Dose–response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT)

Abstract

Introduction

An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development.

Patients and methods

This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV₁) 40%–70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 μg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV₁ area under the curve from 0 to 12 h (AUC_{0–12 h}) on Day 28.

Results

A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo (p<0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 μg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose–response relationships for most of the endpoints. Accordingly, GB 25 μg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 μg BID, respectively, and 14.8% receiving placebo.

Conclusion

This study supports the selection of GB 25 μg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

Keywords:

• pulmonary disease
• chronic obstructive
• muscarinic antagonists
• pulmonary function tests
• dose–response relationship
• drug
• metered-dose inhalers

Supplementary materials

Methods

Independent ethics committees

• Czech Republic: Etická komise, Fakultní nemocnice Královské Vinohrady (FNKV), Praha.

• Germany: Ethics commission at the Hesse Regional Medical Council, Landesärztekammer Hessen, Frankfurt; Ethikkommissionen (EK I und EK II) bei der Ärztekammer Schleswig-Holstein, 23795 Bad Segeberg; Ethikkommission an der medizinischen Fakultät der Rheinischen Friedrich-Wilhelms Universität Bonn, Bonn; Landesärztekammer Brandenburg, Hauptgeschäftsstelle Ethikkommission, Cottbus; Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Freiburg.

• Hungary: Ethics Committee for Clinical Pharmacology (ECCP), Budapest.

• Romania: National Bioethics Committee for Medicines and Medical Devices, Antonescu, Bucharest.

Inclusion criteria

Patients with COPD airflow obstruction had to meet all of the following inclusion criteria to be eligible for enrollment into the study:

1. Male or female patients aged ≥40 years at screening visit, with signed informed consent obtained prior to initiation of any study-related procedure.

2. Patients with a diagnosis of COPD (according to the Global Initiative for Chronic Obstructive Lung Disease guidelines 2015) at least 12 months before screening.

3. Current smoker or ex-smoker with a smoking history of at least 10 pack-years defined as: 1 pack-year = ([number of cigarettes smoked per day] × [number of years of smoking])/20; if applicable, smoking cessation therapy had to be completed 3 months prior to screening or smoking cessation had to be accomplished at least 3 months prior to screening. The smoking status was not permitted to change between screening and the last study visit.

4. A post-bronchodilator forced expiratory volume in 1 s FEV₁≥40% and ≤70% of the predicted normal value (measured 30–45 min after the administration of 80 μg ipratropium via pressurized metered-dose inhaler [pMDI]); a post-bronchodilator FEV₁/forced vital capacity (FVC)<0.7; and a change in FEV₁ from the pre-bronchodilator value (reversibility) of at least 5% at screening (if the criterion was not met at screening, the test could be rescheduled once before randomization).

5. Patients receiving any of the following for at least 4 weeks prior to screening: long-acting muscarinic antagonist (LAMA); long-acting β₂-agonist (LABA); LAMA + LABA; inhaled corticosteroid (ICS) + LABA; ICS + LAMA. Patients with an FEV₁<50% of the predicted normal value and a history of one exacerbation within the past 12 months had to be treated with ICS + LABA or ICS + LAMA before screening.

6. Ability and cooperative attitude to understand and perform required outcome measurements of the protocol (eg, spirometry maneuvers) and ability to understand the risks involved. Ability to be trained to use the dry powder inhaler (DPI) inhalers.

All inclusion criteria were checked at screening. Criteria 3 and 6 were rechecked at randomization (visit [V]2).

Exclusion criteria

Patients with any of the following criteria were not enrolled:

1. Diagnosis of asthma or other respiratory disorders (other than COPD) which may have interfered with data interpretation according to the investigator’s opinion.

2. Patients who had a COPD exacerbation or a lower respiratory tract infection within 8 weeks prior to screening, or during the run-in period, that resulted in the use of an antibiotic, or oral or parenteral corticosteroids, or hospitalization.

3. Patients with a history of ≥2 exacerbations within the last 12 months prior to screening (frequent exacerbators).

4. Patients treated with oral/parenteral β₂-agonists or nebulized bronchodilators or phosphodiesterase (PDE) inhibitors or who received LABA/LAMA/ICS treatment therapy in the 4 weeks prior to screening and during the run-in period.

5. Patients on an ICS treatment that had been initiated, or with the effective dose that had been changed, within 4 weeks prior to screening or during the run-in period (patients on a stable dose of ICS for at least 4 weeks prior to screening were allowed).

6. Patients requiring long-term (at least 12 h daily) oxygen therapy for chronic hypoxemia.

7. Patients with known respiratory disorders other than COPD including but not limited to α-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.

8. Patients with medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the investigator, would have prevented use of anticholinergic agents.

9. Patients who had unstable concurrent disease: eg, uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease, significant hepatic impairment, significant renal impairment, history of cerebrovascular disease, uncontrolled gastrointestinal disease (eg, active peptic ulcer), neurological disease, uncontrolled hematological disease, uncontrolled autoimmune disorders or any other disease or other condition which might have placed the patient at undue risk or potentially compromised the results or interpretation of the study according to the investigator’s opinion.

