Conditions: COPD Chronic Obstructive Pulmonary Disease
Keywords: CHF 5259 Chronic Obstructive Pulmonary Disease (COPD) pMDI (pressurized metered dose inhaler) GLIMMER
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 733
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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.

Arms:
arm 1: CHF 5259 pMDI 6.25 μg, 1 inhalation twice daily (bid); (total daily dose \[TDD\] of CHF 5259 12.5 μg) arm 2: CHF 5259 pMDI 12.5 μg, 1 inhalation bid; (TDD of CHF 5259: 25 μg) arm 3: CHF 5259 pMDI 12.5 μg, 2 inhalations bid; (TDD of CHF 5259: 50 μg) arm 4: CHF 5259 pMDI 25 μg, 2 inhalations bid; (TDD of CHF 5259: 100 μg) arm 5: Placebo, 2 inhalations of CHF 5259 pMDI-matched Placebo bid; arm 6: Tiotropium (TIO) 18 μg, SPIRIVA® HandiHaler®, 2 inhalations once daily (od) of the content of 1 capsule; (TDD of TIO: 18 μg)

Interventions: intervention 1: CHF 5259 intervention 2: Placebo intervention 3: Tiotropium Bromide 18 µg Inhalation Capsule
Intervention descriptions: intervention 1: Dose Response: Test one of four different doses of CHF 5259 intervention 2: Placebo Control intervention 3: Active Control

Protocol document:
Prot_000.pdf: 
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Clinical Study Code: CCD-05993AA3-02
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IND No.: 133681
Date: 9JAN2018
CONFIDENTIAL 
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CCD-05993AA3-02
A 6-week, 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 (glycopyrronium bromide) 
in subjects with Chronic Obstructive Pulmonary Disease (COPD)
Version No.: 3.0
Date: 9JAN2018
The information contained in this document is confidential and will not be disclosed to others without written 
authorization from Chiesi Farmaceutici S.p.A., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy
CLINICAL STUDY PROTOCOL
IND No: 133681
ClinicalTrials.gov ID: NCT03084796


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GENERAL INFORMATION
SPONSOR:
Chiesi Farmaceutici S.p.A.* 
Via Palermo 26/A
43122 Parma - Italy
+ 39 0521 2791
*also reported as Chiesi throughout the text
CLINICAL PROJECT MANAGER:
SPONSOR MEDICAL EXPERT
(Clinical Research Physician)
, MD, FCCP
 (office)
 (mobile)
Readily available in case of medical questions
MONITORING CRO
CENTRAL LABORATORY OF 
ANALYSIS:
OTHER CENTRAL TECHNICAL 
LABORATORIES
Spirometry:
Holter:


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PROTOCOL OUTLINE 
Study title
A 6-week, 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 (glycopyrronium bromide) in subjects with 
Chronic Obstructive Pulmonary Disease (COPD)
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CHF 5259 pMDI (glycopyrronium bromide)
Center(s)
Multi-center, in approximately 120 sites
Indication 
Chronic Obstructive Pulmonary Disease (COPD)
Study design
Randomized, double-blind, placebo and active-controlled, parallel group, 
dose ranging study
Study phase
II
Objectives
Primary objective:
To evaluate the efficacy of CHF 5259 pMDI by comparison with 
placebo in terms of change from baseline in FEV1 AUC0-12h normalized  
by time at Week 6.
Secondary objective:
To evaluate the effect of CHF 5259 pMDI on other lung function 
parameters and clinical outcome measures.
To assess the safety and the tolerability of the study treatments.
Treatment duration
6 weeks
Test product 
dose/route/regimen  
CHF 5259 pMDI: glycopyrronium bromide administered via HFA-
pressurized metered dose inhaler (pMDI), available in 6.25µg per 
inhalation (GB 6.25), 12.5µg per inhalation (GB 12.5) and 25µg per 
inhalation (GB 25).
Treatment A: GB 12.5µg Total Daily Dose
GB 6.25µg per inhalation, 1 inhalation bid*
Treatment B: GB 25µg Total Daily Dose
GB 12.5µg per inhalation, 1 inhalation bid*
Treatment C: GB 50µg Total Daily Dose
GB 12.5µg per inhalation, 2 inhalations bid
Treatment D: GB 100µg Total Daily Dose
GB 25µg per inhalation, 2 inhalations bid
*An adequate number of inhalations from Placebo inhalers will be 
performed to maintain a double blind design.


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Reference product 
dose/route/regimen 
Matched Placebo for CHF 5259 pMDI
Treatment E: 
Matched placebo, 2 inhalations bid
SPIRIVA® HANDIHALER® (tiotropium bromide inhalation powder 
18µg). Inhalation Powder (capsules): each capsule contains 18µg 
tiotropium powder for use with HANDIHALER® device.
Treatment F:
Tiotropium bromide powder 18µg capsule, 2 inhalations qd
Number of subjects
A total of approximately 702 subjects will be randomized in order to reach 
a total of 594 completed and evaluable subjects, considering a non-
evaluable rate of 15%.
Study population
Subjects with moderate COPD
Inclusion/exclusion criteria
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible for 
enrollment into the study:
1. Male or female subjects aged ≥ 40 years who have signed an Informed 
Consent Form prior to initiation of any study-related procedure;
2. 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;
3. 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);
4. A post-bronchodilator FEV1 ≥40% and <80% of the predicted normal 
value (measured 30 to 45 minutes after administration of 84µg 
ipratropium pMDI) and,
a.
a post-bronchodilator FEV1/FVC < 0.7 at screening and,
b.
a demonstrated partial reversibility to ipratropium defined as 
ΔFEV1 ≥ 5% over baseline 30-45 minutes after inhaling 4 puffs of 
ipratropium (21µg/actuation). Note: In case the reversibility 
threshold is not met at screening, the test can be performed once 
before randomization; 
5. Subjects under regular COPD therapy for at least 2 months prior to 
screening with a single or dual LABD with or without an ICS;
a.
inhaled LAMA
b.  inhaled ICS/LABA (fixed or free combination)
c.  inhaled ICS + LAMA
d.  inhaled LABA
e.  inhaled LABA/LAMA (fixed or free combination)
f.  inhaled ICS/LABA/LAMA (fixed or free combination)
6. Symptomatic subjects at screening with a CAT score ≥10. This 


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criterion must be confirmed at randomization (Visit 2);
7. Symptomatic subjects with a BDI focal score ≤ 10.  This criterion must 
be confirmed at randomization (Visit 2);
8. A cooperative attitude and ability to demonstrate correct use of the 
pMDI inhalers and e-diary. This criterion must be confirmed at 
randomization (Visit 2).
If at Visit 1 the inclusion criterion #4 (reversibility) is not met, the subject 
may return to repeat the procedure once before randomization.  
Inclusion criteria # 6-8 should be re-checked at the randomization visit 
(Visit 2). 
Exclusion Criteria:
If a subject meets any of the following criteria, he/she will NOT be enrolled 
into the study:
1. Pregnant (as evident by a positive urine hCG or serum β-hCG test) or 
lactating women and all women physiologically capable of becoming 
pregnant (i.e. women of childbearing potential) UNLESS they are 
willing to use highly effective birth control methods such as:
a. Placement of an intrauterine device (IUD) or intrauterine releasing 
system (IUS);
b. Oral, intravaginal, transdermal combined estrogen and progesterone 
containing hormonal contraception or oral, injectable, implantable 
progestogen only hormonal contraception;
c. Bilateral tubal occlusion;
d. Partner vasectomy (provided that partner is the sole sexual partner 
of the WOCBP trial participant and that the vasectomized partner 
has received medical assessment of the surgical success);
e. Sexual abstinence defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 
treatments.
Pregnancy testing will be carried out during the course of the study in 
all women of childbearing potential: serum pregnancy test will be 
performed at screening, at Visit 4 and at the early termination visit; 
urinary pregnancy test will be performed at screening, Visit 2 and Visit 
3.
Women of non-childbearing potential defined as physiologically 
incapable of becoming pregnant: post-menopausal (defined as no 
menses for 12 months without an alternative medical cause) or 
permanently sterile (hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy) are eligible.  If indicated, as per investigator’s 
request, post-menopausal status may be confirmed by follicle-
stimulating hormone levels (according to local laboratory ranges) in 
women not using hormonal contraception or hormonal replacement 
therapy.
2. Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as 
described in GINA Report 2016, history of allergic rhinitis or atopy 
which may raise contra-indications or impact the efficacy of the study 


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treatment according to Investigator’s judgment;
3. COPD Exacerbations: 
a. 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/intravenous corticosteroid or antibiotic (whichever comes 
last), and ≤ 3 months of intramuscular depot corticosteroids;
b. A Moderate or Severe COPD exacerbation during the run-in 
period; 
4. Use of antibiotics for a lower respiratory tract infection (e.g. 
pneumonia) in the 4 weeks prior to screening or during run-in;
5. Subjects treated with non-cardio-selective β-blockers in the month 
preceding screening or during the run-in period;
6. Not applicable;
7. Subjects requiring long term (at least 12 hours daily) oxygen therapy 
for chronic hypoxemia;
8. Known respiratory disorders other than COPD which may impact the 
efficacy of the study treatment according to the Investigator’s 
judgment. This can include but is not limited to α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, 
lung fibrosis, pulmonary hypertension and interstitial lung disease;
9. Subjects who have a clinically significant cardiovascular condition such 
as, but not limited to, unstable ischemic heart disease, NYHA Class 
III/IV heart failure, acute ischemic heart disease within one year prior 
to study entry, known history of atrial fibrillation or history of 
sustained and non-sustained cardiac arrhythmias diagnosed within the 
last 6 months prior to screening, not controlled with a rate control 
strategy;
10.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 judgment;
11.Subjects whose 12-lead ECG shows Fridericia corrected QT interval 
(QTcF) >450 ms for males or QTcF >470 ms for females at screening 
or randomization visit (criterion not applicable for subjects with a 
pacemaker or permanent atrial fibrillation);
12.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;
13.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 judgment;
14.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 judgment;
15.Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at 
screening;
16.Use of potent cytochrome P450 2D6 and 3A4 inhibitors (e.g. ritonavir, 


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ketoconazole, itraconazole) and inducers within 4 weeks prior to 
screening;
17.Unstable 
or 
uncontrolled 
concurrent 
disease: 
e.g. 
fever, 
hyperthyroidism, diabetes mellitus or other endocrine disease; 
gastrointestinal disease (e.g. active peptic ulcer); neurological disease; 
hematological disease; autoimmune disorders, or other which may 
impact the feasibility of the results of the study according to 
Investigator’s judgment;
18.History of alcohol abuse and/or substance/drug abuse within 12 months 
prior to screening;
19.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;
20.Subjects who are mentally or legally incapacitated, or subjects 
accommodated in an establishment as a result of an official or judicial 
order; 
21.Subjects who have undergone major surgery in the 3 months prior to 
the screening visit or have a planned surgery during the trial.
22.Subjects using marijuana daily or as needed;
Exclusion criteria # 1, 3, 4, 5, 10 and 11 should be re-checked at the 
randomization visit (V2).  
Study plan
The details of the assessments that will be performed during the study are 
summarized in the study flow diagram in table 1.
After a 2-week run-in period, subjects will be randomized to one of the 6 
treatment arms and will enter a 6-week treatment period.  The study will 
last approximately 10 weeks for each subject and a total of 5 clinic visits 
will be performed during the study (see the flow chart below)
A pre-screening visit (Visit 0) will be carried out in order to fully 
explain the study to potential eligible subjects, to obtain their written 
informed consent and to instruct them on screening visit procedures 
(such as medication restrictions).
A screening visit (Visit 1) not more than 7 days after Visit 0 will help 
establish the eligibility of subjects for inclusion in the study (including 
routine hematology and blood chemistry, vital signs, medical history, 
weight and height, smoking status, serum and urine pregnancy tests for 
women of childbearing potential, physical examination, 12-lead ECG, 
CAT (COPD Assessment Test) and BDI assessment, spirometry testing 
pre & post-BD, and training on the use of inhalers). Concomitant 
Medication and Adverse Events will be assessed. Dispensing of 
subject’s diary will be done.  
This visit will be followed by a 14±2 days run-in period. 
Treatments that are disallowed by the protocol are to be discontinued at 
Visit 1. If the subject’s treatment includes an inhaled corticosteroid in 
association 
with 
a 
long-acting 
β2-agonist 
or 
a 
long-acting 
anticholinergic, these treatments will be discontinued and the ICS will 


