled GOLDEN 3 and 4 studies of nebulized glycopyrrolate (GLY) in individuals with moderate-to-very-severe COPD were used to quantify comorbidities and assess their impact on treatment efficacy and safety. RESULTS: Comorbidities that were most prevalent in the GOLDEN 3 and 4 study population were hypertension, high cholesterol and osteoarthritis. Participants were grouped based on their pre-specified comorbidity count into Group A (≤2 comorbidities; n=439) and Group B (>2 comorbidities; n=854). Treatment with GLY resulted in significant improvements in forced expiratory volume in 1 second (FEV1) and St George's Respiratory Questionnaire (SGRQ) total scores, independent of comorbidity prevalence. A higher prevalence of cardiovascular disease (CVD) comorbidities was observed among individuals in Group B, compared with Group A. In a sub-analysis based on prevalence of CVD, treatment with GLY resulted in significant FEV1 improvements independent of CVD prevalence, although values were numerically higher in the CVD group. GLY also led to higher improvements in SGRQ scores in the CVD group. GLY was well tolerated regardless of comorbidity or CVD prevalence, with a lower incidence of serious adverse events compared with placebo. CONCLUSION: A simple comorbidity count demonstrated that a majority of patients with COPD in the GOLDEN 3 and 4 studies had multiple comorbidities, with CVD being common in those with high comorbidity count. Results from this post hoc analysis demonstrate that GLY improved FEV1 and SGRQ scores in individuals with COPD, independent of their comorbidities or CVD status.

Improvement in Lung Function and Patient-Reported Outcomes in Patients with COPD with Comorbid Anxiety and Depression Receiving Nebulized Glycopyrrolate in the GOLDEN 3 and 4 Studies.

BACKGROUND: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited. METHODS: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 µg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV1) and health-related quality of life determined by St George's Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [-]) were examined following 12 weeks of GLY 25 µg twice-daily (BID) or placebo treatment. RESULTS: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (-) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p<0.0001), in the A/D (+) and A/D (-) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was -3.16 (p>0.05) and -3.34 (p<0.001), for the A/D (+) and A/D (-) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (-) group in both treatment arms. CONCLUSION: GLY 25 µg BID resulted in numerical improvements in FEV1, SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments.

The Effect of Metabolic Syndrome Status on Lung Function and Patient-reported Outcomes in Patients with COPD Receiving Nebulized Glycopyrrolate.

BACKGROUND: Concurrent chronic obstructive pulmonary disease (COPD) and metabolic syndrome (MetS) represent an important clinical phenotype with overlapping symptomology. The effect of MetS in COPD patients was assessed following treatment with nebulized glycopyrrolate (GLY; administered via eFlow® Closed System Nebulizer). METHODS: Posthoc analyses were performed on pooled lung function, patient-reported outcome (PRO) and safety data by MetS status from patients treated with placebo, GLY 25 and 50 mcg twice daily in two 12-week studies (GOLDEN 3 and 4; N=1293). Patients with MetS were characterized as having ≥ 3 of hypertension, hyperlipidemia, diabetes, body mass index (BMI) > 30 kg/m2 risk factors. The results are presented for the Food and Drug Administration-approved GLY 25 mcg dose. RESULTS: A total of25% of patients met MetS criteria.At baseline, the MetS subgroup had higher BMIs, more ex-smokers, greater incidences of cardiovascular risk factors, and MetS-specific risk factors were 2-14 times higher than non-MetS. At 12 weeks, GLY produced significant, clinically important improvements (MetS: 0.121 L; non-MetS: 0.083 L) in trough forced expiratory volume in 1 second. In the non-MetS group, significant improvements occurred in the St George's Respiratory Questionnaire (MetS: -2.28, p=0.157; non-MetS: -3.71) and Evaluating Respiratory Symptoms in COPD tool (MetS: 0.42, p=0.574; non-MetS: -1.61) total scores. Incidence of adverse events was similar with GLY versus placebo regardless of MetS status. CONCLUSION: GLY was well-tolerated and significantly improved lung function regardless of MetS status, while significant PRO improvements occurred in non-MetS patients. These results highlight the importance of comorbidities on bronchodilator responses and patient symptoms in COPD patients.

