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Original Research: COPD |

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

Fernando J. Martinez, MD, FCCP; Klaus F. Rabe, MD, PhD; Gary T. Ferguson, MD, FCCP; Leonardo M. Fabbri, MD, FCCP; Stephen Rennard, MD, FCCP; Gregory J. Feldman, MD; Sanjay Sethi, MD; Selwyn Spangenthal, MD; Gregory M. Gottschlich, MD; Roberto Rodriguez-Roisin, MD, PhD, FCCP; Samir Arora, MD; Thomas M. Siler, MD, FCCP; Shahid Siddiqui, MD, MHSA; Patrick Darken, PhD; Tracy Fischer, PharmD; Andrea Maes, PhD; Michael Golden, MS; Chad Orevillo, MPH; Colin Reisner, MD, FCCP
Author and Funding Information

FUNDING/SUPPORT: PINNACLE-1 and PINNACLE-2 were supported by Pearl Therapeutics, Inc., a member of the AstraZeneca Group.

Data contained in this manuscript have previously been published at the 2015 meeting of the European Respiratory Society (Rabe KF, Martinez F, Rodriguez-Roisin R et al. Eur Respir J. 2015;46(suppl 59):PA4363) and the 2016 meeting of the American Thoracic Society (Martinez FJ, Rabe KF, Rodriguez-Roisin R et al. Am J Resp Crit Care Med. 2016;193:A6782; Ferguson GT, Rabe KF, Martinez FJ et al. Am J Resp Crit Care Med. 2016;193:A6790). Data from the published abstracts cited above are included in the following independent review (Radovanovic D, Mantero M, Sferrazza Papa GF, et al. Formoterol fumarate + glycopyrrolate for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med. 2016;10:1045-1055).

aJoan and Sanford Weill Department of Internal Medicine, Weill Cornell Medicine, New York, NY

bLungenClinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; and Department of Medicine, Christian-Albrechts University Kiel, Kiel, Germany

cPulmonary Research Institute of Southeast Michigan, Farmington Hills, MI

dDepartment of Medicine, University of Modena and Reggio Emilia, NOCSAE, Modena, Italy

ePulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE

fClinical Discovery Unit, Early Clinical Development, AstraZeneca, Cambridge, UK; and S. Carolina Pharmaceutical Research, North Grove Medical Park, Spartanburg, SC

gDepartment of Medicine, University at Buffalo, SUNY, Buffalo, NY

hCharlotte Lung and Health, American Health Research, Inc., Charlotte, NC

iRegulatory Affairs, Pearl Therapeutics, Inc., Durham, NC

jRegulatory Affairs and Quality, Pearl Therapeutics, Inc., Durham, NC

kNew Horizons Clinical Research, Cincinnati, OH

lAventiv Research, Columbus, OH

mServei de Pneumologia, Institut Clinic Respiratori, Hospital Clínic; and University of Barcelona, Barcelona, Spain

nMidwest Chest Consultants, St. Charles, MO

oRespiratory, AstraZeneca, Gaithersburg, MD (former employee of Pearl Therapeutics, Inc.)

pBiostatistics, Pearl Therapeutics, Inc., Morristown, NJ

qClinical Development, Pearl Therapeutics, Inc., Morristown, NJ

CORRESPONDENCE TO: Fernando J. Martinez, MD, FCCP, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, Room M-522, Box 130, New York, NY 10065


Copyright 2016, The Authors. All Rights Reserved.


Chest. 2017;151(2):340-357. doi:10.1016/j.chest.2016.11.028
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Background  Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD.

Methods  These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed.

Results  At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms).

Conclusions  We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD.

Trial Registry  ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

Figures in this Article

Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite LAMA or LABA monotherapy.

Fixed-dose combinations (FDCs) deliver combination therapy from single devices. Several LAMA/LABA FDCs are available, including glycopyrrolate/indacaterol,, tiotropium/olodaterol, umeclidinium/vilanterol, and aclidinium/formoterol. These FDCs are administered once daily or bid,,,,, and have demonstrated benefits in lung function, dyspnea, and quality of life vs placebo and monocomponents. As there are no head-to-head trials, it is difficult to make comparisons between these therapies. However, factors that have become increasingly evident are the importance of the inhaler device, patient preference, and adherence., Until now, the obtainable combinations have been available as dry powder inhalers (DPIs) or as a soft mist inhaler. Metered dose inhalers (MDIs) remain the most common inhalers used to deliver short-acting bronchodilators, so many patients may begin inhaled therapy using this device and are familiar with its use.

GFF MDI is an FDC of the LAMA glycopyrrolate (GP) and the LABA formoterol fumarate (FF) in a pressurized MDI. It is formulated using Co-Suspension Delivery Technology developed to overcome the technical difficulties of MDI formulation (eg, sedimentation, creaming, aggregation with particle growth, poor aerosolization properties) using hydrofluoroalkane (HFA) propellants. Drug particles are suspended in the HFA propellant by the use of spray-dried porous particles of distearoyl-phosphatidylcholine. These porous particles form strong associations with the drug particles and minimize drug-drug interactions. These Co-Suspension Delivery Technology formulations have demonstrated excellent stability and dose uniformity, even in the nanogram dose range, with one, two, or three drugs formulated in the same inhaler.,,,

GP and FF have well-established clinical profiles in COPD and are approved both as monotherapies and combinations.,,,, Efficacy and safety data from nine double-blind studies, which evaluated GP MDI at doses of 0.6 to 144 μg and FF MDI at doses of 2.4 to 19.2 μg, supported selection of GP MDI, FF MDI, and GFF MDI doses for phase III evaluation.,,,,,

The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) phase III studies investigated the efficacy and safety of GFF MDI 18/9.6 μg bid vs monocomponent and placebo MDIs. PINNACLE-1 included open-label tiotropium bromide 18 μg DPI (daily, Spiriva HandiHaler) as active comparator (European registration requirement). Lung function, symptom control, and health-related quality of life (HRQoL) end points used to support US registration are presented. e-Appendix 1 presents the list of principal investigators in PINNACLE-1 and PINNACLE-2.