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be switched to an equivalent daily dose of Beclomethasone 
Dipropionate (QVAR® Inhalation Aerosol 80µg/actuation) and this 
treatment regimen should remain stable for the entire run-in period and 
the remainder of the study. Subjects will receive rescue medication 
(albuterol HFA 90µg/actuation) for the treatment or prevention of 
bronchospasm, with instructions for “on demand” (prn) use for the 
entire study period.  
At randomization visit (Visit 2), inclusion/exclusion criteria, adverse 
events and concomitant medications will be reviewed. Eligibility 
recheck will be completed. Smoking status will be checked,  urine 
pregnancy test will be collected if appropriate for women of 
childbearing potential.  24-hour digital ECG Holter device, that would 
have been placed the day before the visit, will be kept on. Training on 
the use of inhalers will be conducted.  Pre-dose vital signs, 12-lead 
ECG, and spirometry testing [FEV1, FVC, IC (slow vital capacity 
maneuver)] will be performed. The BDI and CAT questionnaires will 
be assessed. Subject’s e-diary will be checked for daily data 
transmission. Eligible subjects will then be randomized to one of the 
treatment groups and will receive the 1st dose of study drug under 
medical supervision. The subjects will then undergo a 12-hour post-
dose serial spirometry assessments and 24-hour digital ECG Holter 
Monitoring. Lung function (FEV1, FVC) will be evaluated and 
recorded at the following time points: T-45 and T-15 min before the 1st 
dose of study drug and at 15, 30, 45 min and 1, 2, 3, 4, 6, 8, 10, 11.5 
and 12h after the 1st dose of study drug. Inspiratory Capacity will be 
measured at T-45 min before the 1st dose of study drug.  Vital signs 
(SBP, DBP) will also be assessed before and at 30 min, 1.5, 3.5, 7 and 
11h after the 1st dose of study drug. A 12-lead ECG will be obtained 
before and at 1.5h after the 1st dose of study drug. After the last 
assessment the subjects will then leave the clinical center and will be 
instructed to return the next day to remove the Holter monitor leads 
(24h post 1st [morning] dose of study drug), and in 3 weeks’ time for 
Visit 3. Study drug will be dispensed. Subject e- diary will be re-
dispensed.
At Week 3 (Visit 3), subjects will undergo pre-dose vital signs 
assessment and 12-lead ECG. Pre-dose spirometry testing (trough 
FEV1, FVC, IC) will be performed and TDI will be assessed. Smoking 
status, concomitant medication, urine pregnancy test for women of 
childbearing potential and adverse events will be assessed. Study drug 
will be returned and accountability will be performed. Study drug will 
be dispensed. Subject’s e-diary will be checked for daily data 
transmission. The subject will be instructed to return to the clinical 
center in 3 weeks’ time.
At Week 6 (Visit 4), subjects will come to the clinical center and will 
have the 24-hour digital ECG Holter device, which would have been 
placed the day before the visit, collected.  Physical examination, 
smoking status, concomitant medications, adverse events, serum 
pregnancy test will be performed for women of childbearing potential.  
Routine hematology and blood chemistry will be performed, as well as 
pre-dose TDI questionnaire, vital signs, 12-lead ECG and spirometry 
testing [FEV1, FVC, IC]. The subject will receive the last dose of study 


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drug under medical supervision. The subject will then undergo a 12 
hours post-dose serial spirometry assessment. Post-dose lung function 
(FEV1, FVC) will be evaluated and recorded at the following time 
points: 15, 30, 45 min and 1, 2, 3, 4, 6, 8, 10, 11.5 and 12h after study 
drug intake. Vital Signs  (DBP/SBP) will be measured at 30 mins, 1.5, 
3.5, 7 and 11h post-dose.  A 12-lead ECG will also be checked at 1.5h 
post-dose. Study drug will be returned and accountability will be 
performed. Subject’s e-diary will be returned and checked for daily 
data transmission. After the last, a follow-up phone call will be 
scheduled with the subject.
A safety follow-up phone call (Visit 5) will be performed by the 
investigator or designated staff no later than 1 week after the final visit 
(Visit 4) or Early Termination Visit to check the status of unresolved 
AEs and to record any new AEs that may have occurred after Visit 4, as 
well as related concomitant medications.


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Most relevant allowed 
concomitant treatments
Permitted concomitant medications (from screening visit until the last 
study visit)
1.
Inhaled corticosteroids are permitted in subjects already receiving 
inhaled corticosteroid at a low-to-medium daily dose in association 
with 
a 
long-acting 
β2-agonist 
(LABA) 
or 
a 
long-acting 
anticholinergic (LAMA) for at least 2 months prior to screening. An 
equipotent beclomethasone dipropionate (QVAR®) daily dose will be 
prescribed and will remain constant throughout the study.
ICS*
Low daily 
dose
Medium 
daily dose
BDP extrafine (HFA pMDI) QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA pMDI)
80-160µg
>160-320µg
Flunisolide (HFA pMDI)
160-320µg
>320-640µg
Fluticasone Propionate (HFA pMDI/DPI)
100-250µg
> 250-500µg
Fluticasone Furoate (DPI)
100µg
n.a.
Mometasone Furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA Report, 2016).
Note: ICS monotherapy is not indicated for the treatment of 
COPD.
ICS/LABA for COPD*
ICS/LABA Daily 
Dose
QVAR® 
recommended 
Daily Dose
ADVAIR® DISKUS® 250/50
250/50µg bid
160µg bid
BREO® ELLIPTA® 100/25
100/25µg qd
160µg bid
DULERA® 100/5
200/10µg bid
160µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid
* Doses of these ICS/LABAs are based on FDA-approved US labels 
for COPD, except for DULERA®, where doses are suggested 
based on published clinical trials in COPD. For off-label doses of 
ICS/LABAs please contact the medical monitor to discuss daily 
equivalent of QVAR®.
2.
Short-acting β2-agonist (albuterol) as rescue medication. A minimum 
period of 6 hours should elapse between the use of rescue medication 
and the spirometric measurements.
3.
Mucolytics (e.g. N-acetylcystein) if taken prior to study entry and 
maintained constant during the study period.
4.
Intranasal corticosteroids and oral, intranasal, or ocular antihistamines 
at FDA-approved doses for the treatment of allergy symptoms will be 
allowed during the study period.
5.
Cardioselective β1-blockers if taken for at least 2 months before 
screening and to be maintained at a constant dose during the study.
In case of a concomitant disease, appropriate treatment that, according to 
the investigator, does not interfere with the study evaluation parameters is 
allowed and if it does not qualify under the section “Non-Permitted 
Concomitant Medications”. All concomitant medications should be noted 


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in the relevant section of the Case Report Form.
In case of exacerbations, subjects will be treated according to the standard 
clinical practice. This will constitute a reason for withdrawal from the 
study.
Most relevant forbidden 
concomitant treatments
Non-permitted concomitant medications (from screening visit until the 
last study visit)
The following medications are not permitted during the study:
1.
Inhaled long acting β2-agonists.
2.
Inhaled fixed combination of corticosteroids and long-acting 
β2-agonists (e.g. salmeterol plus fluticasone or formoterol plus 
budesonide). 
3.
Inhaled short acting β2-agonists (other than study “rescue” 
medication).
4.
Inhaled fixed combinations of a short-acting β2-agonist (SABA) and a 
short-acting anticholinergic medication (SAMA).
5.
Inhaled short-acting anticholinergics. 
6.
Inhaled long-acting anticholinergics.
7.
Oral/IV/IM corticosteroids.
8.
Nebulized bronchodilators or corticosteroids.
9.
Inhaled corticosteroids other than study background ICS.
10. Non-cardioselective β-blockers.
11. PDE4 inhibitors (e.g. roflumilast).
12. Leukotriene modifiers.
13. Xanthine derivatives (e.g. theophylline).
14. Any drug with known or possible risk of Torsades de Pointes (TdP) or  
QT interval prolongation (e.g. quinidine, procainamide, amiodarone).
Prior to screening spirometry (Visit 1), the following washout periods 
must be respected:
Caffeinated substances
6 hours
Inhaled and/or nebulized short-acting β2-agonists:
6 hours
Inhaled 
and/or 
nebulized 
short-acting 
muscarinic 
antagonists: 
8 hours
Inhaled combination of short-acting β2-agonists /short-
acting muscarinic antagonists:
8 hours
Inhaled corticosteroids (bid):
24 hours
Inhaled long-acting β2-agonists (bid):
24 hours
Inhaled fixed combinations of ICS/LABAs (bid):
24 hours
Inhaled corticosteroids (qd):                                               
48 hours
Inhaled "ultra-long-acting" β2-agonists (qd):
48 hours
Inhaled fixed combinations of ICS/LABAs (qd):   
48 hours


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Oral leukotriene modifiers:                                                    72 hours
Inhaled LAMA:                                                           
7 days
Xanthine derivatives: 
7 days
PDE4 inhibitors:                                                                
1 month
Oral or parenteral (i.v.) corticosteroid:
1 month
Intramuscular depot corticosteroid:
3 months
Prior to other visits with spirometry (V2  V4) , the following washout 
periods must be respected:
Inhaled short-acting β2-agonists:
6 hours
Caffeinated substances:
6 hours
Efficacy variables
(and/or pharmacokinetics 
variables)
Primary efficacy variable
Change from baseline in FEV1 AUC0-12h normalized by time at Week 6.
Secondary efficacy variables
Change from baseline in FEV1 AUC0-12h normalized by time at Day 1
Change from baseline in FEV1 AUC0-4h normalized by time and in 
FEV1 peak0-4h  at Day 1 and Week 6
Change from baseline in FVC AUC0-12h normalized by time, in FVC 
AUC0-4h normalized by time and in FVC peak0-4h  at Day 1 and Week 6
Time to onset of action (change from baseline in post-dose FEV1 ≥ 100 
mL) at Day 1
Change from baseline in pre-dose morning FEV1 (average of pre-dose 
FEV1 measurements) at Week 3 and Week 6
Change from baseline in pre-dose morning IC at Week 3 and Week 6
TDI focal score at Week 3 and Week 6
TDI response (TDI focal score ≥ 1) at Week 3 and Week 6
Change from baseline in percentage of rescue medication-free days 
during inter-visit periods and entire treatment period
Change from baseline in average use of rescue medication (number of 
puffs/day) during inter-visit periods and entire treatment period
Change from baseline in average E-RS total score and domain scores 
during inter-visit periods and entire treatment period
Safety variables
Adverse Events (AEs) and Adverse Drug Reactions (ADRs)
Vital signs (systolic and diastolic blood pressure) 
24-hour digital Holter ECG parameters (HR, QTcF, QRS, PR)
24-hour HR average, minimum and maximum and hourly average HR
24-hour digital Holter ECG abnormal findings 
Standard blood chemistry and hematology
Sample size calculation
The sample size has been calculated to evaluate the superiority of CHF 
5259 pMDI at different doses over placebo in terms of change from 
baseline in FEV1 AUC0-12h normalized by time at Week 6.
A total of 594 evaluable subjects (99 per group) will provide 80% power to 
detect a mean difference of 120 mL between each dose of CHF 5259 pMDI 
and placebo at a two-sided significance level of 0.0125 (since 4 dose levels 
will be tested, the Bonferroni adjustment has been taken into account: 
0.0125 = 0.05/4), assuming a standard deviation of 250 mL.
Since four dose levels will be tested, the Edwards and Berry method will be 
used to control the family-wise Type I error rate at the 0.05 (two-sided) 
level. In the sample size calculation, the Bonferroni adjustment of the 


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significance level has been taken into account (0.0125 = 0.05/4). This will 
ensure the required power for each test, since the Edwards and Berry 
method is uniformly more powerful than the Bonferroni procedure.
Considering a non-evaluable rate of 15%, a total of approximately 702 
subjects (117 per group) will be randomized.
Statistical methods
Primary efficacy variable
Change from baseline in FEV1 AUC0-12h normalized by time will be 
analyzed using a linear mixed model for repeated measurements including 
treatment, visit, treatment by visit interaction, US regions and smoking 
status at screening as fixed effects, and the baseline value (average of the 
pre-dose FEV1 measurements on Day 1) and baseline by visit interaction as 
covariates. An unstructured covariance matrix will be assumed. 
The adjusted means in each treatment group, the adjusted mean difference 
between treatments and their 95% Confidence Intervals (CIs) will be 
estimated by the model. The CIs and the p-values of the comparisons 
between each dose of CHF 5259 pMDI and placebo at Week 6 will be 
adjusted for multiplicity. The adjustment will be based on the parametric 
simulation method by Edwards and Berry. At each dose level, the 
superiority of CHF 5259 pMDI will be demonstrated by a statistically 
significant difference (adjusted p-value < 0.05) favouring CHF 5259 pMDI.
All the other comparisons between treatments will be performed as 
secondary efficacy analyses with no multiplicity adjustment.
Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy 
analyses.

For change from baseline in FEV1 AUC0-12h normalized by time at Day 
1, the adjusted means in each treatment group and the adjusted mean 
differences between treatments at Day 1 will be estimated with their 
95% CIs and p-values by the same model used for the primary efficacy 
analysis.

Change from baseline in FEV1 AUC0-4h normalized by time and in 
FEV1 peak0-4h at Day 1 and Week 6 and change from baseline in pre-
dose morning FEV1 at Week 3 and Week 6 will be analyzed using the 
same model as for the primary efficacy variable.

Change from baseline in FVC AUC0-12h normalized by time, in FVC 
AUC0-4h normalized by time and in FVC peak0-4h at Day 1 and Week 6 
will be analyzed using a similar model as the one used for the primary 
efficacy analysis.

