| Eligibility |
Inclusion Criteria:
1. Subject's written informed consent obtained prior to any study-related procedures;
2. Male and female aged =40 years;
3. A female is eligible to enter the study if she is of non-childbearing potential i.e.
physiologically incapable of becoming pregnant (e.g. postmenopausal women defined as
being amenorrheic for =12 consecutive months without an alternative medical cause. If
indicated, as per investigator's request, post-menopausal status may be confirmed by
follicle-stimulating hormone levels, according to local laboratory ranges) or women
permanently sterilized (e.g. bilateral oophorectomy, hysterectomy or bilateral
salpingectomy or non-fertile partner). Women physiologically capable of becoming
pregnant [i.e. women of childbearing potential (WOCBP)] are eligible to enter the
study if they have negative pregnancy test at screening and are fulfilling one of the
following criteria:
1. WOCBP with fertile male partners;
2. WOCBP with non-fertile male partners;
4. Male fulfilling one of the following criteria:
1. Male with non-pregnant WOCBP partners;
2. Male with pregnant WOCBP partner;
5. Subject with an established diagnosis of COPD (according to GOLD guidelines, update
2019 [7]) at least 12 months prior to the screening visit;
6. Subject with a smoking history of at least 10 pack-years [pack-years=number of
cigarettes per day x number of years/20]. Current and ex- smokers are eligible.
(Smoking cessation must be at least 6 months prior to the screening. If the subjects
undergo smoking cessation therapy, it must be completed 6 months prior to the
screening visit);
7. Subject with a BMI in the range of 19-32 kg/m2 extremes included;
8. Subject with a post-bronchodilator FEV1 =30% and =70% of the subject normal predicted
value and a post-bronchodilator FEV1/FVC ratio <0.70 measured 10-15 minutes after 400
µg (4 puffs x 100 µg) of salbutamol pMDI. If this criterion is not met at screening,
the test could be repeated once prior to randomisation visit;
9. Subject with at least one COPD exacerbation [i.e. resulting in the use of systemic
(oral/IV/IM) corticosteroids and/or antibiotics or visit to an emergency department or
hospitalisation] in the 12 months preceding the screening visit;
10. Subject on maintenance dual therapy with LABA/LAMA fixed combination within at least 2
months prior to screening visit;
11. Subject with a history of chronic bronchitis defined as chronic cough and sputum
production for more than three months per year for two or more years and known as
'spontaneous sputum producer' subject;
12. Subject must be able to produce an adequate induced sputum sample defined as a load of
at least 300 mg with a viability factor of not less than 70% (with less than 30%
epithelial cells) at screening. The subject may be re-challenged once, if the first
sputum sample does not meet these criteria;
13. Subject must be symptomatic at screening defined as having a CAT score =18;
14. Subject must be able to be trained to correctly use the DPI inhalers and to generate
sufficient PIF (at least 40 L/min) using the In-Check Dial device at screening and
prior to randomisation;
15. Subject must have a cooperative attitude and ability to perform the required outcome
measurements (e.g. spirometry testing, induced sputum...).
Exclusion Criteria:
1. Pregnant or lactating female subject;
2. Subject with a current diagnosis of asthma;
3. Subject who have received or are planned to receive any type of vaccination within 3
weeks of their first dose of investigational product;
4. Subject with a COPD exacerbation [i.e. resulting in the use of systemic (oral/IV/IM)
corticosteroids and/or antibiotics or visit to an emergency department or
hospitalisation] or a lower respiratory tract infection within 6 weeks prior to
screening visit or between screening and randomisation;
5. Subject on any maintenance therapy other than LABA/LAMA fixed combination within 2
months prior to screening visit;
6. Subject receiving treatment with one or more drugs, and related time windows, listed
in the prohibited medication section (see section 5.2.2);
7. Subject requiring long-term (at least 12 hours daily) oxygen therapy for chronic
hypoxemia;
8. Subject participating to a pulmonary rehabilitation programme or completing such a
programme within the last 6 weeks prior to screening visit;
9. Subject with known respiratory disorders other than COPD that in investigator's
opinion would affect efficacy and safety evaluation or place the subject at risk.
This can include but is not limited to known -1 antitrypsin deficiency, active
tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and
interstitial lung disease;
10. Subject having lung cancer or a history of lung cancer;
11. Subject with active cancer or a history of cancer (other than lung) with less than 5
years disease free survival time (whether or not there is evidence of local recurrence
or metastases). Localized carcinoma e.g. basal cell carcinoma (without metastases), in
situ carcinoma of the cervix adequately treated is acceptable;
12. Subject with a known history of intolerance/hypersensitivity to any of the
excipients/components contained in any of the formulations used in the trial;
13. Subject with a diagnosis of depression associated with suicidal ideation or behavior
or with a diagnosis of generalised anxiety disorder that in the investigator's opinion
would place the subject at risk;
14. Subject who has known history of clinically significant cardiovascular conditions such
as, but not limited to, unstable or acute ischemic heart disease within one year prior
to screening visit, NYHA Class III/IV heart failure, known history of sustained and
non-sustained cardiac arrhythmias or history of atrial fibrillation diagnosed in the
last 6 months prior to screening visit and not controlled with therapy rate control
strategy;
15. Subject who has clinically significant abnormal 12-lead ECG that, in the
investigator's opinion, would affect safety, PK or PD evaluation or place the subject
at risk at screening or at randomisation visits;
16. Male subject with a QTcF >450 ms and female subject with a QTcF >470 ms at screening
or at randomisation visits;
17. Subject with a history or symptoms of significant neurological disease including
transient ischemic attack (TIA), stroke, seizure disorder or behavioural disturbances;
18. Subject who has unstable concurrent disease: e.g. uncontrolled hyperthyroidism,
uncontrolled diabetes mellitus or other endocrine disease; significant hepatic
impairment, significant renal impairment; history of cerebrovascular disease;
uncontrolled gastrointestinal disease (e.g. active peptic ulcer, Crohn's disease,
ulcerative colitis, enteritis, unexplained diarrhea, bloody or loose stools);
uncontrolled haematological disease; uncontrolled autoimmune disorders (e.g.
rheumatoid arthritis, inflammatory bowel disease) or other disease or condition.
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