In Vitro Effect of Different Airflow Rates on the Aerosol Properties of Nebulized Glycopyrrolate in the eFlow® Closed System and Tiotropium Delivered in the HandiHaler®.

INTRODUCTION: Personalized therapy for patients with COPD requires appropriate choice of drug and delivery device. Inhalers and nebulizers vary in their drug delivery characteristics, particularly the need for passive or active patient inhalation for appropriate drug dispersal and delivery. In this in vitro analysis, we assessed the aerosol performance and drug delivery of two long-acting muscarinic antagonists, glycopyrrolate (GLY; 25 µg solution; 1 ml) and tiotropium (TIO; 18 µg powder) through their respective delivery systems: the eFlow® Closed System (CS) vibrating membrane nebulizer and the HandiHaler® dry-powder inhaler (DPI). METHODS: The aerosol performances of the eFlow® CS nebulizer and the HandiHaler® were determined using the Next Generation cascade Impactor. The delivered dose of GLY and TIO was determined using different breathing patterns, which varied in tidal volume and peak inspiratory flow rate, respectively, to simulate breathing conditions ranging from normal to severe obstruction. RESULTS: Aerodynamic particle analysis showed generally similar mass median aerodynamic diameter (MMAD, range, 3.6-4.6 µm) and fine particle fraction (FPF, range, 48.2%-63.7%) with GLY delivered using the eFlow® CS nebulizer under all breathing patterns tested. TIO, delivered via the HandiHaler®, showed variations in MMAD (range, 3.8-5.8 µm) and FPF (range, 16.1%-32.4%) under different inspiratory flow rates. The majority of GLY was deposited in stages 2-5 of the impactor, which corresponds with particle sizes in the respirable range (< 5 µm), whereas a large proportion of TIO was deposited in the throat/mouthpiece pre-separator, irrespective of test conditions. The median residual dose of GLY with eFlow® CS was notably lower compared to that of TIO with HandiHaler® (2.4%-4.4% vs. 40%-67%, respectively). CONCLUSIONS: These simulation results highlight the different deposition patterns generated by a DPI device and a vibrating membrane nebulizer, which may help inform device selection and treatment decision in COPD management.

Effect of Gender on Lung Function and Patient-Reported Outcomes in Patients with COPD Receiving Nebulized Glycopyrrolate.

Purpose: The clinical manifestation of COPD can differ by gender, with women experiencing worse lung function and health-related quality of life than men. Additionally, women tend to report more symptoms given the same disease severity. Accordingly, the impact of gender on efficacy and safety in patients with moderate-to-very-severe COPD was examined following 12 weeks of nebulized glycopyrrolate (GLY) 25 µg twice daily (BID) or placebo. Patients and Methods: GLY and placebo pooled data from the replicate 12-week GOLDEN 3 and 4 studies (n=861) were grouped by gender. Endpoints reported were change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) and EXAcerbations of COPD Tool-Respiratory Symptoms (EXACT-RS) total scores. Safety was evaluated by reviewing the incidence of adverse events (AEs) and serious AEs. Results: Men (placebo: 54.7%; GLY: 56.1%) were generally older with a greater proportion of high cardiovascular risk and use of background long-acting ß2-agonists or inhaled corticosteroids. GLY treatment resulted in significant, clinically important improvements in trough FEV1, regardless of gender. Patients treated with GLY reported significant improvements in SGRQ total score, irrespective of gender; however, the improvement was numerically higher in women. Although EXACT-RS improved in both genders, only women experienced a significant improvement. Overall, GLY was well tolerated with a numerically lower incidence of AEs in men than women. Conclusion: Treatment with nebulized GLY resulted in lung function, SGRQ total score, and EXACT-RS total score improvements regardless of gender. However, only EXACT-RS showed significantly greater improvements in women compared with men. Treatment with GLY was generally well tolerated across genders. These data support the efficacy and safety of GLY 25 µg BID in patients with moderate-to-very-severe COPD, independent of gender. Gender similarities in airflow improvement and differences in symptom-reporting augment the evidence supporting the consideration of individualized treatment plans for COPD patients.