Time to onset of action (i.e., change from baseline in post-dose FEV1 ≥ 
100 mL) at Day 1 will be analyzed using a Cox proportional hazard 
model including treatment, US regions and smoking status at screening 
as fixed effects, and baseline (average of the pre-dose FEV1 
measurements on Day 1) as covariate. A Kaplan-Meier plot will be 
presented. 

Change from baseline in pre-dose morning IC at Week 3 and Week 6 
will be analysed using a similar model as the one used for the primary 
efficacy analysis. 

TDI focal score at Week 3 and Week 6 will be analyzed using a 


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similar model as the one used for the primary efficacy analysis.

TDI response at Week 3 and Week 6 will be analyzed using a logistic 
regression model including treatment, US regions and smoking status 
at screening as fixed effects and baseline (BDI [Baseline Dyspnea 
Index] focal score assessed on Day 1) as a covariate.

Change from baseline to each inter-visit period in percentage of rescue 
medication-free days, in average use of rescue medication and in 
average E-RS total score and domain scores will be analyzed using a 
similar model as the one used for the primary efficacy analysis. The 
inter-visit period will be considered instead of visit in the model. 
Comparison between treatments over the entire treatment period will 
also be derived from this model.
Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake 
will be classified as Treatment Emergent Adverse Events (TEAEs). Any 
adverse event started after the informed consent signature and before the 
time of first study drug intake will be classified as pre-treatment adverse 
event. Pre-treatment adverse events will be listed only.
The number of TEAEs and the number and percentage of subjects who 
experienced at least one TEAE will be presented by treatment for all AEs, 
ADRs, serious AEs, serious ADRs, severe AEs, AEs leading to study 
discontinuation and AEs leading to death. Summaries will be presented 
overall and by system organ class and preferred term based on the 
MedDRA dictionary. 
Vital signs
Vital signs (systolic and diastolic blood pressure) and their changes from 
baseline (pre-dose on Day 1) and from pre-dose on Week 6 will be 
summarized by treatment using descriptive statistics and the 95% CI of the 
mean.
Holter
ECG parameters extracted from Holter (HR, QTcF, QRS and PR) and their 
changes from baseline (time-matched on day before V2) will be 
summarized for all timepoints on Day 1 and Week 6 by treatment using 
descriptive statistics and the CI of the mean (95% CI for absolute values 
and 90% CI for the changes from baseline). 
Change from baseline (time-matched on day before V2) in ECG parameters 
extracted from Holter (HR, QTcF, QRS and PR) will be analyzed using a 
linear mixed model for repeated measurements including treatment, 
timepoint, treatment by timepoint interaction, US regions and smoking 
status at screening as fixed effects, and the baseline value (time-matched on 
day before V2), baseline by timepoint interaction and time-averaged 
baseline as covariates. An unstructured covariance matrix will be assumed. 
The number and the percentage of subjects with a
o QTcF >450 ms (males only), >470 ms (females only) or >480 ms 
(males only) and >500 ms (males and females)


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o change from baseline (time-matched on day before V2) in QTcF >30 
ms and >60 ms
at each post-dose timepoint and at any post-dose timepoint will be 
presented by treatment group.
24-hour HR average, minimum and maximum extracted from the Holter 
and their changes from baseline (day before V2) will be summarized by 
treatment using descriptive statistics and the 95% CI of the mean. 
Change from baseline (day before V2) in 24-hour HR average, minimum 
and maximum extracted from Holter will be analyzed using a linear mixed 
model for repeated measurements including treatment, visit, treatment by 
visit interaction, US regions and smoking status at screening as fixed 
effects, and the baseline value (day before V2) and baseline by visit 
interaction as covariates. An unstructured covariance matrix will be 
assumed. 
Hourly average HR will be summarized by treatment using descriptive 
statistics and the 95% CI of the mean. 
The number and the percentage of subjects with abnormal findings 
(including supraventricular arrhythmias, ventricular arrhythmias and non-
sustained ventricular tachycardia) in the 24-hour Holter will be 
summarized by treatment group.
Laboratory parameters
Shift tables from screening to the end of treatment, based on normal 
ranges, will be presented by treatment group for the laboratory parameters.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADR
Adverse Drug Reaction
AE
Adverse Event
AF
Atrial Fibrillation
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area Under the Curve
BD
Bronchodilator
BDI
Baseline Dyspnea Index
BDP
Beclomethasone dipropionate
bid
Bis in die (twice a day)
BTPS
Body Temperature and ambient Pressure Saturated with water vapor
BUN
Blood Urea Nitrogen 
CAT
COPD Assessment Test
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
(e-) CRF
(Electronic) Case Report Form
CV
Cardiovascular
(e-) Diary
(Electronic) Diary
CRO
Contract Research Organization
DBP
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
ECG
ElectroCardioGram
E-RS
EXACT (Exacerbations of Chronic Pulmonary Disease Tool) – Respiratory 
Symptoms
FEF
Forced Expiratory Flow
FEV1
Forced Expiratory Volume in the 1st second 
FF
Formoterol Fumarate
FPFV
First Patient First Visit
FVC
Forced Vital Capacity
GB
Glycopyrronium Bromide
GCP
Good Clinical Practices
GINA 
Global INitiative for Asthma
GMP
Good Manufacturing Practices
GOLD
Global Initiative for Chronic Obstructive Lung Disease
h
hour
hCG
Human Chorionic Gonadotropin hormone
HR
Heart Rate
HFA
Hydrofluoroalkane
IB
Investigator Brochure
IC
Inspiratory Capacity
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid
IRT
Interactive Response Technology
ISO
International Organization for Standardization
ITT
Intention to Treat
IU (D or S)
Intra Uterine (Device or System)
L
Liter


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LABA
Long-Acting β2-adrenergic receptor Agonist
LABD
Long-Acting Bronchodilator
LAMA
Long-Acting Muscarinic Antagonist
LDH
Lactate dehydrogenase
LLN
Lower Limit of Normal
LPLV
Last Patient Last Visit
µg
Microgram
MAOI
Monoamine oxidase inhibitor
MAR
Missing at Random
MCID
Minimal Clinically Important Difference
MedDRA
Medical Dictionary for Regulatory Activities
min
minutes
mL
Milliliters
mMRC
Modified Medical Research Council
NYHA
New York Heart Association
PEF
Peak Expiratory Flow
PIL
Patient Information Leaflet
pMDI
Pressurized Metered Dose Inhaler
PP
Per-Protocol
PR
Time Interval from the beginning of the upslope of the P wave to the beginning 
of the QRS wave in the ECG
prn
Pro re nata (as-needed)
PRO
Patient-Reported Outcome
Q
Quaque (every so-,any hours)
qd
Quaque die (once a day)
QRS
Time Interval from the end of the PR interval to the end of the S wave in the 
ECG
QTc
Time interval between the start of the Q wave and the end of the T wave in the 
ECG (corrected for HR)
QTcF
QT interval corrected for HR using Fridericia’s formula
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
SABA
Short-Acting Beta Agonist
SABD
Short-Acting Bronchodilators
SADR
Serious Adverse Drug Reaction
SAE
Serious Adverse Event
SAMA
Short-Acting Muscarinic Antagonist
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
sGAW
Specific Airway Conductance
SGRQ
St. George’s Respiratory Questionnaire
SUSAR
Suspected Unexpected Serious Adverse Reaction
TDD
Total Daily Dose
TdP
Torsades de Pointes
TEAE
Treatment Emergent Adverse Event
TDI
Treatment Dyspnea Index
ULN
Upper Limit of Normal
VC (SVC / FVC)
Vital Capacity (Slow /Forced)
WHO
World Health Organization


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WOCBP
Woman of Childbearing Potential


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CONTENTS
GENERAL INFORMATION ....................................................................................................................................................2
PROTOCOL OUTLINE ...........................................................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................................................16
CONTENTS.........................................................................................................................................................................19
1. BACKGROUND INFORMATION AND STUDY RATIONALE...............................................................................................22
2. STUDY OBJECTIVES........................................................................................................................................................26
2.1 Primary Objective(s)....................................................................................................................................................26
2.2 Secondary Objective(s) ...............................................................................................................................................27
3. STUDY DESIGN...............................................................................................................................................................27
4. SUBJECT SELECTION CRITERIA.......................................................................................................................................27
4.1 Subject Recruitment ...................................................................................................................................................27
4.2 Inclusion Criteria .........................................................................................................................................................28
4.3 Exclusion Criteria.........................................................................................................................................................28
4.4 Subject Withdrawals ...................................................................................................................................................30
5. CONCOMITANT MEDICATIONS .....................................................................................................................................31
5.1 Permitted Concomitant Medications..........................................................................................................................31
5.2 Non-Permitted Concomitant Medications..................................................................................................................32
6. TREATMENT(S)..............................................................................................................................................................33
6.1 Appearance and Content ............................................................................................................................................33
6.2 Dosage and Administration.........................................................................................................................................34
6.2.1 Selection of doses in the study ................................................................................................................................34
6.2.2 Dosage......................................................................................................................................................................36
6.2.3 Administration .........................................................................................................................................................37
6.2.3.1 Background ICS Medication Kit for Run-in and Treatment Periods (from Visit 1 to Visit 4):.................................37
6.2.4 Subject Training .......................................................................................................................................................39
6.3 Packaging ....................................................................................................................................................................39
6.3.1 Training Kits..............................................................................................................................................................39
6.3.2 Background medication kit for run-in and treatment period ..................................................................................39
6.3.3 Treatment period.....................................................................................................................................................40
6.3.4 Rescue medication...................................................................................................................................................40
6.4 Labeling.......................................................................................................................................................................40
6.5 Treatment Allocation ..................................................................................................................................................40
6.6 Treatment Code ..........................................................................................................................................................40
6.7 Treatment Compliance ...............................................................................................................................................41
6.8 Drug Storage ...............................................................................................................................................................41
6.9 Drug Accountability.....................................................................................................................................................43
6.10 Provision of Additional Care......................................................................................................................................43
7. STUDY PLAN ..................................................................................................................................................................43
7.1 Study Schedule............................................................................................................................................................43
7.1.1 Visit 0 (Pre-screening visit).......................................................................................................................................45
7.1.2 Visit 1 (Screening visit /Week -2) .............................................................................................................................45
7.1.3 Visit 2 (Randomization/ Start of Treatment Period /Week 0)..................................................................................47
7.1.4 Visit 3 (Week 3 of Treatment Period) ......................................................................................................................50
7.1.5 Visit 4 (Week 6 of Treatment Period) ......................................................................................................................51
7.1.6 Follow-up Phone Call (Visit 5) ..................................................................................................................................53
7.1.7 Early Termination Visit.............................................................................................................................................53
7.2 Investigations (by order of conduct):..........................................................................................................................54
7.2.1 BDI Questionnaire....................................................................................................................................................54
7.2.2 TDI Questionnaire ....................................................................................................................................................54
7.2.3 COPD Assessment Test (CAT™)................................................................................................................................54
7.2.4 Vital Signs.................................................................................................................................................................55


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7.2.5 Physical Exam and assessment of oral candidiasis...................................................................................................55
7.2.6 12-lead ECG..............................................................................................................................................................55
7.2.7 24-hour digital ECG Holter Recorder........................................................................................................................56
7.2.8 Pulmonary Function Test .........................................................................................................................................57
7.2.9 Blood Hematology and Chemistry ...........................................................................................................................59
7.2.10 Urine Pregnancy Test.............................................................................................................................................60
7.2.11 Daily Subject Diary .................................................................................................................................................60
7.2.12 Handling of COPD Exacerbations: ..........................................................................................................................60
8. EFFICACY ASSESSMENTS ...............................................................................................................................................61
9. SAFETY ASSESSMENTS...................................................................................................................................................61
10. ADVERSE EVENT REPORTING ......................................................................................................................................61
10.1 Definitions.................................................................................................................................................................61
10.2 Expectedness ............................................................................................................................................................63
10.3 Intensity of Adverse Event ........................................................................................................................................63
10.4 Causality Assessment................................................................................................................................................64
10.5 Action taken with the study drug due to the AE.......................................................................................................64
10.6 Other actions taken...................................................................................................................................................64
10.7 Outcome ...................................................................................................................................................................64
10.8 Recording Adverse Events.........................................................................................................................................65
10.9 Reporting Serious Adverse Events to Chiesi..............................................................................................................65
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB ..........................................66
10.11 General Notes .........................................................................................................................................................66
11. DATA MANAGEMENT..................................................................................................................................................67
12. STATISTICAL METHODS...............................................................................................................................................67
12.1 Sample Size ...............................................................................................................................................................67
12.2 Populations for Analysis............................................................................................................................................68
12.3 Statistical Analysis.....................................................................................................................................................68
12.3.1 Descriptive Statistics ..............................................................................................................................................68
12.3.2 Missing data...........................................................................................................................................................69
12.3.3 Subject demographics and baseline characteristics ..............................................................................................70
12.3.4 Primary efficacy variables ......................................................................................................................................70
12.3.5 Secondary efficacy variables..................................................................................................................................70
12.3.6 Safety variables......................................................................................................................................................71
12.3.7 Interim analysis......................................................................................................................................................72
13. ETHICS AND RESPONSIBILITY ......................................................................................................................................72
14. INFORMED CONSENT..................................................................................................................................................72
15. INSTUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITTEE .........................................................................73
16. DIRECT ACCESS TO SOURCE DOCUMENTS/DATA........................................................................................................73
17. STUDY MONITORING ..................................................................................................................................................73
18. QUALITY ASSURANCE..................................................................................................................................................74
19. INSURANCE AND INDEMNITY......................................................................................................................................74
20. CONFIDENTIALITY........................................................................................................................................................74
21. PREMATURE TERMINATION OF THE STUDY................................................................................................................74
22. CLINICAL STUDY REPORT.............................................................................................................................................74
23. RECORD RETENTION ...................................................................................................................................................74
24. PUBLICATION OF RESULTS ..........................................................................................................................................75
25. REFERENCES................................................................................................................................................................75
APPENDIX I........................................................................................................................................................................81
APPENDIX II.......................................................................................................................................................................82