Study Design and Treatment

Figure 1 shows the patient flow for both studies. PINNACLE-1 was conducted across 160 sites (United States, Australia, and New Zealand), and PINNACLE-2 encompassed 140 sites (United States).

Figure 1
Figure Jump LinkFigure 1 Patient disposition diagrams. FF = formoterol fumarate 9.6 μg; GFF = glycopyrrolate/formoterol fumarate 18/9.6 μg; GP = glycopyrrolate 18 μg; ITT = intent to treat; MDI = metered dose inhaler.Grahic Jump Location

The full Methods description is shown in e-Appendix 2. Briefly, after a 4-week screening period, patients were randomized 7:6:6:6:3 to GFF MDI 18/9.6 μg (also described as and equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10.0 μg), GP MDI, FF MDI (all two actuations bid), open-label tiotropium (once daily), or placebo MDI in PINNACLE-1 and 7:6:6:3 to GFF MDI, GP MDI, FF MDI or placebo MDI in PINNACLE-2 (Fig 2).

Figure 2
Figure Jump LinkFigure 2 Study design. HFA = hydrofluoroalkane. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

During screening, previously prescribed inhalers were stopped; open-label ipratropium bromide (Atrovent HFA MDI qid [Boehringer Ingelheim]) and as-needed open-label albuterol (Ventolin HFA MDI up to qid [GlaxoSmithKline]) were used in the case of COPD symptoms. Ipratropium bromide was discontinued after randomization. Rescue albuterol was continued throughout the study. Patients established on a stable dose of oral corticosteroid and those using inhaled corticosteroid (ICS) or phosphodiesterase-4 inhibitors (or both) at screening could continue treatment. ICS-containing FDCs were discontinued and substituted with a single-agent ICS. Other prohibited medications are listed in e-Appendix 2.

The studies were conducted in accordance with Good Clinical Practice Guidelines including the International Conference on Harmonisation, the US Code of Federal Regulations, and the Declaration of Helsinki. Local institutional review boards approved both protocols, and written informed consent was obtained from patients prior to screening.

Patients

Eligible patients were aged 40 to 80 years, had a clinical history of moderate-to-very severe COPD (using American Thoracic Society [ATS]/European Respiratory Society criteria) and were current/ex-smokers (≥ 10 pack-years). Moderate-to-very severe COPD was defined as postbronchodilator FEV1/FVC ratio < 0.70 and FEV1 < 80% predicted. Patients with FEV1 < 30% predicted were required to have postbronchodilator FEV1 ≥ 750 mL. Dyspnea and disease burden were assessed (visit 2) using the Modified Medical Research Council (MMRC) Dyspnea Scale and the COPD Assessment Test (CAT), respectively; these assessments were not used as entry criteria, as there was no requirement for patients to be symptomatic. Laboratory tests and clinical examinations were performed prior to enrollment to assess eligibility.

The main exclusion criteria were significant diseases other than COPD; pregnant/lactating women; lung volume reduction surgery, including lobectomy or bronchoscopic lung volume reduction ≤ 1 year prior to visit 1; hospitalization due to COPD within 3 months or during screening; smoking status change during screening; long-term oxygen therapy required > 12 hours/d; and inability to produce acceptable/reproducible spirometry results.

Patients could withdraw at any point, and trial investigators could withdraw patients if they met early termination criteria including more than two moderate COPD exacerbations (requiring systemic steroids/antibiotics), one severe COPD exacerbation (requiring hospitalization), or the use of prohibited medications.

Assessments

At each visit, investigators confirmed whether patients had refrained from using COPD medications (including study medications) in the preceding 6 hours. Spirometry was performed in accordance with ATS criteria before administration of study medication at all visits and after administration at all visits except week 4 (visit 6) and week 16 (visit 9) (Fig 2). HRQoL was assessed using St. George’s Respiratory Questionnaire (SGRQ) on day 1 and at weeks 12, 16, 20, and 24.

Daily symptoms, including rescue albuterol use, were recorded in electronic diaries and used to calculate a daily total symptom score (TSS), which was the sum of numeric scores assigned to patient responses for individual symptom questions (cough, shortness of breath, sputum volume, nighttime awakenings, and rescue albuterol use). Adverse events (AEs) were recorded.

A subset of patients from both studies participated in a 12-hour pulmonary function test (PFT) substudy on day 1 and at week 12. In PINNACLE-2, a subset of patients participated in a 24-hour Holter substudy at screening (visit 3) and week 4.

The primary objective of PINNACLE-1 and PINNACLE-2 was to confirm the efficacy of GFF MDI vs monocomponent and placebo MDIs. The primary and secondary end points, and type I error control, varied according to regional regulatory registration requirements. Results are presented here using the US approach (e-Appendix 3).

