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.

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.

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.

Evaluation of systemic absorption and bronchodilator effect of glycopyrronium bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease.

BACKGROUND: Effective bronchodilator therapy depends upon adequate drug deposition in the lung. COPD patients who are unable to administer medications efficiently with conventional inhalers may benefit from the use of a nebulizer device. The aim of this study was to evaluate the systemic bioavailability and bronchodilator response of glycopyrronium bromide (GLY) administered by a novel nebulizer (eFlow® closed system [CS] vibrating membrane nebulizer) or dry powder inhaler (DPI) in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: In this randomized, open-label, single-dose, five-way crossover study, subjects received a sequence of either 50 µg GLY delivered by eFlow CS nebulizer (GLY/eFlow) or 63 µg GLY delivered by DPI (GLY/DPI), with and without activated charcoal, followed by intravenous infusion of 50 µg GLY with a washout period of 7 days between doses. Endpoints included plasma pharmacokinetics, safety and efficacy. RESULTS: The mean (± SD) baseline predicted forced expiratory volume in 1 s (FEV1) of the 30 subjects who completed the study was 51 ± 15%, with a FEV1/forced vital capacity ratio of 50 ± 11%. Without charcoal, the absolute systemic bioavailability of GLY/eFlow and GLY/DPI were approximately 15 and 22%, respectively. Changes from baseline in FEV1 at 60 min post-dose, without administration of charcoal, were 0.180 L and 0.220 L for GLY/eFlow and GLY/DPI, respectively; FEV1 improvements were similar when charcoal was administered (0.220 L for both GLY/eFlow and GLY/DPI). There were no significant differences in spirometry between the two devices. Fewer subjects administered GLY/eFlow reported adverse events (n = 15) than GLY/DPI (n = 18). CONCLUSIONS: After single doses, GLY/DPI delivered numerically higher peak and steady state levels of drug than did GLY/eFlow. Nebulized GLY produced similar bronchodilation but lower systemic levels of drug than GLY/DPI. Slightly higher number of subjects reported adverse events with GLY/DPI than with GLY/eFlow. Nebulized GLY may offer an effective alternative to patients with COPD not adequately treated with other devices. TRIAL REGISTRATION: NCT02512302 (ClinicalTrials.gov). Registered 28 May 2015.

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.

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.

In Vitro Characterization of the eFlow Closed System Nebulizer with Glycopyrrolate Inhalation Solution.

BACKGROUND: Glycopyrrolate administered by a novel, investigational eFlow® Closed System (CS) nebulizer (eFlow CS) is being evaluated for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The eFlow CS is a hand-held, vibrating membrane nebulizer optimized to deliver 1 mL of glycopyrrolate solution into the lung in <3 minutes. Clinical studies have shown improvements in lung function of subjects treated with nebulized glycopyrrolate. METHODS: The aerosol performance of the eFlow CS nebulizer was characterized by delivered dose, aerodynamic droplet size distribution and nebulization time. Simulated use nebulizer performance over 60 days was assessed by volume median diameter (VMD), nebulized amount, and nebulization time. Nebulization outputs were assayed to ensure adequate delivery of glycopyrrolate with an acceptable impurity profile. Aerosol condensates were analyzed for glycopyrrolate concentration and impurities by ultra-high-performance liquid chromatography and compared with non-nebulized samples. RESULTS: The mean mass median aerodynamic diameter, geometric standard deviation, and fine particle fraction were 3.7 µm, 1.7, and 72%, respectively, and independent of formulation strength (25 and 50 µg/mL). Delivered dose was 88% of the nominal dose for both formulation strengths. The mean delivered dose, assessed by breathing simulation, was 56.8% for 25 µg/mL and 62.6% for 50 µg/mL. Nebulization times were 1-2.5 minutes with no apparent increasing trend with use over a 60-day period. The nebulized amount showed no significant changes, whereas the VMD showed a slight, but not pharmaceutically relevant, increase (0.1-0.2 µm) after 60-day simulated use. Glycopyrrolate concentration and impurity levels of nebulized samples were statistically similar to those of non-nebulized samples. CONCLUSION: The eFlow CS generates glycopyrrolate aerosols with high delivered dose, short treatment time, and small droplet size with narrow size distribution suitable for central and peripheral airway deposition. The unit dose vial mitigates medication misuse and ensures dose uniformity. Results support the use of glycopyrrolate/eFlow CS for the treatment of COPD.

Dose selection for glycopyrrolate/eFlow® phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies.