The Effect of Baseline Rescue Medication Use on Efficacy and Safety of Nebulized Glycopyrrolate Treatment in Patients with COPD from the GOLDEN 3 and 4 Studies.

Purpose: Rescue medication use is common in chronic obstructive pulmonary disease (COPD) patients and tends to increase with symptoms and disease severity. An analysis of baseline rescue medication use was conducted to inform on patient phenotypes and subsequent effects on lung function, symptoms, and safety following 12 weeks of nebulized glycopyrrolate (GLY) 25 µg twice daily or placebo in patients with moderate-to-very-severe COPD. Patients and Methods: Pooled data from the 12-week, placebo-controlled GOLDEN 3 and 4 studies (n=781) were used to assign patients into quarters based on baseline rescue medication use (ie, average puffs-per-day) during the run-in period. Placebo-adjusted trough forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) total score and EXAcerbations of COPD Tool-Respiratory Symptoms (EXACT-RS) total score data were reported; safety was evaluated by reviewing the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Baseline rescue medication use was a proxy for disease severity, evidenced by decreased lung function, increased health status scores, symptom scores and use of background long-acting ß2-agonists and inhaled corticosteroids across quarters and treatment groups. Treatment with GLY led to greater improvements from baseline in trough FEV1, SGRQ and EXACT-RS scores compared with placebo in all rescue medication use quarters. Additionally, the SGRQ and EXACT-RS exhibited greater improvement with increased baseline rescue medication use with GLY treatment. In the Q4 patients, SGRQ (≥4-unit reduction) or EXACT-RS (≥2-unit reduction) responders were significantly greater with GLY compared with placebo. AE and SAE incidences were similar across quartiles. Conclusion: These results suggest that baseline rescue medication use assessments may be useful in the management of COPD. Treatment with nebulized GLY improved lung function and symptom scores, regardless of baseline rescue medication use. These results support the use of nebulized GLY for the treatment of COPD, independent of baseline rescue medication use.

Effect of smoking status on lung function, patient-reported outcomes, and safety among patients with COPD treated with indacaterol/glycopyrrolate: Pooled analysis of the FLIGHT1 and FLIGHT2 studies.

BACKGROUND: Smoking continues to be a major risk factor for COPD and may impact the efficacy of COPD treatments, with guidelines supporting the crucial importance for current smokers of smoking cessation. A post-hoc analysis of the FLIGHT1 and FLIGHT2 studies assessed the impact of smoking status on the efficacy and safety of indacaterol/glycopyrrolate (IND/GLY) 27.5/15.6 µg twice daily versus its monocomponents or placebo in patients with COPD. METHODS: This post-hoc analysis of pooled data from the replicate, 12-week, placebo-controlled FLIGHT1 and FLIGHT2 studies compared the efficacy and safety of IND/GLY with that of IND, GLY, and placebo in patients with moderate-to-severe COPD. Baseline data from 2038 patients were pooled and grouped by smoking status (52% were current smokers and 48% were ex-smokers). The effects of treatment on lung function, patient-reported outcomes (PROs), and safety were evaluated by baseline smoking status. RESULTS: Treatment with IND/GLY resulted in significant improvements in lung function measurements compared with placebo, irrespective of smoking status. Improvements in St George's Respiratory Questionnaire and transition dyspnea index were significantly greater than placebo in both current and ex-smokers, whereas changes in COPD assessment test were significant only among current smokers. Improvements in lung function and PROs were greater with IND/GLY compared with its monocomponents in current and ex-smokers. The incidences of AEs and SAEs were similar between current and ex-smokers. CONCLUSIONS: IND/GLY demonstrated significant improvements in lung function and PROs, independent of baseline smoking status. The safety profile of IND/GLY did not differ between current and ex-smokers.

Effect of smoking status on lung function, patient-reported outcomes, and safety among COPD patients treated with glycopyrrolate inhalation powder: pooled analysis of GEM1 and GEM2 studies.

