Functional Respiratory Imaging Study (FRI)

Inclusion criteria

• Subject's written informed consent obtained prior to any study-related procedure.
• Male or Female COPD patients aged ≥ 40 years.
• Smoking history: of at least 10 pack-years (pack-year= number of cigarettes per day x number of years/20).
• Smoking status: current or ex-smokers. Previous smokers are defined as those who have stopped smoking for at least 24 weeks prior to screening visit. (Pipe and/or cigar and/or e-cigarettes smoking cannot be used to calculate pack-year history). If the subjects undergo smoking cessation therapy, it must be completed 3 months prior to study entry.
• Patients with documented COPD at least 12 months according to GOLD 2017.
• Post-bronchodilator (BD) decreased Tiffeneau index: FEV1/FVC < 0.70.
• Patients who present post- BD FEV1 less than 50 % of predicted.
• Patients who present (Functional residual capacity) FRC ≥120% predicted.
• Patients who present CAT assessment ≥10.
• Patients on stable respiratory medications for at least 3 months prior to screening with non extrafine extemporary triple combination. The possible combination therapies prior to screening are:

• fluticasone plus salmeterol plus tiotropium
• fluticasone plus salmeterol plus glycopyrronium
• fluticasone plus salmeterol plus umeclidinium
• fluticasone plus vilanterol plus tiotropium
• fluticasone plus vilanterol plus glycopyrronium
• fluticasone plus vilanterol plus umeclidinium;
• Body Mass Index (BMI) between 18.0 and 32.0 kg/m2 (extremes included) at the screening visit..
• Ability to understand the study procedures and the risks involved and ability to be trained with pMDI training inhalers to use the devices correctly.
• WOCBP fulfilling one of the following criteria:

• WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up visit or
• WOCBP with non-fertile male partners (contraception is not required in this case).

For the definition of WOCBP and of fertile men and the list of highly effective birth control methods, refer the CTFG guidance for more detailed information

• Female patients of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile; e.g. amenorrehic for ≥12 consecutive months without alternative medical cause). Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy (40). If indicated, as per investigator's request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges).

Exclusion criteria

• Pregnant or lactating women.
• Patients with history or current diagnosis of asthma.
• Medical history or current diagnosis of allergic rhinitis or atopy (atopy which may have risen contra-indications or impacted the efficacy of the study treatment according to Investigator's judgment).
• Patients requiring use of the following medications:

• Systemic steroids for COPD exacerbation in the 4 weeks prior to screening;
• Patients with a moderate or severe COPD exacerbation [i.e. resulting in the use of systemic corticosteroids (oral/IV/IM) and/or or antibiotics or need for hospitalisation within 6 weeks prior to screening];
• A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening;
• c-Phosphodiesterase-4 (PDE-4) inhibitors in the 4 weeks prior to screening;
• Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) in the 4 weeks prior to screening;
• Patients treated with non-cardio-selective β-blockers in the week prior to screening.
• Patients 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.
• Patients 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. (This could include but is not limited to α-1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease).
• Lung cancer or history of lung cancer: patients with a diagnosis of lung cancer or a history of lung cancer.
• Lung resection: subjects with a history of lung volume resection.
• Subjects who have a cardiovascular condition such as, but not limited to unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, acute ischemic heart disease in the last year prior to study screening, which may impact the safety of the subject or the evaluation of the result of the study according to the Investigator's judgment; history of atrial fibrillation, history of sustained and non sustained cardiac arrhythmias diagnosed within 24 weeks prior to study entry not controlled with therapy.
• ECG criteria: any clinically significant abnormal 12-lead ECG that in the Investigator's opinion would affect the efficacy or safety evaluation or place the patients at risk. Male patients with a QTcF >450ms and female patients with a QTcF >470ms at screening and/or baseline visits are not eligible.
• Medical history or current diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would have prevented use of anticholinergic agents.
• History of hypersensitivity to M3 antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impacted the efficacy of the study treatment according to the Investigator's judgment.
• Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may have impacted the efficacy or the safety of the study treatment according to Investigator's judgment.
• Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L).
• Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled neurological disease; uncontrolled hematological disease; uncontrolled 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.
• Drugs with hepatoxic potential: Patients receiving treatment with any drug known to have a well defined potential for hepatotoxicity (e.g. isoniazide, nimesulide, ketoconazole) within the previous 3 months before the screening visit.
• Changes in dose, schedule, formulation or product of oral xanthine derivatives (e.g. Theophylline) in the month prior screening visit.
• Participation in an investigational trial: patients who have received any investigational drug within the 30 days (60 days for biologics) before the screening visit or a more appropriate time as determined by the investigator (e.g. approximately 5 half-lives of the investigational drug whatever is longer).
• Treatment with strong CYP3A inhibitors (e.g. erythromycin, itraconazole) within 4 weeks prior to study entry.
• Serology at the screening positive for HIV1 or HIV2 and positive results for Hepatitis which indicates acute or chronic Hepatitis B (i.e. positive HB surface antigen HBsAg, positive and/or positive HB core antibody anti-HBc) or Hepatitis C (positive HCV antibody).