Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA

Abstract

Background

COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD.

Methods

In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed.

Results

Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV₁ at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George’s Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups.

Conclusion

These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators.

Keywords:

• β₂-agonist
• bronchodilator
• COPD
• co-suspension delivery technology
• muscarinic antagonist

Supplementary materials

Study design and inclusion/exclusion criteria

A randomization ratio of 7:6:6:3 was used, as initial modeling suggesting that this is the most efficient for the sample size and treatments in this study. The appropriateness of this ratio was confirmed by the results of PINNACLE-1 and PINNACLE-2.¹

Patients were 40–80 years of age, had an established clinical history of COPD as defined by the American Thoracic Society/European Respiratory Society,² and were current or former smokers with a history of at least 10 pack-years. COPD had to be of at least moderate severity,³ defined as a FEV₁/forced vital capacity ratio of <0.70 at screening, and FEV₁ <80% predicted normal value (calculated using the Third National Health and Nutrition Examination Survey⁴ or local reference equations applicable to other regions) and ≥750 mL if FEV₁ <30% predicted normal (ie, very severe COPD).

Exclusion criteria included diagnosis of a significant disease other than COPD (which, in the opinion of the investigator, could put the patient at risk or could influence either the study results or the patient’s ability to participate); poorly controlled COPD (defined as acute worsening of COPD that required treatment with oral corticosteroids or antibiotics within 6 weeks of, or during, screening); and hospitalization due to poorly controlled COPD within 3 months prior to, or during, screening. The need for long-term oxygen therapy(>12 hour/day), change in smoking status within 6 weeks of or during screening, and poor hand-to-breath coordination (requiring the use of a spacer device with an MDI) were also exclusion criteria.

Statistical analysis

The primary endpoint was analyzed using a repeated measures linear model with baseline FEV₁ (the mean of evaluable 60- and 30-minute predose values on Day 1) and reversibility to albuterol sulfate as continuous covariates and visit, treatment, and treatment-by-visit interaction as categorical covariates. An unstructured variance–covariance matrix was applied, and two-sided P-values and point estimates with two-sided 95% CIs were produced for each treatment difference. Treatment group comparisons for the secondary endpoints were evaluated using a similar repeated measures linear model as for the primary endpoint but included the relevant baseline covariate for each endpoint. Time to onset of action on Day 1 was determined for each treatment using the 5 and 15-minute postdosing FEV₁ assessments and analyzed using an analysis of covariance model, with baseline FEV₁ and reversibility to albuterol sulfate as continuous covariates. For Transition Dyspnea Index and St George’s Respiratory Questionnaire responder analyses, logistic regression was used to compare treatment groups and P-values and odds ratios with 95% CIs were produced for each comparison. The procedure to control Type I error was applied to primary and secondary endpoints only and is described in the main body of the article.

Table S1 Institutional review boards and approval numbers

Table S2 Additional patient-reported outcome endpoints (ITT population, unless stated otherwise)

References

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Acknowledgments

This study was supported by Pearl – a member of the AstraZeneca Group. Employees of the sponsor and employees of AstraZeneca 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. The sponsor did not place any restriction on authors about the statements made in the final article. The authors would like to thank all the patients and their families and the team of investigators, research nurses, and operations’ staff involved in these studies. Medical writing support, under the direction of the authors, was provided by Carol McNair, PhD, of CMC CONNECT, a division of Complete Medical Communications Ltd, Glasgow, UK, funded by AstraZeneca, Cambridge, UK, in accordance with Good Publication Practice (GPP3) guidelines.³⁶ Data included in this manuscript have been presented in a poster at the American Thoracic Society International Conference 2018, San Diego, CA, USA. The PINNACLE studies were supported by Pearl – a member of the AstraZeneca Group.

Disclosure

BJL is one of a number of co-investigators on an AstraZeneca- sponsored grant received by the University of Dundee to support genomic studies in COPD. He has also received speaker fees from AstraZeneca; payment for consulting and speaking from Boehringer Ingelheim and Chiesi; grant support from Boehringer Ingelheim, Chiesi, and Janssen; advisory board and speaker fees from Teva; and consulting fees from Sandoz, Cipla, Dr Reddys, and Lupin. DJC is supported by the National Institute for Health Research (NIHR) Barts Biomedical Research Center and received a grant from Pearl – a member of the AstraZeneca group, for normal recruitment of patients. YG received payment from AstraZeneca for medical institution costs for the clinical study and has received speaker fees from AstraZeneca, Boeh-ringer Ingelheim Japan Co., Ltd, and Kyorin Pharmaceutical Co., Ltd. NZ has received consultancy and lecture fees from Boehringer Ingelheim and Novartis and was on the advisory board of the GOLD committee. KN and SA report no conflicts of interest in this work. RC is an advisory committee member and speaker for AstraZeneca. AM is an employee of Pearl – a member of the AstraZeneca Group. SS and UJM are employees of AstraZeneca, with stock options. CR is an employee of Pearl – a member of the AstraZeneca group and an employee of AstraZeneca.

Author contributions

CR is the guarantor and takes responsibility for the content of this manuscript, including the data and analysis. All authors participated in the analysis and interpretation of data reported. AM made significant contributions to the statistical analysis of the data. BJL, DJC, YG, NZ, KN, RC, and SA participated in the acquisition of reported data. AM, SS, CR, and UJM made substantial contributions to the conception or design of the study. All authors reviewed or critically revised the manuscript, provided final approval of the version to be published, and agreed to be accountable for all aspects of the work.