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APPENDICES
APPENDIX I
Approval of Clinical Study Protocol by the Principal Investigator
APPENDIX II Minimum list of Source Data Required


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1. BACKGROUND INFORMATION AND STUDY RATIONALE
Chronic Obstructive Pulmonary Disease (COPD) currently ranks as the 4th leading cause of 
death in the world, and is expected to be in 3rd place by 2020.[1] COPD is both a preventable and 
treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that 
is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious 
particles or gases (e.g. cigarette smoke, biodiesel fumes).  A mixture of lung abnormalities are 
characteristic of COPD, including small airway and parenchymal disease (obstructive bronchiolitis; 
emphysema), with variable contributions in any given subject.[2]
The NHANES III national survey estimated the U.S. prevalence of COPD to be 10.2% to 20.9% 
based on whether pre- or post-bronchodilator values were used and which diagnostic criterion 
(fixed ratio or lower limit of normal {LLN}) was applied.[3] COPD most often occurs in people 45 
years of age and older who have a history of smoking (current or former smokers). While not 
everybody who smokes gets COPD, approximately 80-90% of the individuals who have COPD 
have smoked.[4]
Smoking cessation can have the greatest influence on stopping the progression of COPD, as well as 
increasing survival and reducing morbidity.[5]  However, long-term quit success rate rarely exceed 
25%.[2][6]
Existing pharmacologic therapy is used to improve airflow, symptoms, exercise capacity, health 
status, and reduce the frequency and severity of exacerbations in stable COPD. To date, there is no 
conclusive evidence that any available pharmacotherapy for COPD modifies the long-term decline 
in lung function.  The main stay of pharmacotherapies for stable COPD are delivered via inhalation 
route, and consist of the following:

Short acting or long-acting bronchodilators (SABD; LABD):
o
Short acting and long-acting β2-adrenergic agonists (SABA; LABA) improve 
spirometric measures including FEV1 by altering airway smooth muscle tone, and 
tend to reduce dynamic hyperinflation (Residual Lung Volume) at rest and during 
exercise, and improve exercise performance.

Adverse events include sinus tachycardia, rhythm disturbances, and 
hypokalemia. 

Despite prior concerns related to the use of LABAs in asthma, no association 
between the use of this class and loss of lung function and increased 
mortality has been reported in COPD.[7][8][9] 
o
Short-acting and long-acting antimuscarinics (SAMA; LAMA). These drugs act 
mainly by blocking the bronchoconstrictor effects of acetylcholine on airway 
muscarinic receptor M3. Tiotropium is a LAMA that has been shown to improve 
lung 
function, 
symptoms, 
health 
status,[10] 
effectiveness 
of 
pulmonary 
rehabilitation,[11][12] and to reduce exacerbations and related hospitalizations[13] 
compared to placebo. Studies have shown that the effect of glycopyrronium, another 
LAMA, versus placebo is similar to that of tiotropium in reducing dyspnea and the 
risk of exacerbations, as well as improving lung function, exercise tolerance, and 
health status in subjects with COPD.[14][15][16][17] 


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
Adverse events of this class of medications are mainly due to their 
anticholinergic activities, and include dry mouth, constipation, urinary 
retention and increased intraocular pressure.

An unexpected small increase in cardiovascular (CV) events in subjects with 
COPD regularly treated with ATROVENT® (ipratropium bromide) has been 
reported.[18][19]

A large, 4-yr long clinical trial in subjects with COPD treated with 
SPIRIVA® HANDIHALER® (tiotropium) added to other standard therapies 
reported no effect on CV risk.[20]
o
Combination Bronchodilators: Combining bronchodilators using a LABA and a 
LAMA increases FEV1, albeit not to the full additive effect of each individual 
component; improves PROs and reduces exacerbations vs monotherapy.  One study 
(FLAME trial) in subjects with post-BD FEV1 ≥25% and < 60% predicted, an 
mMRC score of ≥2, and a history of ≥1 exacerbation reported an 11% further 
reduction in COPD exacerbations with fixed combination of once daily indacaterol 
110µg + glycopyrronium 50µg (LABA+LAMA) compared to fixed combination 
twice daily fluticasone propionate 500µg + salmeterol 50µg (ICS+LABA).[21] 
Combining a SABA and a SAMA or a LABA and LAMA can be done using 
separate inhalers or using a single inhaler containing a fixed dose combination.  

Anti-inflammatory agents
o
Inhaled Corticosteroids (ICS) alone: The available evidence does not support a 
beneficial effect of ICS monotherapy in subjects with COPD.[22]
o
ICS in combination with LABD: Most studies in subjects with mod-severe COPD 
and history of exacerbations found a beneficial effect of ICS+LABA fixed dose 
combination over either component alone in improving lung function, health status, 
and in reducing exacerbations.  Studies that evaluated withdrawal of ICS have 
yielded equivocal results.

High quality evidence has confirmed an increased rate of pneumonia, oral 
candidiasis, 
hoarseness 
and 
skin 
bruising 
with 
ICS 
treatment.[23][24][25][26][27]  Factors associated with a higher risk for 
pneumonia on ICS include: current smokers, age ≥ 55 yrs, have a history of 
prior exacerbation or pneumonia, a BMI < 25 kg/m2, a poor MRC dyspnea 
grade, and/or severe airflow limitation.[28][29] A meta-analysis suggested 
that subjects with COPD with lower blood eosinophil counts (<2%) had more 
pneumonia events than did those with higher counts.[30]

RCTs have reported variable outcomes regarding ICS effect on decreased 
bone mineral density (BMD) [31][32]  and risk of fractures,[33] and 
observational studies suggest an increased risk of diabetes / poorly controlled 
diabetes,[34] cataracts,[35][36] and mycobacterial infections, including 
tuberculosis.[37]

Triple Combination of ICS+LABA+LAMA: Available evidence from RCTs suggests that 
adding a LAMA to an ICS+LABA (or vice-versa) further improves lung function, PROs and 
reduces exacerbations risk.[38][39][40][41][42][43] This step-up therapy can be achieved 
using various available approaches and products. More studies with this combination are 
needed to understand the benefits and risks and the target population.


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Chiesi Farmaceutici has patented MODULITE®, a technology for the development of pMDI as 
HFA solution formulations.  It  currently markets FOSTER®, a fixed dose combination of an 
ICS/LABA (beclomethasone dipropionate 100µg / formoterol fumarate 6µg) for the maintenance 
treatment of asthma (1-2 inhalations bid, and 1 inhalation prn, not to exceed 8 inhalations/day) and 
COPD (2 inhalations bid) in subjects 18 yrs and older.  The product was launched in Germany in 
2006 and is currently available in 35 countries worldwide including Russia and China, but not the 
US.  FOSTER® is dispensed as a Pressurized Inhalation Solution (pMDI, Modulite®) and as a dry 
powder for inhalation (DPI) by the NEXThaler® device, releasing extra-fine particles.[44] 
FOSTER® pMDI has been developed with a high “extrafine” (< 1.1µm) BDP particle size fraction, 
similarly to another HFA BDP marketed formulation (QVAR® Inhalation Aerosol, Teva 
Respiratory, LLC).
Chiesi Farmaceutici is also developing a fixed dose triple combination of an ICS/LABA/LAMA 
(CHF 5993) with beclomethasone dipropionate (BDP) + formoterol fumarate (FF) + 
glycopyrronium bromide (GB), and on Sep 29, 2016 became the first company to submit a 
marketing authorization application with this investigational product to the European Medicine 
Agency (EMEA) for the treatment of COPD.  The product is administered using a single 
pressurized metered dose inhaler (pMDI), specifically formulated to deliver extra-fine particles 
efficiently reaching both central and peripheral airways.
The submission of the EMEA dossier is based on the results of a large and comprehensive 
development program performed by Chiesi since 2009, which included 12 clinical studies involving 
more than 8,000 subjects.[45]
As part of the US development program of this fixed dose triple combination for COPD, a full 
characterization of the individual components (BDP, FF, GB) using the same inhaler device is 
required, including clinical dose-ranging studies at multiple doses, and using appropriate 
comparators for benchmarking purposes. An inhaled formulation of GB delivered via 
hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) using the Modulite® technology 
has been developed  by Chiesi for this purpose and will be used in this dose-ranging trial.
Previously, HFA GB pMDI (CHF 5259) has been assessed as a single dose at 12.5 – 200µg/day, 
and in a multiple dose study over 1 week at 25 – 100µg/day, compared to placebo, in subjects with 
COPD.[46] This will be a longer (6-week), multi-dose, placebo and active-controlled dose-ranging 
trial, conducted in subjects with COPD, to satisfy US FDA’s recommendations for dose-finding. 
Since SEEBRI™ NEOHALER® (glycopyrrolate) inhalation powder [47] has not yet been marketed 
in the US at the time of the development of this protocol, SPIRIVA® HANDIHALER® (tiotropium 
bromide inhalation powder) 18µg once daily was  chosen as the active comparator in this study, 
considering its well characterized efficacy and safety profile.[48] 
Glycopyrronium Bromide (Glycopyrrolate):
Description and Mechanism of Action:
Glycopyrronium bromide (GB), also known as glycopyrrolate,  is a synthetic quaternary ammonium 
compound that acts as a competitive antagonist at muscarinic acetylcholine receptors.  It has similar 
affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, glycopyrrolate exhibits 
pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to 
bronchodilation.[47] The medication, which is the active moiety, is also known as 
glycopyrronium.[49]


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Clinical Efficacy of glycopyrronium bromide:
SEEBRI™ NEOHALER®: In October 2015, the US FDA approved SEEBRI™ NEOHALER® 
(glycopyrrolate) inhalation powder for oral inhalation use (NOVARTIS Pharmaceutical Corp.), for 
the long-term, maintenance treatment of airflow obstruction in subjects with COPD.  Each capsule 
contains 15.6µg of glycopyrronium bromide (glycopyrrolate) inhalation powder. Each delivered 
dose (under standardized in vitro testing at a fixed flow rate of 90 L/min for 1.3 seconds) contains 
13.1 µg of glycopyrronium bromide equivalent to 12.5µg of glycopyrronium (ex-mouthpiece).[47]
Dose selection for SEEBRI™ NEOHALER® in COPD was supported by a 28-day, randomized, 
double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate 
(15.6µg, 31.2µg, 62.4µg, and 124.8µg once-daily and 15.6µg, 31.2µg, and 62.4µg twice-daily) or 
placebo in 388 subjects with COPD.  The dose-ranging results supported the evaluation of 
glycopyrrolate 15.6µg twice-daily in the confirmatory COPD trials for US registration.[50] Two 
replicate phase III, 12-week, randomized, double-blinded, placebo-controlled, parallel-group trials 
(GEM1; n=441 and GEM2; n=432) subsequently evaluated and confirmed the efficacy of 
SEEBRI™ NEOHALER® 15.6µg bid in subjects with moderate-to-severe COPD (30% ≤ predicted 
FEV1 > 80%). The primary endpoint was the change from baseline in FEV1 AUC0-12h following the 
morning dose at Day 85 compared with placebo. In both trials, SEEBRI™ NEOHALER® 
demonstrated a larger increase in mean change from baseline in FEV1 AUC0-12h compared to 
placebo.[51][52] The mean peak FEV1 (maximum FEV1 recorded within 4 hours after the morning 
dose) improvement from baseline for SEEBRI™ NEOHALER® compared with placebo at Day 1 
and at Day 85 ranged between 0.137L and 0.163L.  Subjects treated with SEEBRI™ NEOHALER® 
used less daily rescue albuterol during both trials compared to subjects treated with placebo, and the 
responder rate to the St. George’s Respiratory Questionnaire (SGRQ), defined as an improvement 
in score of 4 or more as threshold, ranged between 49%-55% in the SEEBRI™ NEOHALER® 
treatment arm compared to 41%-42% for placebo.
CHF 5259 pMDI – TRIPLE 9 (TRIGON) study: A phase II, multi-center, randomized, double-
blind, placebo-controlled, 2-way cross-over study evaluated the efficacy and safety of HFA GB 
pMDI (CHF 5259), 12.5µg/inhalation (2 inhalations bid, TDD = 50µg) given for 4 weeks in 100 
symptomatic subjects (BDI focal score ≤10) with moderate-very severe COPD (post-BD FEV1 < 
60% predicted).  Subjects were allowed to continue on an ICS (switched to an equivalent dose of 
QVAR®) if they were receiving it at baseline.[53] HFA GB pMDI was superior to placebo in terms 
of change from baseline in pre-dose (trough) morning FEV1 on Day 28 (primary efficacy variable) 
with a difference in adjusted means (95% CI) between treatments of 0.088L (0.039L; 0.137L) 
(p<0.001), and in FEV1 AUC0-12h normalized by time on Day 28 (key secondary efficacy variable) 
with a difference in adjusted means between treatments of 0.121L (95% CI: 0.079L - 0.162L; p<0.001). 
Superiority was also demonstrated for other lung function parameters (FVC, IC) and clinical 
outcome measures (TDI, SGRQ, rescue medication use). 
Clinical Safety of glycopyrronium bromide:
SEEBRI™ NEOHALER®: The safety database included 3415 subjects with COPD in four 12-week 
lung function trials and one 52-week long-term safety study.[51][52][54][55] A total of 1202 
subjects received treatment with SEEBRI NEOHALER 15.6µg bid.


