A 52-week, randomized, double-blind, double-dummy, placebo- and active- controlled (Roflumilast, Daliresp® 500µg), parallel group, study to evaluate the efficacy and safety of two doses of CHF6001 DPI add-on to maintenance triple therapy in subjects with Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis.

Subjects must meet all the following inclusion criteria to be eligible for
enrolment into the study:
1. Males and females aged >= 40 years with written informed consent obtained
prior to any study-related procedure.
2. Females are eligible to enter the study if she is of
a. non- childbearing potential i.e. physiologically incapable of becoming
pregnant (e.g. postmenopausal women defined as being amenorrhoeic for >=12
consecutive months without an alternative medical cause*) or women permanently
sterilized (e.g. bilateral oophorectomy, hysterectomy or bilateral
salpingectomy).
or
b. childbearing potential, they must have a negative pregnancy test at
screening and must agree to use one or more of the following acceptable
contraceptive measures:
i. Placement of an intrauterine device (IUD) or intrauterine hormone-releasing
system (IUS).
ii. Combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, transdermal).
iii. Progesterone-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, implantable).
iv. Bilateral tubal occlusion.
v. Vasectomized partner.
vi. Double barrier method: condom and an occlusive cap (diaphragm or cervical/
vault caps) with a vaginal spermicidal agent.
Reliable contraception should be maintained throughout the study. Abstinence is
acceptable where it is in line with the subject*s
preferred and usual lifestyle. Pregnancy tests will be performed at screening
(urine and serum tests) and at randomization (urine test
only) in all women of childbearing potential.
3. Subjects with an established diagnosis of COPD (according to GOLD 2020) at
least 12 months before the screening visit, with
chronic bronchitis (defined as productive cough for at least 3 months in each
of the prior two consecutive years) and/or with chronic productive cough >=12
months prior to screening.
4. 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 [pack-years =
(number of cigarettes per day x number of years)/20] (If the subjects undergo
smoking cessation therapy, it must be completed 3 months prior to the screening
visit). E-cigarettes and pipe smokers are allowed. E-cigarettes cannot be used
to calculate pack-year history.
5. A post-bronchodilator FEV1 <50% of the patient predicted normal value and a
post-bronchodilator FEV1/FVC ratio < 0.7 after 400µg
(4 puffs x 100µg) of salbutamol pMDI. If this criterion is not met at
screening, the test can be repeated once before randomization.
6. A documented history (e.g. medical record verification) of at least one
moderate or severe COPD exacerbation in the previous year.
Documented visits to an emergency department due to COPD exacerbation
associated with prescription of systemic steroids/antibiotics, are considered
acceptable to fulfil this criterion. A stay in emergency room >=24h will be
considered a severe event.
7. Symptomatic subject at screening defined as having a CAT score >=10.
8. Subjects prescribed with maintenance triple therapy (free or fixed
combination of ICS, LABA, LAMA) according to GOLD 2020 recommendations, for at
least 12 months prior to screening and receiving regular maintenance triple
therapy for at least 3 months prior to the screening visit. ICS must be in an
approved dose for COPD.
9. Subjects are willing and able to be trained to use correctly the DPI
inhalers (NEXThaler®).
10. Subjects are willing and able to be trained to use correctly the electronic
devices with COPD questionnaires, to understand and to
perform required outcome measurements of the protocol (e.g. spirometry
manoeuvres etc.) and ability to understand the risks involved.

EXCLUSION CRITERIA
The presence of any of the following will exclude a patient from study
enrolment:
1. Subjects with a diagnosis of current asthma. Those with prior history of
asthma in childhood are eligible.
2. Subjects with a moderate or severe COPD exacerbation i.e. resulting in the
use of systemic corticosteroids (oral/IV/IM corticosteroids) and/or antibiotics
or need for hospitalisation or a lower respiratory tract infection 4 weeks
prior to study entry and during run-in period.
3. Pregnant and Lactating women.
4. Subjects requiring long term (at least 15 hours daily) oxygen therapy for
chronic hypoxemia.
5. Subjects with known α-1 antitrypsin deficiency as the underlying cause of
COPD.