Change from baseline in morning predose trough FEV1 at week 24 was the primary efficacy end point and over 24 weeks (using all assessments) was a secondary end point. Other secondary end points included peak change from baseline in FEV1 within 2 hours postdose at week 24, time to onset of action (defined as the first time point at which the difference from placebo MDI for change from baseline in FEV1 was statistically significant) on day 1, change from baseline in SGRQ total score at week 24, and change from baseline in average daily rescue albuterol use over 24 weeks. Other end points included mean daily TSS and rescue albuterol (daytime and nighttime) use.

The PFT substudy evaluated the effect of treatment on lung function parameters over 12 hours. The primary end point for this substudy was 0- to 12-hour postdose area under the FEV1 curve (FEV1 AUC0-12) at week 12. The 24-hour Holter substudy evaluated the cardiac safety of study treatments. The primary end point was a change from baseline in 24-hour averaged mean heart rate (HR) at week 4.

Statistical Analysis

The primary analyses were conducted using the intent-to-treat (ITT) population. The safety population was similar to the ITT population but was analyzed according to treatment received. All efficacy end points were relative to predose baselines obtained at or prior to day 1.

For PINNACLE-1 and PINNACLE-2, 2,054 and 1,614 patients, respectively, were required to achieve approximately 90% power across all five key comparisons for change from baseline in morning predose trough FEV1 at week 24 with type I error, controlled at 5% (two-sided) using sequential testing. A repeated-measures linear model was used to analyze primary end points and included visit, treatment, treatment by visit, and baseline covariates for FEV1, bronchodilator reversibility, smoking status, and ICS use. The covariance matrix was unstructured. Similar models were used for secondary end points. A combination of sequential testing and the Hochberg procedure was used to control multiplicity for secondary end points. P values < .05, but not included in the type I error procedures or not significant due to these procedures, are referred to as nominally significant.

Patients

Overall, 2,103 patients were randomized in PINNACLE-1 and 1,615 in PINNACLE-2 (Fig 1). Across both studies, 718 and 585 patients, respectively, participated in the PFT substudy, and 585 patients participated in the PINNACLE-2 Holter substudy.

Baseline characteristics in both studies were similar across treatment arms (Table 1). Overall, of 3,699 patients with evaluable data, 7.2%, 41.6%, 5.1%, and 45.6% of patients were in Global Initiative for Chronic Obstructive Lung Disease (GOLD) categories A, B, C, and D, respectively. Overall, 87.2% of patients were symptomatic as defined by a CAT score ≥ 10, and 57.1% had an MMRC grade ≥ 2.0.

Table Graphic Jump Location
Table 1 Patient Demographics and Baseline Characteristics (ITT Population)
a Open-label.
b Former smokers are defined as those who stopped smoking at least 6 weeks prior to the first screening visit.
c Number of pack-years smoked = (number of cigarettes each day/20) × number of years smoked.
d Response is defined as improvement in FEV1 postalbuterol administration vs prealbuterol administration of ≥12% and ≥ 200 mL.

CAT = COPD assessment test; FF = formoterol fumarate 9.6 μg; GFF = glycopyrrolate/formoterol fumarate 18/9.6 μg; GP = glycopyrrolate 18 μg; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; ITT = intent to treat; MDI = metered dose inhaler; MMRC = Modified Medical Research Council Dyspnea Scale; NA = not applicable; SGRQ = St. George’s Respiratory Questionnaire.

Efficacy

In both studies, GFF MDI, GP MDI, and FF MDI showed significant improvements vs placebo MDI in change from baseline in morning predose trough FEV1 at week 24 (all P < .0001; data not shown for GP MDI and FF MDI vs placebo MDI) (Table 2). GFF MDI showed significant differences vs placebo MDI of 150 mL and 103 mL in PINNACLE-1 and PINNACLE-2, respectively (all P < .0001). In PINNACLE-1, GFF MDI showed significant differences of 59 mL and 64 mL vs GP MDI and FF MDI, respectively (all P < .0001). In PINNACLE-2, GFF MDI showed significant differences of 54 mL (P = .0003) and 56 mL (P = .0002) vs GP MDI and FF MDI, respectively. The change from baseline in morning predose trough FEV1 over 24 weeks was similar but with slightly larger estimated differences vs placebo MDI (Fig 3, Table 2). A prospective subgroup analysis of the pooled ITT population showed that the benefits of GFF MDI on change from baseline in morning predose trough FEV1 over 24 weeks were consistent regardless of concomitant ICS use (e-Table 1).

Table Graphic Jump Location
Table 2 Primary and Secondary Spirometry End Points (ITT Population)
a Open-label.
b P < .0001.
c P < .001.
d P < .01.
e The onset of action was defined as the first time point at which the difference compared with placebo MDI for change from baseline in FEV1 was statistically significant.

LSM = least squares mean. See Table 1 legend for expansion of other abbreviations.

Figure 3
Figure Jump LinkFigure 3 Mean change (95% CI) from baseline in trough morning predose FEV1 over 24 weeks by treatment arm for each study (ITT population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

For peak change from baseline in FEV1 within 2 hours postdose at week 24 (Table 2), GFF MDI showed significant differences vs placebo and monocomponent MDIs in both PINNACLE-1 and PINNACLE-2 (all P < .0001). The change from baseline in peak FEV1 within 2 hours postdose over 24 weeks was similar (Fig 4). For onset of action on day 1 (Table 2), GFF MDI showed a significant difference from placebo MDI at 5 min, which was the first time point assessed in both studies, with respective differences of 187 mL and 186 mL (all P < .0001).