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In the two 12-week trials with SEEBRI™ NEOHALER®, the most common adverse reactions 
(incidence ≥ 2% and higher than placebo) were upper respiratory tract infection and 
nasopharyngitis.  The proportion of subjects who discontinued treatment due to adverse reactions 
was 2.4% for the SEEBRI™ NEOHALER®-treated subjects and 3.8% for placebo-treated subjects. 
Other adverse reactions occurring more frequently with SEEBRI™ NEOHALER® than with 
placebo, but with an incidence < 1% include rash, pruritus, gastroenteritis, hypersensitivity, atrial 
fibrillation, insomnia, pain in extremity, dysuria, vomiting, productive cough, and diabetes 
mellitus/hyperglycemia.
In the 52-week long safety trial comparing glycopyrrolate 15.2µg bid to indacaterol 27.5µg qd, 
(GEM3; n=507) adverse reactions were consistent with those observed in the 12-week long 
placebo-controlled trials. Additional adverse reactions that occurred with a frequency ≥ 2% in the 
group receiving glycopyrrolate that exceeded the frequency seen in the indacaterol 75µg treatment 
arm were: diarrhea, nausea, upper abdominal pain, fatigue, bronchitis, pneumonia, rhinitis, back 
pain, arthralgia, dyspnea, and wheezing.[55]
Additional adverse reactions that have been identified during worldwide post-approval use of 
glycopyrrolate, the active ingredient in SEEBRI™ NEOHALER®, at higher than the recommended 
dose are angioedema and paradoxical bronchospasm.[47]
CHF 5259 pMDI – TRIPLE 9 (TRIGON) study:[53] Overall, no safety concerns were raised with 
GB compared to placebo in the clinical trial described above. Twenty (20.6%) patients experiencing 
25 TEAEs during treatment with CHF 5259 pMDI and 17 (17.7%) patients experiencing 21 TEAEs 
during treatment with placebo. Six TEAEs led to study treatment discontinuation: 4 (4.1%) patients 
due to 4 TEAEs (2 TEAEs of COPD exacerbation, 1 TEAE of bronchial carcinoma and 1 TEAE of 
death) during treatment with CHF 5259 pMDI and 2 (2.1%) patients due to 2 TEAEs of COPD 
exacerbation during treatment with placebo. No clinically significant ECG abnormalities were 
found. 
Like other antimuscarinic agents, glycopyrrolate should be used with caution in subjects with 
narrow-angle glaucoma and in subjects with urinary retention as it may exacerbate these 
conditions.[56]
More detailed description of the efficacy and safety data available with CHF 5259 pMDI can be 
found in section 6.2.1 and in the Investigator’s Brochure.
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments), ICH E6 Good Clinical Practices and all other applicable laws and regulations.
2. STUDY OBJECTIVES
2.1 Primary Objective(s)

To evaluate the efficacy of CHF 5259 pMDI by comparison with placebo in terms of change 
from baseline in FEV1 AUC0-12h normalized by time at Week 6.


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2.2 Secondary Objective(s)

To evaluate the effect of CHF 5259 pMDI on other lung function parameters and clinical 
outcome measures.

To assess the safety and the tolerability of the study treatments.
3. STUDY DESIGN 
This is a phase II, multi-center, randomized, double-blind, placebo and active-controlled, parallel 
group, dose ranging study to evaluate the efficacy and safety of 4 doses of CHF 5259 
(glycopyrronium bromide HFA pMDI) delivered twice daily, in adult subjects with COPD. 
Following a 2-week run-in period, eligible subjects will be randomized to one of 6 study treatments 
arms (1:1:1:1:1:1) for 6 weeks. A follow-up phone contact for adverse events assessment will be 
conducted approximately 1 week after the last clinic visit. The study will last approximately 10 
weeks for each subject and a total of 5 clinic visits and a follow-up call will be performed during 
the study. 
The end of the trial is defined as the last visit of the last subject in the trial.
4. SUBJECT SELECTION CRITERIA
4.1 Subject Recruitment
Assuming a 40% screening failure rate, and a post-randomization non-evaluable rate of 15%, 
approximately 1170 subjects will be screened and 702 randomized (117 per group) to yield 594 
evaluable subjects. Recruitment will occur at approximately 120 participating outpatient study 
centers within the US.


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4.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Male or female subjects aged ≥ 40 years who have signed an Informed Consent Form prior 
to initiation of any study-related procedure;
2. A diagnosis of COPD (according to GOLD Report, 2017[2]) at least 12 months before the 
screening visit;
3. 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);
4. A post-bronchodilator FEV1 ≥40% and <80% of the predicted normal value (measured 30 to 
45 minutes after administration of 84µg ipratropium pMDI) and,
a. a post-bronchodilator FEV1/FVC < 0.7 at screening and,
b. a demonstrated partial reversibility to ipratropium defined as ΔFEV1 ≥ 5% over 
baseline 30-45 minutes after inhaling 4 puffs of ipratropium (21µg/actuation); 
Note: In case the reversibility threshold is not met at screening, the test can be 
performed once before randomization. 
5.  Use of regular COPD therapy for at least 2 months prior to screening with a single or dual 
LABD with or without an ICS;
a. inhaled LAMA
b. inhaled ICS/LABA (fixed or free combination)
c. inhaled ICS + LAMA
d. inhaled LABA
e. inhaled LABA+LAMA (fixed or free combination)
f.
inhaled ICS+LABA+LAMA (fixed or free combination)
6. Presence of COPD symptoms at screening with a CAT score ≥10. This criterion must be 
confirmed at randomization (Visit 2);
7. Presence of dyspnea with a BDI focal score ≤ 10. This criterion must be confirmed at 
randomization (Visit 2);
8. A cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and the e-
diary. This criterion must be confirmed at randomization (Visit 2).
If at Visit 1 the inclusion criterion #4 (reversibility) is not met, the subject may return to repeat the 
procedure once before randomization.  
Inclusion criteria # 6-8 should be re-checked at the randomization visit (Visit 2). 
4.3 Exclusion Criteria
If a subject meets any of the following criteria, he/she will NOT be enrolled into the study:
1. Pregnant (as evident by a positive urine hCG or serum β-hCG test) or lactating women and 
all women physiologically capable of becoming pregnant (i.e. women of childbearing 
potential) UNLESS they are willing to use highly effective birth control methods such as:
a. Placement of an intrauterine device (IUD) or intrauterine releasing system (IUS);
b. Oral, intravaginal, transdermal combined estrogen and progestogen containing 
hormonal contraception or oral, injectable, implantable progestogen only hormonal 
contraception;
c. Bilateral tubal occlusion;


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d. Partner vasectomy (provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomized partner has received medical assessment 
of the surgical success);
e. Sexual abstinence defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.
Pregnancy testing will be carried out during the course of the study in all women of 
childbearing potential: serum pregnancy test will be performed at screening, at Visit 4 and at 
the early termination visit; urinary pregnancy test will be performed at screening, Visit 2 and 
Visit 3.  Women of non-childbearing potential defined as physiologically incapable of 
becoming pregnant: post-menopausal (defined as no menses for 12 months without an 
alternative medical cause) or permanently sterile (hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy) are eligible.  If indicated, as per investigator’s request, post-
menopausal status may be confirmed by follicle-stimulating hormone levels (according to 
local laboratory ranges) in women not using hormonal contraception or hormonal 
replacement therapy.
2. 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);
3. COPD Exacerbations:
a. 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/intravenous corticosteroid 
or antibiotic (whichever comes last), and ≤ 3months of intramuscular depot 
corticosteroid;
b. A moderate or severe COPD exacerbation during the run-in period; 
4. Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) in the 4 weeks 
prior to screening or during run-in;
5. Subjects treated with non-cardio-selective β-blockers in the month preceding screening or 
during the run-in period;
6. Not applicable;
7. Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia;
8. Known respiratory disorders other than COPD which may impact the efficacy of the study 
treatment according to the Investigator’s judgment. This can include but was not limited to 
α-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung 
fibrosis, pulmonary hypertension and interstitial lung disease;
9. Subjects who have a clinically significant cardiovascular condition such as, but not limited 
to, unstable ischemic heart disease, NYHA Class III/IV heart failure, acute ischemic heart 
disease within one year prior to study entry, known history of atrial fibrillation or history of 
sustained and non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to 
screening, not controlled with a rate control strategy;
10. 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 
judgment;
11. Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for 
males or QTcF >470 ms for females at screening or randomization visit (criterion not 
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12. 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;
13. History of hypersensitivity to M3 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 judgment;
14. 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 judgment;
15. Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening;
16. Use of potent cytochrome P450 2D6 and 3A4 inhibitors (e.g. ritonavir, ketoconazole, 
itraconazole) and inducers within 4 weeks prior to screening;
17. Unstable or uncontrolled concurrent disease: e.g. fever, hyperthyroidism, diabetes mellitus 
or other endocrine disease; gastrointestinal disease (e.g. active peptic ulcer); neurological 
disease; hematological disease; autoimmune disorders, or other which may impact the 
feasibility of the results of the study according to Investigator’s judgment;
18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening;
19. 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;
20. Subjects who are mentally or legally incapacitated, or subjects accommodated in an 
establishment as a result of an official or judicial order; 
21. Subjects who have undergone major surgery in the 3 months prior to the screening visit or 
have a planned surgery during the trial.
22. Subjects using marijuana daily or as needed;
Exclusion criteria # 1, 3, 4, 5, 10 and 11 should be re-checked at the randomization visit (Visit 2).  
4.4 Subject Withdrawals
Subjects may be discontinued from the study for any of the following reasons:

An adverse event occurs that, in the opinion of the investigator, makes it unsafe for the 
subject to continue taking the study drug or undergo study procedures.  In this case, the 
appropriate measures will be taken;
o
COPD Exacerbations: Subjects who experience a moderate or severe COPD 
exacerbation any time after screening (V1) will be instructed to visit the site as 
soon as possible for an Early Termination Visit and will be withdrawn 
permanently from the study. The Adverse Event form will be completed and 
appropriate medical management of the COPD exacerbation according to 
standard medical practice will be ensured by the study investigator, with the aim 
to preserve the research subject’s well-being at all times.

Definitions of a moderate and a severe COPD exacerbation are provided 
in section 7.2.12 of the study protocol.