BACKGROUND: Smoking is a major risk factor for COPD and may impact the efficacy of COPD treatments; however, a large proportion of COPD patients continue to smoke following diagnosis. METHODS: This post-hoc analysis of pooled data from the replicate 12-week, placebo-controlled GEM1 and GEM2 studies assessed the impact of smoking status on the efficacy and safety of glycopyrrolate 15.6 µg twice daily vs placebo in patients with moderate-to-severe COPD. Data from 867 patients enrolled in GEM1 and GEM2 were pooled for analysis and grouped by smoking status (57% current smokers, 43% ex-smokers). Forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 12 h, trough FEV1, forced vital capacity, St George's Respiratory Questionnaire (SGRQ) total score, COPD assessment test (CAT) score, transition dyspnea index (TDI) focal score, daily symptom scores, and rescue medication use were assessed in current smokers and ex-smokers. Incidences of adverse events (AEs) and serious AEs (SAEs) were also assessed. RESULTS: Treatment with glycopyrrolate resulted in significant improvements in all lung function measures, independent of smoking status. In both current and ex-smokers, changes from baseline in trough FEV1 were less marked in patients taking inhaled corticosteroids (ICS) than those not receiving ICS. Changes from baseline in SGRQ total score and rescue medication use were significantly greater with glycopyrrolate compared with placebo, regardless of smoking status. Changes in the CAT score, TDI focal score, and daily symptom scores significantly improved versus placebo, but only in current smokers. Improvements in patient-reported outcomes (PROs) with glycopyrrolate relative to placebo were numerically greater in current smokers than ex-smokers. The incidences of AEs and SAEs were similar regardless of smoking status. CONCLUSIONS: In this post-hoc analysis of GEM1 and GEM2, glycopyrrolate use led to significant improvements in lung function, independent of baseline smoking status; improvements were less marked among patients receiving background ICS, regardless of baseline smoking status. Improvements in PROs were greater with glycopyrrolate than placebo, and the magnitude of changes was numerically greater among current smokers. The safety profile of glycopyrrolate was comparable between current smokers and ex-smokers.

Efficacy of Indacaterol/Glycopyrrolate in Patients with COPD by Airway Reversibility at Baseline: A Pooled Analysis of the FLIGHT1 and FLIGHT2 12-Week Studies.

Bronchodilator reversibility occurs in patients with COPD. Pooled analysis of two 12-week, placebo-controlled randomised studies (FLIGHT1 [NCT01727141]; FLIGHT2 [NCT01712516]) assessed the effect of bronchodilator reversibility on lung function, patient-reported outcomes, and safety in 2,043 patients with moderate-to-severe COPD treated with indacaterol/glycopyrrolate (IND/GLY) 27.5/15.6 µg twice daily. Reversibility was defined as post-bronchodilator increase in forced expiratory volume in one second (FEV1) of ≥12% and ≥0.200 L. Overall, mean reversibility (mean post-bronchodilator FEV1 increase) was 22.8%, and 54.5% of patients met reversibility criteria. IND/GLY resulted in significant (p < 0.05) placebo-adjusted improvements from baseline at Week 12 in reversible and non-reversible patients in FEV1 area under the curve from 0 to 12 hours (0.308 L and 0.170 L, respectively), trough FEV1 (0.260 L and 0.174 L), St. George's Respiratory Questionnaire total score (-6.3 and -3.5), COPD Assessment Test total score (-2.3 and -1.2), daily rescue medication use (-1.52 and -0.79), and daily total symptom score (-0.86 and -0.63); Transition Dyspnoea Index focal score also showed improvements (1.93 and 1.29) at Week 12, irrespective of reversibility status. Improvements in lung function and rescue medication use were significantly (p < 0.05) greater in IND/GLY patients in the reversible subgroup compared with the non-reversible subgroup. The safety profile was similar across treatment groups and reversibility subgroups. Overall, treatment with IND/GLY led to significant improvements in lung function and PROs in patients with moderate-to-severe COPD, regardless of reversibility status, with greater improvements in the reversible subgroup. Safety profile was not affected by reversibility status.

Efficacy and safety of glycopyrrolate in patients with COPD by reversibility: pooled analysis of GEM1 and GEM2 12-week studies.