6. Subjects with primary diagnosis of emphysema not related to COPD
7. Subjects with clinically significant respiratory disorders other than COPD.
This can include but is not limited to active tuberculosis, significant
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and
interstitial lung disease.
8. Subjects with lung volume reduction surgery.
9. Subjects having lung cancer or a history of lung cancer or lung cancer with
full recovery less than 1 year after completing cancer therapy.
10. Subjects with active cancer or a history of cancer (other than the lung)
with full recovery less than 1 year after completing cancer therapy or any
untreated localized carcinoma.
11. Subjects with a history of allergy or hypersensitivity to anticholinergics,
β2-agonists, corticosteroids, PDE-4 inhibitors or any of the excipients
contained in any of the formulations used in the trial or a medical condition
such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck
obstruction that in the investigator*s opinion would contra-indicate study
participation.
12. Subjects under Roflumilast treatment within 6 months before study entry.
13. Subjects with a diagnosis of depression, generalised anxiety disorder,
suicidal ideation or behaviour that might, according to the investigator
judgement, place the patient at undue risk.
14. Subjects who have clinically significant cardiovascular condition such as,
but not limited to unstable ischemic heart disease, NYHA Class III/IV left
ventricular failure, acute ischemic heart disease within one year prior to
study entry, known history of atrial fibrillation or of sustained and
non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to
study entry, not controlled with a rate and/or rhythm control strategy or with
recurrent episodes in the last 6 months.
15. An abnormal and clinically significant 12-lead ECG finding in relation to
the subject*s medical history that results in active medical problem which may
impact the safety of the patient according to investigator*s judgement. An
abnormal and clinically significant finding that would exclude the subject from
study participation is defined as an ECG tracing that is interpreted as, but
not limited to, any of the following:
• atrial fibrillation with rapid ventricular rate >120 bpm
• sustained or non-sustained ventricular tachycardia
• second degree AV block Mobitz type II and third-degree AV block (unless
pacemaker or defibrillator had been inserted)
• QTcF >=480 msec (at screening visit). Criterion not applicable for subjects
with pacemaker and with permanent atrial fibrillation.
16. Subjects with a significant neurological disease including transient
ischemic attack (TIA), stroke, seizure disorder or behavioural disturbances
that in investigator*s opinion, would place the patient at risk by
participating to the study.
17. Subjects who have a history or current evidence of clinically significant
and uncontrolled disease: e.g. hyperthyroidism, diabetes mellitus or other
endocrine disease; significant renal impairment; history of cerebrovascular,
gastrointestinal (e.g. active peptic ulcer); neurological disease; uncontrolled
haematological abnormalities; uncontrolled autoimmune disorders, or other
disease. Significance of renal impairment should be assessed in case of CKD
(Chronic Kidney Disease) presence in medical history. In this case, serum
creatinine level should be checked. Patients will not be allowed to the study
if eGFR value <60 mL/min/1.73 m2* (please see the note for reference to
creatinine level). Uncontrolled is defined as any disease or condition that
might, in the judgement of the investigator, place the patient at undue risk
through participation to the study or might compromise the interpretation of
the results if the disease/condition exacerbated during the study;
18. Subjects with clinically significant laboratory abnormalities indicating a
significant or unstable concomitant disease that might, in the judgement of the
investigator, place the patient at undue risk or potentially compromise the
results or interpretation of the study. In case some parameters are clinically
significant at screening, they can be retested once before randomization.
19. Subjects with moderate or severe hepatic impairment (Child-Pugh B or C).
20. Subjects with a known or suspected history of alcohol abuse and/or
substance/drug abuse within 12 months prior to screening visit.
21. Subjects having received any other investigational drug within the
preceding 30 days (60 days for biologics), or a longer and more appropriate
time as determined by the investigator (e.g., approximately five half-lives of
the previous investigational drug).
22.Subjects with severe immunological diseases (eg: HIV infection, multiple
sclerosis, lupus erythematosus, etc) confirmed in their medical history.
23.Subjects with current severe acute infectious diseases, or patients being
treated with immunosuppressive medicinal products (ie, methotrexate,
azathioprine, infliximab, etanercept, etc) 3 months prior to study entry and
during run-in period.