The subject is lost to follow-up;


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
The subject withdraws consent;

The subject's safety is affected by violation of inclusion or exclusion criteria or use of 
non-permitted concomitant medication;

The subject is unwilling or unable to adhere to the study requirements, i.e, non-
compliance;

The sponsor or the regulatory authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular 
subject. 
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawals of subjects should be avoided.  However, 
should a subject discontinue the study, all efforts will be made to complete and report the 
observations as thoroughly as possible.
In case of withdrawal, the Investigator must fill in the “Study Termination” page in the eCRF, 
reporting the main reason for withdrawal.   
If a subject is withdrawn/drops-out of the study after receiving the test treatment, the subject study 
number and corresponding test treatments should not be reassigned to another subject.
5. CONCOMITANT MEDICATIONS
5.1 Permitted Concomitant Medications
1. Inhaled corticosteroids are permitted in subjects already receiving them at low-to-medium 
daily dose in association with a long-acting β2-agonist (LABA) or a long-acting 
anticholinergic (LAMA) for at least 2 months prior to screening. The subject’s current ICS 
will be discontinued at the screening visit and an equipotent beclomethasone dipropionate 
(QVAR®) daily dose will be prescribed instead and will remain constant throughout the 
study.
ICS*
Low daily dose
Medium daily dose
BDP extrafine (HFA pMDI) QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA pMDI)
80-160µg
>160-320µg
Flunisolide (HFA pMDI)
160-320µg
>320-640µg
Fluticasone propionate (HFA pMDI/DPI)
100-250µg
>250-500µg
Fluticasone furoate (DPI)
100µg
n.a.
Mometasone furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA Report, 2016) 
ICS/LABA for COPD*
ICS/LABA 
Daily Dose
QVAR® recommended Daily Dose
ADVAIR® DISKUS® 
250/50
250/50µg bid
160µg bid
BREO® ELLIPTA® 
100/25
100/25µg qd
160µg bid


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* Doses of these ICS/LABAs are based on FDA-approved US labels for COPD, except for 
DULERA®, where doses are suggested based on published clinical trials in COPD. For off-
label doses of ICS/LABAs please contact the medical monitor to discuss daily equivalent of 
QVAR®.
2. Short-acting β2-agonist (albuterol) as rescue medication. A minimum period of 6 hours 
should elapse between the use of rescue medication and the spirometric measurements.
3. Mucolytics (e.g. N-acetyl cystein) if taken prior to study entry and maintained constant 
during the study period.
4. Intranasal corticosteroids and oral, intranasal, or ocular antihistamines at FDA-approved 
doses for the treatment of allergy symptoms will be allowed during the study period.
5. Cardioselective β1-blockers if taken for at least 2 months before screening and to be 
maintained at a constant dose during the study.
In case of a concomitant disease, appropriate treatment that, according to the investigator, does not 
interfere with the study evaluation parameters is allowed and if it does not qualify under the section 
“Non-Permitted Concomitant Medications”.  All concomitant medications should be noted in the 
relevant section of the Case Report Form.
In case of exacerbations, subjects will be treated according to the standard clinical practice. This 
will constitute a reason for withdrawal from the study.
5.2 Non-Permitted Concomitant Medications
The following medications are not permitted during the total study period, starting from screening 
visit (V1).  Subjects who take any of these medications during the run-in period (V1-V2) should not 
be randomized into the study. Subjects who take any of these medications during the randomized 
treatment period (V2-V4) will be carefully evaluated by the investigator for Early Withdrawal on 
the basis of the potential impact on efficacy or safety evaluations and in the best interest of the 
subject.
1. Inhaled long acting β2-agonists.
2. Inhaled fixed combination of corticosteroids and long-acting β2-agonists (e.g. salmeterol 
plus fluticasone or formoterol plus budesonide). 
3. Inhaled short acting β2-agonists (other than study “rescue” medication).
4. Inhaled fixed combinations of a short-acting β2-agonist (SABA) and a short-acting 
anticholinergic medication (SAMA).
5. Inhaled short-acting anticholinergics. 
6. Inhaled long-acting anticholinergics.
7. Oral/IV/IM corticosteroids.
8. Nebulized bronchodilators or corticosteroids.
9. Inhaled corticosteroids other than study background ICS.
10. Non-cardioselective β-blockers.
11. PDE4 inhibitors (e.g. roflumilast).
12. Leukotriene modifiers.
13. Xanthine derivatives (e.g. theophylline).
14. Any drug with known or possible risk of Torsades de Pointes (TdP) or QT interval 
prolongation (e.g. quinidine, procainamide, amiodarone).
DULERA® 100/5
200/10µg bid
160µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid


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Prior to screening spirometry (Visit 1), the following washout periods must be respected:
Caffeinated substances
6 hours
Inhaled and/or nebulized short-acting β2-agonists:
6 hours
Inhaled and/or nebulized short-acting muscarinic antagonists: 
8 hours
Inhaled combination of short-acting β2-agonists /short-acting muscarinic 
antagonists:
 
8 hours
Inhaled corticosteroids (bid): 
24 hours
Inhaled long-acting β2-agonists (bid):
24 hours
Inhaled fixed combinations of ICS/LABAs (bid):
24 hours
Inhaled corticosteroids (qd):                                                
 
48 hours
Inhaled "ultra long-acting" β2-agonists (qd):
48 hours
Inhaled fixed combinations of ICS/LABAs (qd):                  
48 hours
Oral leukotriene modifiers:                                                    
 
72 hours
Inhaled LAMA:                                                                     
7 days
Xanthine derivatives:
 
7 days
PDE4 inhibitors                                                                   
 
1 month
Oral or parenteral (i.v.) corticosteroid:
1 month
Intramuscular depot corticosteroid:
3 months
Prior to other visits with spirometry (V2  V4), the following washout periods must be respected:
Inhaled short-acting β2-agonists:
6 hours
Caffeinated substances:
6 hours
6. TREATMENT(S)
The double-blinded study drug will be supplied to the clinical site under the responsibility of the 
Sponsor, who will also provide the Pharmacist/Investigator with appropriate certificates of 
analytical conformity.
6.1 Appearance and Content
Study drug 
Chiesi has patented MODULITE®, a technology for the development of pMDI as HFA solution 
formulations. Since the non-CFC propellant Norflurane (HFA-134a) has poor solvency properties, 
ethanol has been included in the formulation to enhance the solubility of the active ingredients (co-
solvent). Hydrochloric acid has been added as pH adjuster for the stabilisation of the formulation. 
All the included excipients are extensively used in pharmaceutical preparations.

CHF 5259 pMDI 6.25µg - Test product 
Active ingredient: Glycopyrronium bromide 6.25µg per inhalation
Excipient: HFA-134a propellant, ethanol anhydrous, hydrochloric acid
Presentation: each canister contains 120 doses


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
CHF 5259 pMDI 12.5µg - Test product 
Active ingredient: Glycopyrronium bromide 12.5µg per inhalation
Excipient: HFA-134a propellant, ethanol anhydrous, hydrochloric acid
Presentation: each canister contains 120 doses

CHF 5259 pMDI 25µg - Test product 
Active ingredient: Glycopyrronium bromide 25µg per inhalation
Excipient: HFA-134a propellant, ethanol anhydrous, hydrochloric acid
Presentation: each canister contains 120 doses

CHF 5259 pMDI Matched Placebo 
Active ingredient: None
Excipient: HFA-134a propellant, ethanol anhydrous
Presentation: each canister contains 120 doses

QVAR® (HFA beclomethasone dipropionate) Inhalation Aerosol - Background ICS 
medication for Run in and Treatment Period
Active ingredient: beclomethasone dipropionate 80µg per inhalation
Excipient: HFA-134a propellant, ethanol anhydrous
Presentation: each canister contains 120 doses

SPIRIVA® HANDIHALER® (tiotropium bromide inhalation powder) - Reference product
Active ingredient: 18µg tiotropium (equivalent to 22.5µg tiotropium bromide monohydrate) 
per capsule
Excipient: lactose monohydrate
Presentation: Blister containing 10 hard capsules 
6.2 Dosage and Administration 
6.2.1 Selection of doses in the study
An inhaled formulation of glycopyrronium bromide delivered via hydrofluoroalkane (HFA-134a) 
pressurized metered dose inhaler (CHF 5259 pMDI) under development by Chiesi will be used for 
the purpose of this phase II dose-ranging study.  This formulation uses the Modulite® technology 
and contains the same excipients as in FOSTER® (fixed combination ICS+LABA available in EU).  
The rationale of dose selection in this study is based on the following completed clinical trials and 
discussions with FDA. 
GLYCO study - Part 1 and 2[46]: HFA GB pMDI (CHF 5259) was assessed as a single dose (Part 
1) at 12.5, 25, 50, 100 and 200µg/day, and using repeated dosing over 1 week (Part 2) at 12.5, 25 
and 50µg bid compared to placebo in 24 and 38 subjects with COPD, respectively. 

In the single dose study, the highest mean FEV1 and FVC occurred during the first 4h post-
inhalation, and for all doses, the mean changes from baseline in FEV1 were statistically 
significant at each timepoint up to 6h post-dose, and at some timepoints thereafter.  The 
overall number of patients with at least one TEAE reported was similar across the different 
doses of CHF 5259 and was lower compared to that observed with placebo.  The most 
frequently reported TEAE was headache. Two subjects were withdrawn from the study due 
to TEAEs: atrial fibrillation following inhalation of placebo and ventricular extrasystoles 


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following treatment with 50μg CHF 5259 pMDI.  Overall, all doses of GB were safe and 
well tolerated.

In the 1-week treatment study, all doses tested demonstrated superiority over placebo (one-
sided p <0.001, adjusted for multiplicity) in the primary endpoint of trough FEV1 at 12h 
post-dose on Day 7.  This difference was clinically significant with the GB 50 and 
100µg/day doses (≥ 120mL). Between-dose comparisons revealed statistically significant (p 
≤ 0.037)  differences in favor of the GB 50 vs the 25µg/day dose on peak and trough FEV1 
on Days 7 and 8; in FEV1 AUC0-12h on Day 8, in sGAW AUC0-12h and VC AUC0-12h on Day 
7.  No statistically significant differences were observed between the GB 50 and 100µg/day 
doses in derived lung function and body plethysmography parameters. Sixteen (44.4%), 12 
(35.3%), and 15 (39.5%) subjects had at least one TEAE during treatment with 25, 50, and 
100µg/d CHF 5259 pMDI, respectively. Fifteen (42.9%) subjects had at least one TEAE 
during placebo inhalation and 12 (35.3%) subjects had at least one TEAE during treatment 
with tiotropium. TEAEs that were reported in more than 2 subjects during any treatment 
were headache, cough, and back pain, but only headache was reported in more than 2 
subjects during any treatment with CHF 5259 pMDI. No SAEs occurred. At Day 1, at 30 
minutes time point, the largest mean QTcF increase was 2.4 ms after 12.5µg bid of CHF 
5259, and 1.1 ms after 50µg bid. The largest mean QTcF increase was observed at time 
point 8 h after 50µg bid of CHF 5259 (6.3ms). At Day 7, at 30 minutes time point, the 
largest mean QTcF increase was 5.8 ms after 12.5µg bid of CHF 5259, but 4.2ms after 50µg 
bid.  The largest mean QTcF increase was observed at time point 3 h after 50µg bid of CHF 
5259 (7.9 ms).
TRIPLE 3 study[57]: This multi-center, randomized, double-blind, active controlled, 4-way cross-
over, multi-dose study evaluated the efficacy of 3 doses of GB-HFA pMDI 12.5µg (1 inhalation 
bid) , 25µg (1 inhalation bid) and 25µg (2 inhalations bid) added to FOSTER® (BDP+FF 100/6µg, 
2 inhalations bid), compared to FOSTER® alone, in 178 patients with COPD and 30% ≤FEV1 ,60% 
and ≥60 mL post-BD (ipratropium, 84µg) partial reversibility. Treatments were for 1 week, 
separated by 1 week washout period. On the primary endpoint of FEV1 AUC0-12h normalized by 
time on Day 7,  the addition of HFA GB pMDI at daily doses of 50 and 100µg for 7 days resulted in 
both a statistically (p<0.001) and clinically significant lung function improvement of 100 and 
112mL respectively over FOSTER® alone.  The magnitude of improvement with the 25µg/d dose 
was statistically significant at 87 mL (p<0.001). The difference was statistically significant between 
the 100µg vs. 25µg/d doses, but not between the 50 and 100µg/d doses.  In general, there were no 
significant advantages with the 100µg over the 50µg daily dose. Overall, TEAEs and TEADRs 
were reported less frequently during treatment with any FOSTER® + GB combination than in 
FOSTER® alone. SAEs were reported in 3 patients receiving FOSTER® + GB combination (abscess 
intestinal on FOSTER® + GB 25µg/d; Bladder transitional cell carcinoma stage II on FOSTER® + 
GB 50µg/d; and enteritis infectious and acute prerenal failure on FOSTER® + GB 100µg/d.  No 
deaths were reported during the study.
CARSAF study[58]: provided supportive evidence in 191 patients with moderate to severe COPD 
that HFA GB pMDI 12.5 and 25µg 2 inhalations bid conferred an additional bronchodilator effect 
when added to FOSTER® (BDP/FF 100/6µg 2 inhalations bid)
TRIPLE 9 (TRIGON study)[53]:  The efficacy and safety of 4-week treatment with HFA GB 
pMDI (CHF 5259) 12.5µg/actuation  (2 inhalations bid) was investigated in a randomized, double-
blind, placebo-controlled, 2-way cross-over study in 100 symptomatic subjects with COPD (post-


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BD FEV1 < 60% predicted, BDI focal score ≤10). HFA GB pMDI was superior to placebo in terms 
of change from baseline in pre-dose (trough) morning FEV1 on Day 28 (primary efficacy variable), 
and in FEV1 AUC0-12h normalized by time on Day 28 (key secondary efficacy variable); and in 
other lung functions (FVC, IC) and clinical outcome measures (TDI, SGRQ, rescue medication 
use). No active control was included in this study.  Overall, no safety concerns were raised with GB 
compared to placebo.
These studies supported the conclusion that HFA GB pMDI 50µg/day is the optimal dose to 
incorporate into the fixed triple inhaler combination program (CHF 5993) that was conducted and 
filed in Europe. 
 