BACKGROUND: Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials. Bronchodilator responses and safety assessments supported dose selection. METHODS: Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 µg twice daily [BID]) or aclidinium bromide 400 µg BID. The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV1). Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE. Lung function data collected in both studies were pooled. RESULTS: The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects. On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups. Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV1 (12.5 µg BID: 0.122 L; 25 µg BID: 0.123 L; 50 µg BID: 0.137 L) and FEV1 AUC0-12 (12.5 µg BID: 0.145 L; 25 µg BID: 0.178 L; 50 µg BID: 0.180 L). The improvements in lung function for the glycopyrrolate 25 and 50 µg BID doses were comparable to those with aclidinium bromide 400 µg BID (FEV1: 0.149 L; FEV1 AUC0-12: 0.172 L). Acceptable safety profiles were observed across all groups in both studies. CONCLUSIONS: The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 µg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD.

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).

Long-term safety of glycopyrrolate/eFlow® CS in moderate-to-very-severe COPD: Results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study.

BACKGROUND: The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow® Closed System (eFlow® CS) nebulizer in subjects with moderate-to-very-severe COPD. METHODS: Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 µg twice daily (BID) or tiotropium 18 µg once daily (OD) and treated for 48 weeks. Subjects represented the general COPD population with real-world characteristics including severe disease, presence of comorbidities, and receiving background COPD therapy. Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Secondary endpoints included the number of subjects with major adverse cardiovascular events (MACE); change from baseline in trough forced expiratory volume in 1 s (FEV1), and assessment of patient-reported outcomes. RESULTS: 1086 subjects received at least one dose of study drug. The overall incidence of TEAEs was comparable for subjects treated with glycopyrrolate (69.4%) or tiotropium (67.0%). Serious TEAEs occurred at similar rates in both treatment groups (glycopyrrolate, 12.3%; tiotropium, 10.5%). The most frequent TEAEs were COPD exacerbation/worsening and cough. Discontinuation due to TEAEs was higher in the glycopyrrolate group (10.0%) than the tiotropium group (2.8%) and related, in part, to the open-label study design, prior use of long-acting muscarinic antagonists and aerosol-airway interactions. Fewer subjects in the glycopyrrolate group experienced MACE (glycopyrrolate, n = 3 [0.5%]; tiotropium, n = 8 [1.7%]). Nebulized glycopyrrolate treatment resulted in improvements in trough FEV1 that were maintained over 48 weeks. Patient-reported health outcomes showed improvements, supporting the increases in trough FEV1. CONCLUSIONS: Treatment with nebulized glycopyrrolate was well tolerated over 48 weeks with the most common adverse events being COPD worsening and cough. The overall and cardiac safety and tolerability profile and improvements in pulmonary function and patient-reported health outcomes support the use of nebulized glycopyrrolate as a maintenance treatment for moderate-to-very-severe COPD. CLINICAL TRIAL REGISTRATION NUMBER: NCT02276222.

Efficacy and safety of glycopyrrolate/eFlow® CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials.

BACKGROUND: SUN-101 is a combination of glycopyrrolate delivered through an innovative, electronic nebulizer, intended for the treatment of patients with COPD. The objective of this study was to assess the efficacy and safety of this new drug device combination. METHODS: Replicate Phase III randomized, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of glycopyrrolate solution administered by an investigational eFlow® Closed System (eFlow® CS) nebulizer in subjects with moderate-to-very-severe COPD, including those with continued background use of a long-acting beta2-agonist ± inhaled corticosteroid and/or history of cardiovascular (CV) disease. Subjects were randomized in a 1:1:1 ratio to receive placebo or glycopyrrolate (25 µg or 50 µg twice daily [BID]) for 12 weeks. The primary efficacy endpoint was the change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 12 compared with placebo. Secondary endpoints included change from baseline in forced vital capacity (FVC) after 12 weeks, change from baseline in health status measured by St George's Respiratory Questionnaire (SGRQ) at 12 weeks/end of study (EOS), and change in rescue medication use, as well as change from baseline in FEV1 area under the curve from 0 to 12 h after 12 weeks in the GOLDEN 3 sub-study. Daytime and night-time symptoms were recorded using an electronic diary. Safety was monitored throughout the study, including major adverse cardiovascular events. RESULTS: A total of 653 subjects were randomized in GOLDEN 3 and 641 in GOLDEN 4. Treatment with glycopyrrolate 25 µg BID and 50 µg BID resulted in statistically significant and clinically important changes from baseline in trough FEV1 compared with placebo at Week 12 (GOLDEN 3: 0.105 L and 0.126 L; p ≤ 0.0001; GOLDEN 4: 0.084 L and 0.082 L; p ≤ 0.0001). Nebulized glycopyrrolate 25 µg BID and 50 µg BID also resulted in improvements in FVC change from baseline versus placebo at Week 12 (GOLDEN 3: 0.149 L and 0.167 L, p < 0.001; GOLDEN 4: 0.130 L and 0.113 L, p < 0.01), and in SGRQ change from baseline score versus placebo at Week 12/EOS (GOLDEN 3: -3.072 [p < 0.05] and -1.848; GOLDEN 4: -3.585 and -3.557, p < 0.01). LS mean change from baseline in EXACT-respiratory symptoms total score at Week 12 for placebo and nebulized glycopyrrolate 25 and 50 µg BID were -0.936, -1.903 and -1.502 for GOLDEN 3 and -0.376, -1.647 and -1.532 for GOLDEN 4. Rescue medication use was unchanged. Nebulized glycopyrrolate was well tolerated at both doses based on the incidence of adverse events and CV events. CONCLUSIONS: The results of these studies demonstrated statistically significant and clinically important improvements in pulmonary function and patient-reported health outcomes, with an acceptable safety profile, support the use of glycopyrrolate/eFlow® CS as a potential maintenance treatment for moderate-to-very-severe COPD.