Figure 4
Figure Jump LinkFigure 4 Mean change (95% CI) from baseline in peak FEV1 within 2 hours postdose over 24 weeks by treatment arm for each study (ITT population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

In PINNACLE-1 only, GFF MDI showed significant differences in SGRQ total score at week 24 vs placebo (–2.52) and GP MDIs (–2.33) (Table 3). GFF MDI-treated patients were more likely to achieve the minimum clinically important difference of 4 units in SGRQ total score vs GP MDI and placebo MDI in PINNACLE-1 (all P < .05). In PINNACLE-1 and PINNACLE-2, GFF MDI showed a significant reduction in rescue albuterol use over 24 weeks vs placebo MDI (–1.08 and –1.04 puffs/d, respectively) (Table 3). In PINNACLE-2, a significant reduction vs GP MDI (–0.57) was seen, with nominal significance vs FF MDI (–0.29). In both studies, there was a nominally significant difference in change from baseline in mean daily TSS over 24 weeks for GFF MDI vs placebo MDI (Table 3). GFF MDI showed a nominally significant difference in change from baseline vs GP MDI in both studies but not vs FF MDI.

Table Graphic Jump Location
Table 3 Health Status, Rescue Medication, and Patient Symptoms (ITT Population)
a Open-label.
b P < .01.
c P < .05.
d P < .0001.

MCID = minimum clinically important difference. See Table 1 and 2 legends for expansion of other abbreviations.

In the 12-hour PFT substudy of PINNACLE-1, GFF MDI showed significant improvements in FEV1 AUC0-12 at week 12 vs placebo MDI, GP MDI, and FF MDI of 237 mL (P < .0001), 102 mL (P < .0001), and 56 mL (P = .0196), respectively. Similarly in the PINNACLE-2 PFT substudy, GFF MDI showed significant improvements in FEV1 AUC0-12 at week 12 vs placebo MDI, GP MDI, and FF MDI of 209 mL (P < .0001), 98 mL (P < .0001), and 67 mL, respectively (P = .0056) (e-Fig 1). GFF MDI significantly improved evening 12-hour postdose trough FEV1 by 144 mL in PINNACLE-1 and by 158 mL in PINNACLE-2 vs placebo MDI (both P < .0001), with significant improvements vs GP MDI (61 mL; P = .0196) and FF MDI (65 mL; P = .0145) in PINNACLE-2.

Safety and Tolerability

In PINNACLE-1 and PINNACLE-2, 58.8% to 62.9% and 52.5% to 56.1% of patients, respectively, reported one or more AEs (Table 4). Across both studies, the most common AEs included nasopharyngitis, cough, upper respiratory tract infection, sinusitis, and dyspnea, which occurred with a frequency similar to that with placebo MDI in each active treatment group.

Table Graphic Jump Location
Table 4 Summary of Adverse Events (Safety Population)
a Open-label.

GERD = gastroesophageal reflux disease; TEAE = treatment-emergent adverse event. See Table 1 legend for expansion of other abbreviations.

Rates of serious AEs were similar for active treatment and placebo MDI. Rates of AE-related discontinuations were similar across treatment groups in both studies and were slightly lower in the FF MDI and open-label tiotropium arms vs the other treatment arms in PINNACLE-1. The incidence of cardiovascular events of special interest was low and similar across treatment groups in both studies.

Few deaths were observed, and all were considered not related to the study drug. No important trends were observed in clinical laboratory results, vital signs, or electrocardiograms.

24-Hour Holter Substudy

Change from baseline in 24-hour mean HR at week 4 was similar across treatment groups, with the CI excluding clinically relevant differences. No important differences were observed for other Holter substudy end points at week 4, including changes from baseline in daytime and nighttime mean HRs, maximum and minimum 24-hour HRs, and frequency of isolated ventricular events, supraventricular events, and atrial fibrillation (e-Table 2).

The PINNACLE-1 and PINNACLE-2 results demonstrated that GFF MDI, formulated with the novel Co-Suspension Delivery Technology, conferred greater benefits vs placebo and monocomponent MDIs in patients with moderate-to-very severe COPD. GFF MDI had a safety and tolerability profile similar to that of placebo MDI, monocomponent MDIs, and open-label tiotropium.

In both studies, GFF MDI provided clinical benefit in morning predose trough FEV1 vs monocomponent and placebo MDIs at week 24 and also over 24 weeks. These improvements in trough FEV1 vs placebo were of a magnitude anticipated from phase III studies reported for LAMA/LABA FDCs delivered by DPI or soft mist inhaler. Notably, peak change from baseline in FEV1 within 2 hours postdose showed differences for GFF MDI vs GP MDI at week 24 > 100 mL in both studies (PINNACLE-1, 133 mL; PINNACLE-2, 126 mL), with improvements vs FF MDI exceeding 80 mL.