PURPOSE: Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies. PATIENTS AND METHODS: Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV1. FEV1 area under the curve from 0 to 12 hours (AUC0-12 h), trough FEV1, St George's Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed. RESULTS: Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV1 AUC0-12 h, trough FEV1, SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV1 AUC0-12 h (0.165 vs 0.078 L; P<0.001) and trough FEV1 (0.173 vs 0.070 L; P<0.001) were clinically relevant (based on minimal clinically important differences) and significantly greater in reversible compared with nonreversible patients receiving GLY. The safety profile of GLY was not affected by reversibility status. CONCLUSION: In this post hoc analysis, GLY was associated with significant improvements in lung function and patient-reported outcomes compared with placebo, mostly independent of reversibility status. In patients receiving GLY, improvements in lung function were greater in reversible compared with nonreversible patients. Reversibility status did not meaningfully impact the safety profile of GLY.

Efficacy and safety of a novel, nebulized glycopyrrolate for the treatment of COPD: effect of baseline disease severity and age; pooled analysis of GOLDEN 3 and GOLDEN 4.

BACKGROUND: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294). METHODS: Patients were grouped by baseline predicted post-bronchodilator FEV1 (<50%, ≥50%) and age (<65, ≥65, ≥75 years). RESULTS: GLY (25 and 50 µg BID) produced significant improvements in trough FEV1 in FEV1% predicted <50% (0.070 L, 0.079 L) and ≥50% (0.112 L, 0.126 L) subgroups (P<0.01 vs placebo), and in patients aged <65 (0.056 L, 0.086 L), ≥65 (0.140 L, 0.124 L), and ≥75 (0.144 L, 0.120 L) years (P<0.05 vs placebo). St George's Respiratory Questionnaire (SGRQ) total score was significantly improved with GLY 25 and 50 µg BID (P<0.05 vs placebo) in FEV1% predicted <50% (-3.237, -3.061) and ≥50% (-3.392, -2.322) and in <65 years (-3.447, -2.318) and ≥65 years (-3.053, -3.098) subgroups. In patients aged ≥75 years, GLY 25 µg reduced SGRQ total score by -6.278 units (P<0.01 vs placebo). The incidence of treatment-emergent adverse events was similar between GLY and placebo across all subgroups, and the overall incidence of cardiovascular events was low. CONCLUSIONS: Nebulized GLY improved lung function and health status and was well tolerated over 12 weeks in patients with moderate-to-very-severe COPD, irrespective of baseline disease severity and age. CLINICAL TRIAL REGISTRATION: NCT02347761, NCT02347774.

The Role of Inhalation Delivery Devices in COPD: Perspectives of Patients and Health Care Providers.

Background: Inhaled medications form the foundation of pharmacologic treatment for chronic obstructive pulmonary disease (COPD).The Delivery Makes a Difference (DMaD) project was conducted to better understand health care provider (HCP) and patient perspectives about the role of inhalation delivery devices in COPD, and to examine the nature of educational efforts between HCPs and patients on proper device technique. Methods: Data were derived from 2 original quantitative, web-based, descriptive, cross-sectional surveys distributed to HCPs who manage COPD (n=513) and patients with COPD (n=499) in the United States. Descriptive statistics were used to assess data across important demographic variables. Inferential statistics were used to assess differences in attitudinal, descriptive, and behavioral measures that were cross-tabulated with demographic data. Results: When prescribing medication for newly diagnosed patients with stable or unstable COPD, only 37% of HCPs considered type of device to be highly important, with only 45% of HCPs assessing device technique in every newly diagnosed patient. Patients with COPD were also relatively unconcerned with proper device technique (64% never concerned), regardless of their COPD severity. Although patients did not identify education as a significant impediment to proper device use, they reported inconsistent educational experiences. Conclusions: We found that HCPs and patients prioritize medication over device when selecting treatments, showing limited concerns about proper device use. These results highlight the need to coordinate professional education with patient-directed educational efforts to further promote proper device selection and use in COPD management.

Effect of background long-acting beta2-agonist therapy on the efficacy and safety of a novel, nebulized glycopyrrolate in subjects with moderate-to-very-severe COPD.