Efficacy and safety of nebivolol in Hispanics with stage I-II hypertension: a randomized placebo-controlled trial.

OBJECTIVE: Hispanics have lower rates of hypertension control compared with black and white patients. Nebivolol is a vasodilatory ß1-selective blocker, with neutral metabolic effects. This phase IV trial evaluated the efficacy and safety of nebivolol in Hispanics with stage I-II hypertension. METHODS: Self-identified Hispanics with stage I-II hypertension were randomized to receive a double-blind treatment: placebo (n = 136) or nebivolol (n = 141, starting dose 5 mg/day) for 8 weeks. Nebivolol dosage could be uptitrated at 2-week intervals to 10, 20, or 40 mg/day, as needed to achieve diastolic blood pressure (DBP) control (JNC7 criteria). Efficacy outcome measures were the mean changes from baseline to the end of week 8 in trough-seated DBP (primary) and systolic blood pressure (SBP) (secondary). Safety and tolerability were also assessed. RESULTS: Baseline SBP/DBP (mmHg) was similar in both treatment groups (nebivolol: 156/100; placebo: 157/101). A total of 135 (96%) and 121 (89%) nebivolol- and placebo-treated participants completed the double-blind phase, respectively. Compared with the placebo, nebivolol treatment was associated with significant mean reductions in both trough-seated DBP and SBP (DBP: -11.1 mmHg vs. -7.3 mmHg, p < 0.0001; SBP: -14.1 mmHg vs. -9.3 mmHg; p = 0.001). Treatment-emergent adverse event (TEAE) rates were 17% (nebivolol) and 22% (placebo); the most frequent TEAEs were headache (4% vs. 6%, respectively), upper respiratory tract infection (2% vs. 2%), and dizziness (1% vs. 3%). CONCLUSIONS: In Hispanics with stage I-II hypertension, 8-week nebivolol monotherapy resulted in significant reductions in blood pressure. The safety and tolerability profile of nebivolol was similar to that of placebo.

Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse model.

BACKGROUND: Cardiovascular disease remains the leading cause of morbidity and premature mortality in most industrialized countries as well as in developing nations. A pro-oxidative state appears to promote and/or exacerbate vascular disease complications. Furthermore, a state of low-grade chronic inflammation can promote increased oxidative stress and lead to endothelial cell and platelet dysfunction ultimately contributing to thrombogenesis. OBJECTIVES: In this study, the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis. The influence of free astaxanthin, the active drug of CDX-085, on human endothelial cells and rat platelets was evaluated to investigate potential mechanisms of action. METHODS AND RESULTS: Oral administration of CDX-085 (0.4% in chow, approximately 500 mg/kg/day) to 6-8 week old C57BL/6 male mice for 14 days resulted in significant levels of free astaxanthin in the plasma, liver, heart and platelets. When compared to control mice, the CDX-085 fed group exhibited significant increases in basal arterial blood flow and significant delays in occlusive thrombus formation following the onset of vascular endothelial injury. Primary human umbilical vein endothelial cells (HUVECs) and platelets isolated from Wistar-Kyoto rats treated with free astaxanthin demonstrated significantly increased levels of released nitric oxide (NO) and significantly decreased peroxynitrite (ONOO-) levels. CONCLUSION: Observations of increased NO and decreased ONOO- levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug). These studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.