The available LAMA/LABA FDCs all improve lung function, dyspnea, and quality of life vs placebo and monocomponents, and there may now be an increased focus on these agents since a LAMA/LABA FDC has been shown to decrease the incidence of moderate or severe exacerbations compared with an ICS/LABA FDC. However, the absence of head-to-head trials makes it difficult to compare the various LAMA/LABA combinations. PINNACLE-1 and PINNACLE-2 contrast with other LAMA/LABA FDC studies because enrollment required a diagnosis of COPD defined using spirometry but did not require patients to be symptomatic; 12.3% of patients had CAT scores < 10, and 42.7% had an MMRC grade < 2.0. Phase III studies of other LAMA/LABA FDCs have prespecified symptomatic COPD in the inclusion criteria.,,, Further investigations are required to determine the characteristics of patients with COPD who would benefit most from LAMA/LABA FDCs. Currently, GOLD recommends LAMA/LABA combination therapy as an alternative option for patients remaining symptomatic on a single agent.

In both PINNACLE-1 and PINNACLE-2 studies, patients in the placebo arm used rescue medication more often than patients in the other arms and withdrew from the study in higher proportions. In this context, GFF MDI led to a statistically significant reduction in rescue medication use over 24 weeks vs placebo MDI and vs GP MDI/FF MDI in PINNACLE-2; this was within the range demonstrated for other LAMA/LABA FDCs.,,,, HRQoL (by SGRQ results) showed a statistically significant but modest improvement with GFF MDI vs placebo MDI (and GP MDI) in PINNACLE-1 only. In phase III studies of currently available LAMA/LABA FDCs, mean improvement of SGRQ total scores of up to –5.51 have been published.,,,,

Limitations of this study include the open-label nature of the tiotropium arm. There was a slightly lower dropout rate in the open-label tiotropium arm vs the GFF MDI and GP MDI arms in PINNACLE-1, despite the lung function benefit observed with GFF MDI and the lack of safety-related effects that would have led to differential dropout. Since tiotropium 18 μg was administered in an open-label manner, patients who knew they were receiving active drug might have perceived their treatment positively, influencing their decision to remain in the trial. The open-label nature of tiotropium treatment may also have affected the results for some end points.

In conclusion, the PINNACLE-1 and PINNACLE-2 results demonstrate the efficacy and safety of GFF MDI 18/9.6 μg, a LAMA/LABA Co-Suspension Delivery Technology FDC MDI given bid in patients with moderate-to-very severe COPD.

Author contributions: F. J. M. and C. O. are the guarantors and take responsibility for the content of this manuscript, including the data and analysis. F. J. M., G. T. F., R. R-R., C. O., and C. R. contributed to study conception and design, acquisition of data, and analysis and interpretation of data. K. F. R., L. M. F., S. Sethi, P. D., and T. F. contributed to study conception and design and analysis and interpretation of data. S. R. contributed to study design and conception and data interpretation. G. M. G., T. M. S., and S. Siddiqui contributed to acquisition of data and analysis and interpretation of data. G. J. F., S. Spangenthal, and S. A. contributed to acquisition of data. M. G. contributed to study conception and design.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: F. J. M. reports personal fees from Adept, Afferent, Amgen, AstraZeneca, Axon, Axon Communication, Boehringer Ingelheim, Clarion, ConCert, Forest, Genentech, GlaxoSmithKline, Ikaria/Bellerophon, Informa, Janssen, Kadmon, Lucid, Methodist Hospital, Novartis, Nycomed/Takeda, Pearl Therapeutics, Inc., Pfizer, Prime, Roche, Sunovion, Theravance, Unity Biotechnology, Veracyte, and WebMD. He has received nonfinancial support from Biogen/Stromedix, Boehringer Ingelheim, Centocor, and Gilead and grants from the National Institutes of Health. He has received personal fees for delivering CME programs for Academic CME, American Thoracic Society, Annenberg, California Society for Allergy and Immunology, CME Incite, Falco, Haymarket Communications, Integritas, InThought, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, Potomac, UpToDate, and Western Society of Allergy and Immunology. He has received royalty fees from Informa and has spoken on behalf of AstraZeneca and Nycomed/Takeda. He is currently a member of the GOLD Scientific Committee. K. F. R. reports grants from Boehringer Ingelheim, the German Federal Ministry of Education and Research (BMBF), and Novartis. He has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Intermune, Novartis, and Takeda. G. T. F. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Pearl Therapeutics, Inc., Sunovian, and Theravance. He has received grants from Forest and personal fees from GlaxoSmithKline, Meda, Mylan, and Verona. L. M. F. reports grants, personal fees, and nonfinancial support from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratori Guidotti, Merck Sharp & Dohme, Menarini, Novartis, and Takeda. He has received personal fees and nonfinancial support from Boston Scientific, Mundipharma, and Pearl Therapeutics, Inc. He has received personal fees from Bayer, Kyorin, and Zambon and has received grants from Biofutura Italia, Dompè, Malesci, Pfizer, and Vree Health Italia. S. R. reports grants from Almirall, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, NHLBI, Nebraska DHHS, Nycomed, Otsuka, and Pfizer. He has received personal fees from ABIM, Able Associates, Advantage Healthcare, Align2Action, Almirall, APT, ATS, AstraZeneca, Baxter, Boehringer Ingelheim, Chiesi, CIPLA, ClearView Healthcare, Cleveland Clinic, CME Incite, Complete Medical Group, COPDFoundation, Cory Paeth, CSA, CSL, CTS Carmel, Daiichi Sankyo, Decision Resources, Dunn Group, Easton Associates, Elevation Pharma, FirstWord, Forest, Frankel Group, Gerson, Gilead, GlaxoSmithKline, Grifols, GroupH, Guidepoint Global, Haymarket, HealthStar, Huron Consulting, Incite, Inthought, IntraMed (Forest), Johnson & Johnson, LEK, McKinsey, Medical Knowledge, MedImmune, Methodist Health System, Navigant, NCI Consulting, Novartis, Nuvis, Pearl Therapeutics, Inc., Penn Technology, Pfizer, PlanningShop, Prescott, Pro Ed Comm, ProiMed, PSL FirstWord, Pulmatrix, Quadrant, Qwessential, Regeneron, Saatchi and Saatchi, Schlesinger Associates, Strategic North, Synapse, Takeda, Theron, and WebMD. He is employed by AstraZeneca and also retains professorship and a part-time appointment at the University of Nebraska Medical Center. S. Sethi reports grants from AstraZeneca, Dey, and Pearl Therapeutics, Inc. He has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cempra, CSL Behring, Forest, GlaxoSmithKline, Merck, Pearl Therapeutics, Inc., Pulmonx, Reckitt Benckiser, Sunovion, and Theravance. R. R-R. reports grants and personal fees from Almirall and Menarini. He has received personal fees from AstraZeneca, Boehringer Ingelheim, Ferrer, Mylan, Novartis, Pearl Therapeutics, Inc., Takeda, and TEVA. He is a member of the GOLD Board of Directors and of the Scientific Committee. T. M. S. reports grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Forest Research, Novartis, Oncocyte, Pearl Therapeutics, Inc., Proterix, Sunovian, and Theravance. He has received personal fees from AstraZeneca and Vapotherm. S. Siddiqui is an employee of AstraZeneca. P. D., T. F., A. M., M. G., C. O., and C. R. are employees of Pearl Therapeutics, Inc. None declared (G. J. F., S. Spangenthal, G. M. G., S. A.).

