A 6-week Dose Ranging Study of CHF 5259 pMDI in Subjects With Chronic Obstructive Pulmonary Disease

A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

The purpose of this study is to evaluate the dose-response of different doses of CHF 5259 pMDI on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.

This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose-ranging 6-arm parallel group study to identify the optimal dose of CHF 5259 pMDI (pressurized metered dose inhaler) with respect to lung function as well as other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol and background inhaled corticosteroid (ICS) as needed, patients were randomized to one of the 6 study treatment groups. Following randomization, subjects were assessed after 3 weeks and 6 weeks of study treatment at the study center. A follow-up phone was performed a week after the last visit.

During the study, daily symptoms, rescue and background medication use and compliance with the study drug were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. At screening and subsequent visits, subjects underwent physical and vital signs examinations, spirometry measurements, and 12-lead electrocardiogram (ECG). Symptoms and chronic obstructive pulmonary disease (COPD) health status were assessed through validated questionnaires. Routine hematology, blood chemistry, and pregnancy testing were performed before enrollment and at end of study. 24-hour (24-H) digital recording of ECGs (Holter) was performed before and after the first dose and just before the last dose of study treatment.

Inclusion Criteria:

• Male or female subjects aged ≥ 40 who have signed an Informed Consent Form prior to initiation of any study-related procedure.
• Subjects with a diagnosis of COPD (according to GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD Report) at least 12 months before the screening visit.
• Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years
• A post-bronchodilator forced expiratory volume in the 1st second (FEV1) ≥50% and <80% of the predicted normal value and,
• a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) < 0.7 at screening and
• a demonstrated reversibility to ipratropium defined as ΔFEV1 ≥ 5% over baseline 30-45 minutes after inhaling 4 puffs of ipratropium
• Subjects under regular COPD therapy for at least 2 months prior to screening with either inhaled long-acting muscarinic antagonist (LAMA), inhaled ICS/ long-acting β2-agonist (LABA), inhaled ICS + LAMA
• Symptomatic subjects at screening with a CAT score ≥10. This criterion must be confirmed at randomization
• Symptomatic subjects with a BDI focal score ≤ 10. This criterion must be confirmed at randomization
• A cooperative attitude and ability to demonstrate correct use of the inhalers and e-diary.

Exclusion Criteria:

• Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use highly effective birth control methods
• Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as described in global initiative for asthma (GINA) Report 2016, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study treatment according to Investigator's judgment)
• COPD Exacerbations: a moderate or severe COPD exacerbation that has not resolved ≤14 days prior to screening and ≤30 days following the last dose of any oral/systemic corticosteroid or antibiotic (whichever comes last). A Moderate or Severe COPD exacerbation during the run-in period
• Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening or during run-in
• Subjects treated with non-cardio-selective β-blockers in the month preceding screening or during the run-in period
• Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as needed
• Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia
• Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according the Investigator's judgment.
• Subjects who have clinically significant cardiovascular condition
• Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement
• Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening visit
• Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents
• History of hypersensitivity to M3 receptor antagonists, β2-adrenergic receptor agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impact the efficacy of the study treatment according to the Investigator's judgement
• Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement
• Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening
• Use of potent cytochrome P450 2D6 and 3A4 inhibitors within 4 weeks prior to screening
• Unstable or uncontrolled concurrent disease; fever, endocrine disease, gastrointestinal disease; neurological disease; hematological disease; autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgment
• History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening
• Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
• Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order.
• Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.