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

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 with
respect to lung function and other clinical efficacy and safety outcomes.

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

During the study, daily symptoms, rescue and background medication use and compliance with
the study drug will be recorded via a subject diary. Treatment-Emergent Adverse Events
(TEAEs) will be assessed and recorded throughout the study. At screening and subsequent
visits, subjects will undergo physical and vital signs examinations, spirometry measurements,
and 12-lead ECG. Symptoms and COPD health status will be assessed through validated
questionnaires. Routine hematology, blood chemistry, and pregnancy testing will be performed
before enrollment and at end of study. 24-hour digital recording of ECGs (Holter) will be
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 FEV1 ≥50% and <80% of the predicted normal value and,

- a post-bronchodilator FEV1/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 LAMA, inhaled ICS/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 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.