Other contributions: The authors thank all the patients and their families and the team of investigators, research nurses, and operations staff involved in these studies. The authors thank Earl St. Rose of Pearl Therapeutics, Inc. for his contributions to PINNACLE-1 and PINNACLE-2. The authors acknowledge Everest Clinical Research for their work on the statistical analyses for the PINNACLE studies. Medical writing support, under the direction of the authors, was provided by Catherine Stanton from Complete Medical Communications and was funded by AstraZeneca. Co-Suspension is a trademark of the AstraZeneca group of companies.

Role of sponsors: Employees of the sponsor, Pearl Therapeutics, Inc., a member of the AstraZeneca Group (C. O., C. R., P. D., T. F., and M. G.), and employees of AstraZeneca (S. Siddiqui), were involved in various aspects of the conception and design of the study, acquisition of data and analysis and interpretation of data, and input into manuscript development. Prior to his employment by AstraZeneca, S. R. was involved in various aspects of the conception and design of the study, acquisition of data, analysis and interpretation of data, and input into manuscript development. He continued to provide input into the interpretation of data after commencing employment at AstraZeneca. The sponsor did not place any restriction on authors about the statements made in the final article.

Additional information: The e-Appendixes, e-Figure, and e-Tables can be found in the Supplemental Materials of the online article.

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016.http://www.goldcopd.org/. Accessed October 4, 2016.
 
Bateman E.D. .Ferguson G.T. .Barnes N. .et al Dual bronchodilation with QVA149 vs single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42:1484-1494 [PubMed]journal. [CrossRef] [PubMed]
 
Beeh K.M. .Korn S. .Beier J. .et al Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med. 2014;108:584-592 [PubMed]journal. [CrossRef] [PubMed]
 
Beeh K.M. .Westerman J. .Kirsten A.M. .et al The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32:53-59 [PubMed]journal. [CrossRef] [PubMed]
 
Decramer M. .Anzueto A. .Kerwin E. .et al Efficacy and safety of umeclidinium plus vilanterol vs tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2:472-486 [PubMed]journal. [CrossRef] [PubMed]
 
D'Urzo A.D. .Rennard S.I. .Kerwin E.M. .Mergel V. .Leselbaum A.R. .Caracta C.F. . Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15:123- [PubMed]journal. [CrossRef] [PubMed]
 
Buhl R. .Maltais F. .Abrahams R. .et al Tiotropium and olodaterol fixed-dose combination vs mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45:969-979 [PubMed]journal. [CrossRef] [PubMed]
 
Mahler D.A. .Kerwin E. .Ayers T. .et al FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) vs its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:1068-1079 [PubMed]journal. [CrossRef] [PubMed]
 
Tashkin D.P. .Ferguson G.T. . Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14:49- [PubMed]journal. [CrossRef] [PubMed]
 
Cohen J.S. .Miles M.C. .Donohue J.F. .Ohar J.A. . Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA. Int J Chron Obstruct Pulmon Dis. 2016;11:785-797 [PubMed]journal. [PubMed]
 
Sulaiman I, Cushen B, Greene G, et al. Objective assessment of adherence to inhalers by COPD patients [Published online ahead of print, July 13, 2016].Am J Respir Crit Care Med.
 