Following consultation with the US FDA, this planned study will be a longer (6-week), multidose, 
placebo and active-controlled dose-ranging trial, conducted in subjects with COPD, to satisfy US 
FDA’s recommendations for dose-finding. The study will test 4 doses of CHF 5259 pMDI (6.25, 
12.5, 25 and 50µg twice daily) vs placebo and an active comparator SPIRIVA® HANDIHALER® 
(tiotropium bromide 18µg once daily) in adult subjects with moderate COPD.  The chosen doses of 
glycopyrrolate in CHF 5259 are in close proximity to the doses tested in the US FDA-approved  
SEEBRI® NEOHALER® inhalation powder development program (15.6µg, 31.2µg, and 62.4µg 
glycopyrrolate bid; Novartis Pharmaceuticals Corp. East Hanover, NJ),[50] and to the doses tested 
in a single-dose as part of an on-going investigational program using a co-suspension formulation 
delivered via pMDI (14.4, 28.8, 57.6, and 115.2μg of glycopyrronium, ex-actuator; Pearl 
Therapeutics, Inc).[59] 
6.2.2 Dosage
6.2.2.1 Background Medication for Run-in and Treatment Periods: 
At the screening visit (Visit 1), all eligible subjects who have been receiving an ICS in combination 
with a LABA or LAMA will be switched to an equipotent dose of QVAR® as run-in / background 
therapy:

QVAR® 80µg (HFA beclomethasone dipropionate - Teva Respiratory, LLC) 
1-2 inhalations twice per day (Total daily dose: Beclomethasone dipropionate 160-320µg)
This treatment will be maintained at stable dose and regimen (160-320µg daily) throughout the 
study from screening until the end of the study.
6.2.2.2 Randomized Treatment Period:
An adequate number of inhalations from Placebo inhalers will be performed to maintain a double 
blind design:
Treatment A: CHF 5259 pMDI 6.25µg – CHF 5259 12.5µg Total Daily Dose
o
One inhalation of CHF 5259 pMDI 6.25µg bid plus one inhalation of CHF 5259 pMDI 
matched placebo bid. 
Treatment B: CHF 5259 pMDI 12.5µg – CHF 5259 25µg Total Daily Dose
o
One inhalation of CHF 5259 pMDI 12.5µg bid plus one inhalation of CHF 5259 pMDI 
matched placebo bid. 


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Treatment C: CHF 5259 pMDI 12.5µg – CHF 5259 50µg Total Daily Dose
o
One inhalation of CHF 5259 pMDI 12.5µg bid plus one inhalation of CHF 5259 pMDI 
12.5µg bid. 
Treatment D: CHF 5259 pMDI 25µg – CHF 5259 100µg Total Daily Dose
o
One inhalation of CHF 5259 pMDI 25µg bid plus one inhalation of CHF 5259 pMDI 25µg 
bid. 
Treatment E: CHF 5259 pMDI Matched Placebo
o
One inhalation of CHF 5259 pMDI matched Placebo bid plus one inhalation of CHF 5259 
pMDI matched Placebo bid. 
Treatment F (open label arm): SPIRIVA® HANDIHALER® (tiotropium bromide inhalation 
powder), capsules for oral inhalation use, corresponding to 18µg TDD
Two inhalations of the powder contents of a single SPIRIVA capsule (18µg) once daily
6.2.3 Administration
To the extent possible, the time of dosing of study drug must remain constant for each subject 
for the whole duration of the study.
All previous COPD medications will have to be withdrawn during the course of the study except as
described in Section 5.
6.2.3.1 Background ICS Medication Kit for Run-in and Treatment Periods (from Visit 1 to Visit 
4):
At Visit 1 (screening visit), all subjects who have been receiving an ICS in combination with a 
LABA or LAMA, including those scheduled for Visit 1.1 for a repeat Reversibility test, will be 
switched to an equipotent dose of QVAR® to cover the 2 week run-in period:

One commercial pack of QVAR® containing 120 actuations of beclomethasone dipropionate 
80µg (total daily dose of 160 or 320µg daily).
At Visit 2 and Visit 3, the Investigator, or designee, will contact the IRT system to dispense to each 
subject allowed to continue in the study:

One commercial pack of QVAR® containing 120 actuations of beclomethasone dipropionate 
80µg at each of Visit 2 and Visit 3 (total daily dose of 160 or 320µg daily).
QVAR® will be taken only by subjects previously on ICS at time of screening and will be continued 
during the entire study from Visit 1 to Visit 4.   The dose will remain constant throughout the study 
period. 
The run-in/background ICS therapy will be administered daily from Visit 1 to Visit 4 as prescribed 
by the investigator, immediately after the study drug intake:

1-2 inhalations in the morning (between 8-10 am)

1-2 inhalations in the evening (between 8-10 pm)


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The first dose of run-in/background ICS medication must be administered at hospital/study site at 
the end of Visit 1.
Subjects issued QVAR® should be instructed to refrain from taking their morning dose of QVAR® 
before reporting to the study site at V1.1, V2, V3 and V4. During the randomized treatment periods 
(on visits 2, 3 and 4), QVAR® (if prescribed) should be taken at the clinic immediately after the 
study drug intake.
6.2.3.2 Randomized Treatment Period (from Visit 2 to Visit 4):
At randomization visit (Visit 2), after the confirmation of the eligibility, the subject will be 
randomized to one of the following treatment arms. 
For Treatment Arms A, B, C, D and E (CHF-5259 pMDI treatments and placebo), each subject will 
receive one box at Visit 2 and one box at Visit 3 containing two pMDI inhalers of randomized 
medication: one canister plus actuator will be labeled with number 1 and the other one with number 
2.
The study drug will be administered twice-a-day (in the morning and in the evening):
Morning administration (between 8-10 am):
One inhalation from the inhaler numbered 1
One inhalation from the inhaler numbered 2
Evening administration (between 8-10 pm): 
One inhalation from the inhaler numbered 1
One inhalation from the inhaler numbered 2
For Treatment Arm F (Open Label arm), each subject will receive one SPIRIVA® HANDIHALER® 
commercial pack carton at Visit 2 and one commercial pack carton at Visit 3 containing 30 
SPIRIVA capsules (3 unit-dose blister cards) and 1 HANDIHALER® inhalation device.
The study drug will be administered once-a-day (in the morning):
Morning administration (between 8-10 am):
Two inhalations of the powder contents of a single SPIRIVA® capsule (18µg) once daily
The same kit box will be used for morning and evening administration, where evening 
administration is applicable. 
Administration will be done according to the package instruction leaflets. A package leaflet will be 
included with study drugs in local language. 
The first administration of study drug will take place at the study site on visit 2 (V2) before the 
background ICS medication intake (if applicable), under medical supervision.
To the extent possible, the time of dosing must remain constant for each subject for the whole 
duration of the study.
On study visit days, study drug should not be taken before coming to the clinic.


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6.2.3.3 Rescue Medication 
COPD Rescue Medication – Open Label:
Albuterol HFA (a short-acting β2-adrenergic receptor agonist, or SABA):  Each canister contains 
200 actuations, at 90µg/actuation. At V1, the investigator will prescribe and supply each subject 
(through local procurement) with 1 canister of albuterol to use as COPD rescue treatment for the 
treatment of bronchospasm, as 1-2 inhalations Q 4-6h as needed (prn). Albuterol may be re-supplied 
by the investigator to the subject at subsequent visits during the study as needed, based on 
assessment of used and remaining doses.  The maximum dose allowed is 8 puffs per day.  If the 
subject’s needs exceed 4 puffs/day on ≥ 2 consecutive days during the run-in period, or uses ≥ 4 
puffs/day above their run-in average on ≥ 2 consecutive days during the treatment period, or uses 
≥8 puffs/day on any given day, he/she must contact the investigator.  A minimum period of 6 hours 
should elapse between the use of rescue medication and the spirometric measurements.  Albuterol 
will not be provided by the study sponsor. 
6.2.4 Subject Training
During the Visit 1 (screening), each subject will receive one training kit containing pMDI placebo 
(see description in Section 6.3.1). With this kit, the subject will be instructed on how to use the 
pMDI according to the instructions for use. The training kit will be kept at the site by the 
Investigator (i.e., will not be dispensed to the subjects) and they will be used again at Visit 2 
(randomization) in order to check again the proper use of the inhaler and if needed training can be 
repeated at following clinical visits. 
The Investigator will instruct subjects on how to use QVAR® and SPIRIVA® by reading together 
and showing the QVAR® and SPIRIVA® leaflets to the subjects. At each visit, the morning 
administration of QVAR® and SPIRIVA® will be closely supervised by the Investigator to check 
whether it is conducted in accordance with the leaflet instruction.
6.3 Packaging 
All study drug(s) will be prepared in accordance with Good Manufacturing Practices (GMP) as 
required by the current Good Clinical Practices (GCP). 
The Sponsor will supply the background ICS medication (QVAR®, for Run-in and the randomized 
treatment periods) and study drugs for the randomized treatment period.
6.3.1 Training Kits
The training kit is one box. The box will contain one CHF 5259 pMDI placebo. 

Primary packaging: 1 canister plus 1 standard actuator

Secondary packaging: 1 box containing one canister plus one actuator
6.3.2 Background medication kit for run-in and treatment period 

Primary packaging: 1 canister containing 120 actuations, with a beige plastic actuator with a 
dose counter and gray dust cap[60]

Secondary packaging: 1 commercial box containing 1 canister of QVAR® 80µg Inhalation 
Aerosol 


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6.3.3 Treatment period
For Treatment Arms A, B, C, D, and E (CHF 5259 pMDI treatments and placebo), each subject will 
receive one box at Visit 2 and one box at Visit 3.
Each box will contain 2 pMDI inhalers of CHF 5259 pMDI 6.25µg, 12.5µg, 25µg or placebo. 

Primary packaging: 1 canister plus standard actuator

Secondary packaging: box containing 2 canisters plus 2 standard actuators 
For Treatment F (Open Label arm treatment), at randomization (Visit 2) and Visit 3, each subject 
will be provided with 1 SPIRIVA® inhalation powder commercial box and 1 HANDIHALER® 
inhalation device. 

Primary packaging: blister containing 10 hard capsules 

Secondary packaging: box containing 3 blisters
6.3.4 Rescue medication
Starting at Visit 1 the rescue medication (albuterol) will be prescribed and provided by the 
Investigator to all subjects (purchased locally) for use throughout the study, according to the 
manufacturer’s label.
6.4 Labeling
All the supplies provided by Chiesi will be labeled according to the 21 CFR 312.6 of the GMP as 
well as to local law and regulatory requirements.
6.5 Treatment Allocation
A balanced block randomization scheme stratified by US Region (based on US Census Bureau 
Regions: West, Midwest, South, Northeast) will be prepared via a computerized system. Subjects 
will be centrally assigned to one of the six treatment arms at the end of the run-in period through an 
IRT system (Interactive Response Technology) with a 1:1:1:1:1:1 ratio.
The IRT will allocate the subject to a certain treatment group using a list-based randomization 
algorithm and will assign the study drug kit number corresponding to the treatment group assigned 
to the subject. The IRT will also generate a confirmation after every IRT transaction is performed.
The Investigator will call the IRT at each visit (from pre-screening to follow-up call) to record the 
subject number at pre-screening, to enroll and randomize the subject, to obtain the medication kit 
numbers and to register the subject status in the system. Detailed instructions for use of IRT will be 
provided to the site.
6.6 Treatment Code
Study drug will be packaged and uniquely numbered. Each primary packaging in the medication kit 
will have a numbered label that matches the kit number on the label of the outside packaging. The 
IRT will be used to assign both initial and subsequent kits in order to have an inventory control and 
subject dosing tracking. The IRT will also maintain quantities, kit numbers, drug types, batch/code 
numbers, expiration dates and do not dispense after these dates. The IRT will monitor inventory 
levels at all sites and manage the study drug re-supply. The IRT will also track subject screen 
failures and discontinuations from the study.


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The medication list will be provided to the labeling facility but will not be available to subjects, 
Investigators, monitors or employees of the center involved in the management of the trial before 
unblinding of the data, unless in case of emergency.
The Sponsor’s clinical team will also be blinded during the study as they will not have direct access 
to the randomization list nor to the medication list.
In case of emergency, unblinding of the treatment code will be done through the IRT. The treatment 
group will be disclosed and confirmation will follow (by fax and/or notification email). The IRT 
will be designed to send a confirmation (by fax and/or notification email) to the site for every 
transaction performed by the Investigators. The Investigator will be provided with username and 
password for randomization purposes and separate username and password to unblind the study 
drug in case of emergency situation, where he/she considers essential to know what treatment the 
subject was taking. The IRT will promptly notify the Sponsor and the Clinical Monitor whenever a 
treatment code is unblinded. 
Users from Chiesi Corporate Pharmacovigilance will have their own passwords to unblind subjects 
in case of SUSARs to be reported to the competent Regulatory Authorities and Ethic Committees. 
The subject will be provided with a card with the phone numbers of study site and Investigator to be 
called in case of emergency.
6.7 Treatment Compliance
Compliance will be evaluated on the basis of the information recorded daily by the subject on the 
digital platform (e-diary) as well as the information recorded in the eCRF during the treatment 
visits. 
The evaluation of compliance will be done using the following formula:
DRUG
ED
ADMINISTER
OF
%
100
DOSES
SCHEDULED
OF
NUMBER
TOTAL
DOSES
ED
ADMINISTER
OF
NUMBER
TOTAL


The total number of scheduled doses will be calculated on the basis of the extent (days) of exposure 
of each subject. A range 65-135 % will be taken into account for a satisfactory level of compliance.
Subjects with compliance level less than 75% will receive additional coaching during study Visits 2 
and 3.
6.8 Drug Storage
The Pharmacist/Investigator will be responsible for the safe storage of all medications assigned to 
this study, in a secure place with restricted access, and maintained within the appropriate ranges of 
temperature and humidity.
Background ICS Medication Kit for Run-in and Treatment Periods:
The boxes of QVAR® must be stored not above 25˚C (77˚F) either by Pharmacist/Investigator at the 
study site and by subjects at home. 