10. Patients who had concomitant disease of poor prognosis (eg, cancer).

11. Patients who had clinically significant cardiovascular conditions, including unstable ischemic heart disease, New York Heart Association (NYHA) class III/IV left ventricular failure, acute ischemic heart disease within 1 year prior to screening, history of sustained and non-sustained cardiac arrhythmias diagnosed in the past 6 months (sustained meant lasting >30 s and/or ending only with external action, and/or leading to hemodynamic collapse; non-sustained meant >3 beats in <30 s, and/or ending spontaneously, and/or asymptomatic), clinically significant impulse conduction blocks.

12. Patients with known atrial fibrillation (AF):

    1. Paroxysmal AF.

    2. Persistent: AF episode lasting >7 days or requiring termination by cardioversion, either with drugs or by direct current cardioversion (DCC) within 6 months prior to screening.

    3. Long standing persistent: continuous AF diagnosed for <6 months and/or without a rhythm control strategy.

    4. Permanent: AF diagnosed for at least 6 months with a resting ventricular rate ≥100/min not controlled with a rate control strategy (ie, selective β-blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy).

13. Patients who had clinically significant abnormal 12-lead electrocardiogram (ECG) that might have placed the patient at undue risk or potentially compromised the results or interpretation of the study according to the investigator’s opinion.

14. Patients whose 12-lead ECG showed a QT interval corrected for heart rate (QTcF)>450 ms for males or QTcF>470 ms for females.

15. Patients with clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease that might have placed the patient at undue risk or potentially compromised the results or interpretation of the study according to the investigator’s opinion.

16. Pregnant or lactating women and all women of childbearing potential, unless they were willing to use highly effective birth control methods, such as:

    1. Placement of an intrauterine device or intrauterine releasing system.

    2. Oral, intravaginal, transdermal combined estrogen and progestogen containing hormonal contraception or oral, injectable, implantable progestogen-only hormonal contraception.

    3. Bilateral tubal occlusion.

    4. Partner vasectomy (provided that the partner of the study participant was the sole sexual partner and that successful sterilization had been confirmed after surgery).

    5. Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.

    For all women of childbearing potential, serum pregnancy tests were performed at V0, at V10 and at early termination (ET) visits. Urinary pregnancy tests were performed at V0 and on Day 1 of each treatment period (V2, V5 and V8); female patients of non-childbearing potential, defined as physiologically incapable of becoming pregnant (postmenopausal [no menses for 12 months without an alternative medical cause] or permanently sterilized by hysterectomy, bilateral salp-ingectomy or bilateral oophorectomy), were eligible. If indicated, as per investigator’s request, postmenopausal status may have been confirmed by follicle-stimulating hormone levels (according to local laboratory range) in women not using hormonal contraception or hormonal replacement therapy.

17. Known intolerance/hypersensitivity or any contraindication to treatment with M3-antagonists or any of the excipients contained in the formulations used in the study.

18. Patients who had evidence of alcohol or drug abuse, not compliant with the study protocol or not compliant with the study treatments according to investigator’s judgment.

19. Patients with major surgery within 3 months prior to screening or planned during the study, which may have affected patient’s compliance with study procedures.

20. Patients who had participated in another clinical study with an investigational drug administered within 2 months prior to screening.

All exclusion criteria were checked at screening (V1). Criteria 2, 4, 5, 13 and 14 were rechecked at randomization (V2).

Figure S1 Change from baseline in pre-dose (morning) IC on Day 28 (ITT population).

Notes: Baseline (pre-dose on visit 2) 1.903 (SD 0.547) L. Data are adjusted mean and 95% CIs. *p<0.05 vs GB 12.5 μg BID.

Abbreviations: BID, twice daily; GB, glycopyrronium bromide; IC, inspiratory capacity; ITT, intention-to-treat.

Table S1 Proportion of patients with an FEV₁ response on Day 28 (ie, change from baseline in morning pre-dose FEV₁≥100 mL; ITT population)

Acknowledgments

The authors would like to thank the investigators and patients at the investigative sites for their support of this study. Writing support was provided by David Young of Young Medical Communications and Consulting Ltd. This support was funded by Chiesi Farmaceutici SpA. This study was funded by Chiesi Farmaceutici SpA. Employees of the sponsor were involved in study design, oversaw the conduct and analysis of the study and (as authors) took part in the decision to submit the manuscript.

Disclosure

KMB declares that no personal payments were received from any pharmaceutical entity in the past 5 years. KMB is a full-time employee of Insaf Respiratory Research Institute. The institution has received compensation for services on advisory boards or consulting for Ablynx, Almirall, AstraZeneca, Berlin Chemie, Boehringer, Chiesi, Cytos, Mundipharma, Novartis, Pohl Boskamp and Zentiva. The institution has received compensation for speaker activities in scientific meetings supported by Almirall, AstraZeneca, Berlin Chemie, Boehringer, Cytos, ERT, GSK, Novartis, Pfizer, Pohl Boskamp and Takeda. The institution has further received compensation for design and performance of clinical trials from Almirall, Altana/Nycomed, AstraZeneca, Boehringer, Cytos, GSK, Infinity, Medapharma, MSD, Mundipharma, Novartis, Parexel, Pearl Therapeutics, Pfizer, Revotar, Teva, Sterna, and Zentiva. AE, HP, DS and MAN are employees of Chiesi, the study sponsor. The authors report no other conflicts of interest in this work.