Braido F. .Chrystyn H. .Baiardini I. .et al “Trying, but failing”—the role of inhaler technique and mode of delivery in respiratory medication adherence. J Allergy Clin Immunol Pract. 2016;4:823-832 [PubMed]journal. [CrossRef] [PubMed]
 
Rogueda P. . Novel hydrofluoroalkane suspension formulations for respiratory drug delivery. Expert Opin Drug Deliv. 2005;2:625-638 [PubMed]journal. [CrossRef] [PubMed]
 
Joshi V. .Lechuga-Ballesteros D. .Flynn B. .et al Development of mono, dual and triple combination pMDIs without co-formulation effect. RDD Europe. 2011;2:383-386 [PubMed]journal
 
Lechuga-Ballesteros D. .Noga B. .Vehring R. .Cummings R.H. .Dwivedi S.K. . Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma. Future Med Chem. 2011;3:1703-1718 [PubMed]journal. [CrossRef] [PubMed]
 
Lechuga-Ballesteros D, Vehring R, Joshi V, et al. A new formulation platform for metered dose inhaler combination products: cosuspensions of engineered phospholipid microparticles with micronized actives. Poster presented at the annual meeting of the American Association of Pharmaceutical Sciences (AAPS); October 23-27, 2011;Washington, DC.
 
Vehring R. .Lechuga-Ballesteros D. .Joshi V. .Noga B. .Dwivedi S.K. . Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir. 2012;28:15015-15023 [PubMed]journal. [CrossRef] [PubMed]
 
Buhl R. .Banerji D. . Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:729-741 [PubMed]journal. [PubMed]
 
Campbell M. .Eliraz A. .Johansson G. .et al Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med. 2005;99:1511-1520 [PubMed]journal. [CrossRef] [PubMed]
 
Chapman K.R. .Beeh K.M. .Beier J. .et al A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, vs tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med. 2014;14:4- [PubMed]journal. [CrossRef] [PubMed]
 
Kerwin E. .Hebert J. .Gallagher N. .et al Efficacy and safety of NVA237 vs placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012;40:1106-1114 [PubMed]journal. [CrossRef] [PubMed]
 
Reisner C. .Orevillo C. .Fernandez C. .et al Pooled analyses of five phase 2b studies support dose selection of glycopyrrolate-formoterol fumarate (GFF) MDI (PT003) 18/9.6 μg for phase III development. Eur Respir J. 2013;42:P4153- [PubMed]journal
 
Orevillo C, Gotfried M, Denenberg MB, et al. Combination glycopyrronium and formoterol fumarate inhalation aerosol (PT003) at a dose of 14.4/9.6 μg provides superior improvement in inspiratory capacity compared to tiotropium dry powder inhaler (DPI) in subjects with moderate to severe COPD.http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A3759. Accessed June 14, 2016.
 
Reisner C, Fernandez C, St Rose E, et al. Characterization of the dose response of Pearl Therapeutics' LAMA MDI (GP MDI, PT001) from 36 micrograms to 600 nanograms BID; results from an integrated analysis of phase IIb studies in patients with COPD.http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A4274. Accessed June 15, 2016.
 
Tashkin D.P. .Martinez F.J. .Rodriguez-Roisin R. .et al A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD. Respir Med. 2016;120:16-24 [PubMed]journal. [CrossRef] [PubMed]
 
Fabbri L.M. .Kerwin E.M. .Spangenthal S. .et al Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension Delivery Technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD. Respir Res. 2016;17:109- [PubMed]journal. [CrossRef] [PubMed]
 
Sethi S. .Fogarty C. .Hanania N.A. .et al Efficacy of formoterol fumarate delivered by metered dose inhaler using Co-suspension™ delivery technology versus Foradil® aerolizer® in moderate-to-severe COPD: a randomized, dose-ranging study. Chronic Obstr Pulm Dis (Miami). 2017;4:818-830 [PubMed]journal
 
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GlaxoSmithKline. COPD assessment test.http://www.catestonline.org/. Accessed June 15, 2016.
 
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St. George's University of London. St George's Respiratory Questionnaire (SGRQ).http://www.healthstatus.sgul.ac.uk/. Accessed October 4, 2016.
 
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Wedzicha J.A. .Banerji D. .Chapman K.R. .et al Indacaterol-glycopyrronium vs salmeterol-fluticasone for COPD. N Engl J Med. 2016;374:2222-2234 [PubMed]journal. [CrossRef] [PubMed]
 
Dahl R. .Jadayel D. .Alagappan V.K. .Chen H. .Banerji D. . Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study. Int J Chron Obstruct Pulmon Dis. 2013;8:501-508 [PubMed]journal. [PubMed]
 
Donohue J.F. .Maleki-Yazdi M.R. .Kilbride S. .Mehta R. .Kalberg C. .Church A. . Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107:1538-1546 [PubMed]journal. [CrossRef] [PubMed]
 
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Singh D. .Jones P.W. .Bateman E.D. .et al Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014;14:178- [PubMed]journal. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1 Patient disposition diagrams. FF = formoterol fumarate 9.6 μg; GFF = glycopyrrolate/formoterol fumarate 18/9.6 μg; GP = glycopyrrolate 18 μg; ITT = intent to treat; MDI = metered dose inhaler.Grahic Jump Location
Figure Jump LinkFigure 2 Study design. HFA = hydrofluoroalkane. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 Mean change (95% CI) from baseline in trough morning predose FEV1 over 24 weeks by treatment arm for each study (ITT population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 Mean change (95% CI) from baseline in peak FEV1 within 2 hours postdose over 24 weeks by treatment arm for each study (ITT population). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Patient Demographics and Baseline Characteristics (ITT Population)
a Open-label.
b Former smokers are defined as those who stopped smoking at least 6 weeks prior to the first screening visit.
c Number of pack-years smoked = (number of cigarettes each day/20) × number of years smoked.
d Response is defined as improvement in FEV1 postalbuterol administration vs prealbuterol administration of ≥12% and ≥ 200 mL.