BACKGROUND: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta2-agonist (LABA) use on the efficacy and safety of nebulized GLY. METHODS: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed. RESULTS: Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P<0.001) and St George's Respiratory Questionnaire total score (SGRQ; LABA-yes: -2.957 and -3.888; LABA-no: -3.301 and -2.073, respectively; P<0.05). Incidence of treatment-emergent adverse events (TEAEs) was similar in LABA subgroups, and lower in GLY 25 µg vs placebo. In the 48-week active-controlled study, GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 (LABA-yes: 0.106 and 0.092 L; LABA-no: 0.096 and 0.096 L, respectively) and in SGRQ total score (LABA-yes: -5.190 and -3.094; LABA-no: -4.368 and -4.821, respectively). Incidence of TEAEs was similar between GLY and TIO, and across LABA subgroups. Exacerbation rates were similar across treatments and LABA subgroups, and cardiovascular events of special interest were more frequent in the LABA-no subgroup. Nebulized GLY, combined with LABA, did not generate any additional safety signals. CONCLUSION: Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA.

Efficacy and Safety of Nebulized Glycopyrrolate/eFlow® Closed System in Patients with Moderate-to-Very-Severe Chronic Obstructive Pulmonary Disease with Pre-Existing Cardiovascular Risk Factors.

Purpose: The purpose of this study was to assess the effect of pre-existing cardiovascular (CV) risk factors on the efficacy and safety of nebulized glycopyrrolate (GLY) in patients with chronic obstructive pulmonary disease (COPD). Methods: A total of 2379 patients from 3 phase III studies (12-week, placebo-controlled Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer [GOLDEN] -3 and -4, and 48-week, active-controlled GOLDEN-5) stratified by high (n=1526) or low (n=853) CV risk were randomized to placebo, GLY 25 mcg or 50 mcg twice daily, or tiotropium (TIO; 18 mcg once daily). Safety, lung function, patient-reported outcomes (PROs), and exacerbations were assessed by CV risk. Results: Treatment-emergent adverse events (TEAEs) were similar across CV risk subgroups, with serious TEAEs higher in the high CV risk subgroup. In the 12-week studies, discontinuation due to TEAEs with GLY 25 mcg and 50 mcg was similar between CV risk subgroups, and lower than placebo (high risk: 6.2%, 3.6%, 9.0%; low risk: 3.2%, 4.5%, 9.9%, respectively). In the 48-week, open-label study, discontinuation rates were higher with GLY versus TIO (high risk: 10.7%, 3.7%; low risk: 8.7%, 1.2%, respectively). Rates of CV events of special interest were similar across CV risk subgroups. Regardless of CV risk, GLY led to significant improvements in efficacy and PRO assessments at 12 weeks versus placebo, whereas changes were similar between GLY and TIO at 48 weeks, except for PROs in the low risk subgroup. Exacerbation rates were similar across all treatment groups. Conclusions: Nebulized GLY had an acceptable safety profile and improved lung function and PROs in COPD patients, irrespective of CV risk status.

Dual Bronchodilation with Indacaterol Maleate/Glycopyrronium Bromide Compared with Umeclidinium Bromide/Vilanterol in Patients with Moderate-to-Severe COPD: Results from Two Randomized, Controlled, Cross-over Studies.

PURPOSE: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 µg and once-daily UMEC/VI 62.5/25 µg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.

After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A-D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500-microg tablet of roflumilast. The molecular mode of action of roflumilast--PDE4 inhibition and subsequent enhancement of cAMP levels--is well established. To further understand its functional mode of action in chronic obstructive pulmonary disease (COPD), for which roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed. COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and gases, particularly tobacco smoke. In addition, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies. COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need. In vivo, roflumilast mitigates key COPD-related disease mechanisms such as tobacco smoke-induced lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and pulmonary hypertension. In vitro, roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of roflumilast on the disease mechanisms of COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease, COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a PDE4 inhibitor, roflumilast is not a direct bronchodilator. In summary, roflumilast may be the first-in-class PDE4 inhibitor for COPD therapy. In addition to being a non-steroid, anti-inflammatory drug designed to target pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of roflumilast that putatively addresses additional COPD mechanisms. This enables roflumilast to offer effective, oral maintenance treatment for COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease.