A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease

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Abstract

Background

Long-acting muscarinic antagonist/long-acting β ₂-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI).

Methods

This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV ₁ AUC _0–12) on Day 7 relative to baseline FEV ₁. Secondary endpoints included pharmacokinetics and safety.

Results

GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV ₁ AUC _0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI ( p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated.

Conclusions

GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD.

Trial registration

ClinicalTrials.gov NCT01085045. Registered 9 March 2010.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-016-0491-8) contains supplementary material, which is available to authorized users.

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Most cited references 16

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

Stephanie Harris, Marc Decramer, Alison Church … (2014)

Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD. In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2). 1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups. Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD. GlaxoSmithKline. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Minimal clinically important differences in COPD lung function.

James Donohue (2005)

The FEV1 is widely used by physicians in the diagnosis, staging, treatment, monitoring, and establishing prognosis for patients with COPD. The MCID is the smallest difference which patients perceive as beneficial and which would mandate a change in patient management. A precise MCID for FEV1 has not been established. In attempt to establish a MCID for predose or trough FEV1, several limitations need to be addressed. There are issues such as reproducibility, repeatability, acceptability, variability, placebo effect, and equipment effects. Patient factors, such as baseline level of FEV1, albuterol reversibility, diurnal variation, influence the results. Nonetheless, using anchoring techniques, a change in pre dose FEV1 of about 100 mL can be perceived by patients, correlates with fewer relapses following exacerbations and is in the range usually achieved with bronchodilators approved for COPD. In the future, consistent reporting of spirometric variables, such as a predose FEV1 and other outcomes, can be incorporated into a more quantitative effort to establish the MCID. Also distributional/statistical methods may be useful in determining the MCID FEV1.

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Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study

Marc Miravitlles, Heinrich Worth, Juan Soler-Cataluna … (2014)

Background Few studies have investigated the 24-hour symptom profile in patients with COPD or how symptoms during the 24-hour day are inter-related. This observational study assessed the prevalence, severity and relationship between night-time, early morning and daytime COPD symptoms and explored the relationship between 24-hour symptoms and other patient-reported outcomes. Methods The study enrolled patients with stable COPD in clinical practice. Baseline night-time, early morning and daytime symptoms (symptom questionnaire), severity of airflow obstruction (FEV1), dyspnoea (modified Medical Research Council Dyspnoea Scale), health status (COPD Assessment Test), anxiety and depression levels (Hospital Anxiety and Depression Scale), sleep quality (COPD and Asthma Sleep Impact Scale) and physical activity level (sedentary, moderately active or active) were recorded. Results The full analysis set included 727 patients: 65.8% male, mean ± standard deviation age 67.2 ± 8.8 years, % predicted FEV1 52.8 ± 20.5%. In each part of the 24-hour day, >60% of patients reported experiencing ≥1 symptom in the week before baseline. Symptoms were more common in the early morning and daytime versus night-time (81.4%, 82.7% and 63.0%, respectively). Symptom severity was comparable for each period assessed. Overall, in the week before baseline, 56.7% of patients had symptoms throughout the whole 24-hour day (3 parts of the day); 79.9% had symptoms in ≥2 parts of the 24-hour day. Symptoms during each part of the day were inter-related, irrespective of disease severity (all p < 0.001). Early morning and daytime symptoms were associated with the severity of airflow obstruction (p < 0.05 for both). Night-time, early morning and daytime symptoms were all associated with worse dyspnoea, health status and sleep quality, and higher anxiety and depression levels (all p < 0.001 versus patients without symptoms in each corresponding period). In each part of the 24-hour day, there was also an association between symptoms and a patient’s physical activity level (p < 0.05 for each period). Conclusions More than half of patients experienced COPD symptoms throughout the whole 24-hour day. There was a significant relationship between night-time, early morning and daytime symptoms. In each period, symptoms were associated with worse patient-reported outcomes, suggesting that improving 24-hour symptoms should be an important consideration in the management of COPD. Electronic supplementary material The online version of this article (doi:10.1186/s12931-014-0122-1) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Colin Reisner: +001-973-975-0320 , creisner@pearltherapeutics.com

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 6 January 2017

Publication date PMC-release: 6 January 2017

Publication date (Print): 2017

Volume: 18

Electronic Location Identifier: 8

Affiliations

[1 ]Pearl Therapeutics Inc., 280 Headquarters Plaza, East Tower, 2nd Floor, Morristown, NJ 07960 USA

[2 ]Department of Medicine, University of Modena and Reggio Emilia, NOCSAE, Modena, Italy

[3 ]Clinical Research Institute of Southern Oregon, Medford, OR USA

[4 ]Spartanburg Medical Research, Spartanburg, NC USA

[5 ]American Health Research, Charlotte, NC USA

[6 ]Lungen Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany

[7 ]Department of Medicine, Christian-Albrechts University Kiel, Kiel, MI USA

[8 ]Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI USA

[9 ]Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College; New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY USA

[10 ]Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC USA

[11 ]Pearl Therapeutics Inc., Durham, NC USA

[12 ]Pearl Therapeutics Inc., Redwood City, CA USA

Article

Publisher ID: 491

DOI: 10.1186/s12931-016-0491-8

PMC ID: 5216561

PubMed ID: 28061907

SO-VID: 385bbe32-8fb3-4dea-83bc-af53ee6fd5cd

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 September 2016

Date accepted : 13 December 2016

Funding

Funded by: Pearl Therapeutics Inc., a member of the AstraZeneca Group.

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: copd,lama,laba,lung function,bronchodilators,copd maintenance,co-suspension™ delivery technology,metered dose inhaler

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ScienceOpen disciplines: Respiratory medicine

Keywords: copd, lama, laba, lung function, bronchodilators, copd maintenance, co-suspension™ delivery technology, metered dose inhaler

A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease

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Biomarkers for Inflammatory Lung Disease

Most cited references 16

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

Minimal clinically important differences in COPD lung function.

Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study

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