CAT = COPD assessment test; FF = formoterol fumarate 9.6 μg; GFF = glycopyrrolate/formoterol fumarate 18/9.6 μg; GP = glycopyrrolate 18 μg; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; ITT = intent to treat; MDI = metered dose inhaler; MMRC = Modified Medical Research Council Dyspnea Scale; NA = not applicable; SGRQ = St. George’s Respiratory Questionnaire.

Table Graphic Jump Location
Table 2 Primary and Secondary Spirometry End Points (ITT Population)
a Open-label.
b P < .0001.
c P < .001.
d P < .01.
e The onset of action was defined as the first time point at which the difference compared with placebo MDI for change from baseline in FEV1 was statistically significant.

LSM = least squares mean. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 Health Status, Rescue Medication, and Patient Symptoms (ITT Population)
a Open-label.
b P < .01.
c P < .05.
d P < .0001.

MCID = minimum clinically important difference. See Table 1 and 2 legends for expansion of other abbreviations.

Table Graphic Jump Location
Table 4 Summary of Adverse Events (Safety Population)
a Open-label.

GERD = gastroesophageal reflux disease; TEAE = treatment-emergent adverse event. See Table 1 legend for expansion of other abbreviations.

References

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016.http://www.goldcopd.org/. Accessed October 4, 2016.
 
Bateman E.D. .Ferguson G.T. .Barnes N. .et al Dual bronchodilation with QVA149 vs single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42:1484-1494 [PubMed]journal. [CrossRef] [PubMed]
 
Beeh K.M. .Korn S. .Beier J. .et al Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med. 2014;108:584-592 [PubMed]journal. [CrossRef] [PubMed]
 
Beeh K.M. .Westerman J. .Kirsten A.M. .et al The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32:53-59 [PubMed]journal. [CrossRef] [PubMed]
 
Decramer M. .Anzueto A. .Kerwin E. .et al Efficacy and safety of umeclidinium plus vilanterol vs tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2:472-486 [PubMed]journal. [CrossRef] [PubMed]
 
D'Urzo A.D. .Rennard S.I. .Kerwin E.M. .Mergel V. .Leselbaum A.R. .Caracta C.F. . Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15:123- [PubMed]journal. [CrossRef] [PubMed]
 
Buhl R. .Maltais F. .Abrahams R. .et al Tiotropium and olodaterol fixed-dose combination vs mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45:969-979 [PubMed]journal. [CrossRef] [PubMed]
 
Mahler D.A. .Kerwin E. .Ayers T. .et al FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) vs its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:1068-1079 [PubMed]journal. [CrossRef] [PubMed]
 
Tashkin D.P. .Ferguson G.T. . Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14:49- [PubMed]journal. [CrossRef] [PubMed]
 
Cohen J.S. .Miles M.C. .Donohue J.F. .Ohar J.A. . Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA. Int J Chron Obstruct Pulmon Dis. 2016;11:785-797 [PubMed]journal. [PubMed]
 
Sulaiman I, Cushen B, Greene G, et al. Objective assessment of adherence to inhalers by COPD patients [Published online ahead of print, July 13, 2016].Am J Respir Crit Care Med.
 
Braido F. .Chrystyn H. .Baiardini I. .et al “Trying, but failing”—the role of inhaler technique and mode of delivery in respiratory medication adherence. J Allergy Clin Immunol Pract. 2016;4:823-832 [PubMed]journal. [CrossRef] [PubMed]
 
Rogueda P. . Novel hydrofluoroalkane suspension formulations for respiratory drug delivery. Expert Opin Drug Deliv. 2005;2:625-638 [PubMed]journal. [CrossRef] [PubMed]
 
Joshi V. .Lechuga-Ballesteros D. .Flynn B. .et al Development of mono, dual and triple combination pMDIs without co-formulation effect. RDD Europe. 2011;2:383-386 [PubMed]journal
 
Lechuga-Ballesteros D. .Noga B. .Vehring R. .Cummings R.H. .Dwivedi S.K. . Novel cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and asthma. Future Med Chem. 2011;3:1703-1718 [PubMed]journal. [CrossRef] [PubMed]
 
Lechuga-Ballesteros D, Vehring R, Joshi V, et al. A new formulation platform for metered dose inhaler combination products: cosuspensions of engineered phospholipid microparticles with micronized actives. Poster presented at the annual meeting of the American Association of Pharmaceutical Sciences (AAPS); October 23-27, 2011;Washington, DC.
 
Vehring R. .Lechuga-Ballesteros D. .Joshi V. .Noga B. .Dwivedi S.K. . Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir. 2012;28:15015-15023 [PubMed]journal. [CrossRef] [PubMed]
 
Buhl R. .Banerji D. . Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:729-741 [PubMed]journal. [PubMed]
 
Campbell M. .Eliraz A. .Johansson G. .et al Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med. 2005;99:1511-1520 [PubMed]journal. [CrossRef] [PubMed]
 
Chapman K.R. .Beeh K.M. .Beier J. .et al A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, vs tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med. 2014;14:4- [PubMed]journal. [CrossRef] [PubMed]
 
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