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Study drug for randomized Treatment Period:
CHF 5259 pMDI active and matched placebo.
The pMDI kits must be stored between 2˚C (36˚F) and 8°C (46˚F) by Pharmacist/Investigator at the 
study site.  At the clinic visit, the kit to be dispensed must be removed from the refrigerator and the 
canister(s) should be taken out of the mouthpiece(s) (actuators) and warmed with the hands for a 
few minutes before administration to the subject. The canister(s) should never be warmed by 
artificial means.
The subject should never inhale cold medication.
Once dispensed, the subjects will be instructed to keep the boxes at home at ambient temperature 
not above 25°C (77˚F) but not in the refrigerator. At this temperature condition, the residual shelf 
life of the pMDI kits will be two months (60 days). Therefore, the Pharmacist/Investigator at the 
study site must write the use-by-date on the kit labels once the kits are removed from the 
refrigerator, before assigning to the subjects. The use-by-date corresponds to the dispensing date 
plus 2 months. Please note that the use-by-date must not exceed the total shelf life of the product.
Open Label arm treatment: Spiriva powder for inhalation
SPIRIVA® HANDIHALER®: Commercial pack must be stored at ambient temperature, not above 
25˚C (77˚F) either by Pharmacist/Investigator at the study site and by subjects at home.
pMDI for training:
The pMDI training kits must be kept at site and not dispensed to the subjects. The pMDI training 
kits must be stored between 2˚C (36˚F) and 8°C (46˚F) by Pharmacist/Investigator at the study site. 
At the screening visit, the kit to be dispensed must be removed from the refrigerator and the 
canister(s) should be taken out of the mouthpiece(s) (actuators) and warmed with the hands for a 
few minutes before administration to the subject. The canister(s) should never be warmed by 
artificial means.
The subject should never inhale cold medication.  
Once used, the pMDI training kit must be kept at site at ambient temperature not above 25°C 
(77˚F), but not in the refrigerator. At this temperature condition, the residual shelf life of the pMDI 
will be three months (90 days). Therefore, the Pharmacist/Investigator at the study site must 
write the use-by-date on the kit labels once the pMDI is removed from the refrigerator, before 
using it. The use-by-date corresponds to the dispensing date plus 3 months. Please note that the 
use-by-date must not exceed the total shelf life of the product. Subject will use the same training kit 
at screening and randomization. 
The site must check the Min/Max temperatures once daily for adequate storage of ambient kits. 
The Min/Max temperatures must be recorded in a dedicated temperature tracking form. Any 
deviation to the requirement for storage will be promptly reported and Sponsor shall assess if the 
affected study drugs can still be used.


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6.9 Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the management of 
all the study drugs to be used for the study. Study drugs that should be stored in a locked, secure 
storage facility with access limited to those individuals authorized to dispense the study drugs.
An inventory will be maintained by the Investigator or pharmacist (or other designated individual), 
to include a signed account of all the study drug(s) received, dispensed and returned by each subject 
during the trial.
At the conclusion or termination of the study, the Investigator or the pharmacist shall conduct and 
document a final drug supply (used and unused) inventory. An explanation will be given for any 
discrepancies. The study drugs supplied, used or unused, will be returned to the designated 
distribution center under Sponsor’s responsibility. Return and destruction will not occur until 
authorized by Chiesi.
6.10 Provision of Additional Care
At completion of subject’s study participation, it is under the Investigator’s responsibility to 
prescribe the more appropriate treatment for the subject or to restore the initial therapy or to refer 
the subject to the General Practitioner. 
7. STUDY PLAN
7.1 Study Schedule
Table 1:  Study Flow Diagram


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Pre-
Screening
Screening
Treatment period
Follow-
Up
Visits
V0
V1
V2
V3
V4
V5
ET
Time (Weeks)
-2
0
3
6
7
Early
Termination
Window (days)
±2
±2
±2
±2
Informed consent form 

IRT – visit confirmation call







Demographic data

BDI questionnaire 


TDI questionnaire 



COPD Assessment Test (CAT)


Vital signs (SBP/DBP) a





Weight and Height

Physical examination



Medical history/Previous medication 

Concomitant medications 






Smoking Status





12-lead ECG b





Spirometry (pre & post BD) c

Pre-dose spirometry d




Post-dose serial spirometry 12h e


Hematology and Blood Chemistry



Serum pregnancy test f



Urinary pregnancy test f 



Inclusion / exclusion criteria


Eligibility recheck g

Training for use of pMDI Inhalers and e-diary


Dispensation of rescue albuterol h

24-hour holter recording  i


Schedule next visit






Randomization

e-diary completion
 (daily)
Study drug dispensation (D) / Return (R) and 
Accountability
D
D/R
R
R
Subject diary dispensation (D) /return (R)
D
D/R
D/R
R
R
Dispensation (D) of background ICS (QVAR®) j / 
return (R)
D
D/R
D/R
R
R
Adverse Events assessment 






Check for COPD Exacerbations






a At V2 and V4: SBP/DBP will be measured pre-dose and at 30 mins, 1.5h, 3.5h, 7h and 11h post-dose. At V1, V3 and Early Termination: SBP/DBP 
will be measured before the expected time of study drug administration.
b At V2 and V4: Local 12-lead ECG will be done prior to study drug intake and at 1.5h post-dose. At V1, V3 and Early Termination: Local 12-lead 
ECG will be done before the expected time of study drug administration.
c  At V1: Spirometry (FVC maneuver) will be carried out before and 30 to 45 minutes after the inhalation of 84µg of ipratropium pMDI.
d  At V2, V3, V4 and ET: Pre-dose FEV1, FVC at T -45’and T -15’ before the expected time of study drug administration. IC will be measured only 
once at T-45’ using SVC maneuver, before the FVC maneuver.
e  At V2 and V4:  Post-dose serial spirometry (FEV1, FVC) at T15’, T30’, T45’, T1h, T2h, T3h, T4h, T6h, T8h, T10h, T11.5h, T12h.
f  In women of childbearing potential only.
g  Eligibility recheck only for exclusion criteria #1, 3, 4, 5, 10, 11 and inclusion criteria # 6-8.
h One commercial albuterol HFA MDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1,
and resupplied as needed at V2-V3 based on assessment of doses used between visits.
i At V2: the 24h digital device will be placed the day before the visit and will be removed the day after the visit. At V4: the 24-hour digital device will 
be placed the day before the visit and will be removed upon arrival to the site (before any assessment).
j all subjects who have been receiving an ICS in combination with a LABA or LAMA at V1 will be switched to an equipotent dose of QVAR® and 
continued on same dose until V4 or Early Termination.


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7.1.1 Visit 0 (Pre-screening visit)
A pre-screening visit will be carried out in order to fully explain the study to potential eligible 
subject. The following procedures will take place: 
-
The written informed consent signed by the subject will be collected after the study has been 
fully explained by the investigator. The investigator or his/her designee should provide the 
subject ample time and opportunity to inquire about details of the trial and to decide whether 
or not to participate in the trial.
-
Demographic data will be collected.
-
Instructions will be given to the subject for the screening visit (Visit 1) such as concomitant 
medications to be withdrawn prior to the visit.
-
As soon as the informed consent is signed, the investigator (or his/her designee) will connect 
to IRT to allocate a unique subject’s number before discharge. 
-
A subject card with the Investigator’s contact details will be handed out to the subject.
-
An appointment for the screening visit (Visit 1) will be scheduled in the morning before 
9:00 am, within 1 week. The appointment day may vary depending on the washout period 
necessary for the subject prior to the screening visit. Subjects will be instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
Not to take albuterol or caffeinated substances in the 6 hours preceeding the next 
visit, and to abstain from all non-permitted medications in accordance with section 
5.2. unless absolutely necessary
7.1.2 Visit 1 (Screening visit /Week -2)
A screening visit will be carried out in the morning (before 9:00 am) in order to identify eligible 
consenting subjects for the study.
If any of the washouts for non-permitted medications have not been respected, the visit needs to be 
re-scheduled within 2 days. Only one re-scheduling is allowed. If any of the relevant washouts is 
not respected again on the rescheduled visit, the subject will be discontinued and recorded in the 
IRT and eCRF as screen failure.
The following procedures will take place:
-
The BDI questionnaire will be completed and BDI focal score will be assessed. Only 
subjects with a BDI focal score ≤ 10 are eligible (see section 7.2.1).
-
The COPD Assessment Test (CAT) will be completed to evaluate if the subject’s symptoms 
burden (see section 7.2.3). Subjects at screening with a CAT score ≥10 are eligible. 
-
Check for COPD exacerbations.
-
Weight and height will be recorded.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator and background ICS (QVAR®) administration, after 5 minutes of 
rest, in resting position (see section 7.2.4).
-
A 12-lead ECG will be performed before spirometry, bronchodilator and background ICS 
(QVAR®) administration, after 5 minutes of rest (see section 7.2.6). A subject will not be 
eligible in case of QTcF >450 ms for males or QTcF >470 ms for females, or in case of 


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abnormal and clinically significant 12-lead ECG that results in active medical problem 
which may impact the safety of the subject according to investigator’s judgment.
-
A medical history and smoking status will be recorded. Previous medications in the past 3 
months must be collected.
-
Concomitant medications taken by the subject will be recorded. Intake of non-permitted 
medication constitutes a non-eligibility criterion for enrollment in the study.
-
A full physical examination will be performed including assessment of oral candidiasis.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
A blood sample will be collected before bronchodilator administration, after an overnight 
fasting (at least 10h), for the assessments of (see section 7.2.9):
standard hematology and blood chemistry;
a serum -HCG test will be performed in women of childbearing potential.
The blood samples must be collected after vital signs and 12-lead ECG recording.
In case of non-interpretable data, another determination must be performed as soon as 
possible and prior to Visit 2 (randomization visit).
-
Pre-bronchodilator spirometry will be performed: the subjects will have to perform a FVC 
maneuver to assess parameters (FEV1, FVC) (see section 7.2.8).
-
Post-bronchodilator spirometry will be performed:  FEV1 and FVC test within 30-45 
minutes after intake of 4 puffs (4 x 21µg) of ATROVENT® HFA (ipratropium bromide 
HFA) will be performed. To be eligible, the following 3 criteria must be met:
o
post-bronchodilator FEV1 must be ≥40% and <80% of the subject’s predicted 
normal value, and
o
FEV1/FVC < 0.7, and
o
a post-bronchodilator increase in FEV1 ≥5% from baseline (reversibility)
 If the reversibility criterion is not met, this test can be performed once more before Visit 2 
after an appropriate washout from bronchodilators. 
-
Any AE occurred since the signature of the informed consent will be checked and recorded. 
In case of any clinically significant abnormality revealed during the physical examination or 
screening procedures, it will be recorded in the subject’s medical history, unless its start date 
is after the informed consent signature date. In this case, it will be recorded as an adverse 
event.
-
Conduct a review of all Inclusion and Exclusion criteria.  If the subject is not eligible, the 
investigator will access the IRT to record the status of the subject as a screen failure. At the 
discretion of the investigator, a subject who fails to meet all inclusion/exclusion criteria 
(screening failure) at V1 may be re-screened again, up to one additional time, after 1 month 
from the date of the initial screening failure.   A re-screened subject will be treated as a new 
subject.
-
If the subject is eligible for entry into the run-in period, he/she will be trained, with training 
kits containing placebo, to the proper use of pMDI (see section 6.2.4). The corresponding 
tear-off label will be placed in the subject specific dispensation tracking form. 
-
Subject will be instructed on how to record the medications intake (background ICS and 
rescue), respiratory symptoms, and adverse events in the electronic Diary (see section 
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The investigator will access IRT also in order to obtain the background ICS medication (one 
commercial box containing 1 canister of QVAR®) to be dispensed to the subject (previously 
on ICS at time of screening), together with instructions for use. Subject will be instructed to 
inhale 1 or 2 puffs (depending on the equipotent dose to previous ICS therapy, see section 
5.1) of run-in medication in the morning (before 10:00 am) and 1 or 2 puffs in the evening 
(before 10:00 pm). The first administration of background ICS medication (QVAR®) 
will take place at the clinic visit (before 10:00 am) under medical supervision. 
-
Subject will be instructed to stop the non-permitted COPD medications in accordance with 
section 5.2.
-
Rescue albuterol, for as needed use, will be dispensed by the Investigator. Subjects will keep 
this rescue medication throughout the study period (will be re-supplied if needed); 
nevertheless subject will be instructed to bring this medication at each visit in order to check 
the need for replacement.
Before discharge
-
Background ICS medication for the run-in period (QVAR®) will be dispensed for those 
subjects previously receiving an ICS and the corresponding tear-off label will be placed in 
the subject specific dispensation tracking form and the kit number will be recorded in the 
corresponding electronic CRF (eCRF). The subjects will be instructed to inhale 1 or 2 puffs 
in the morning and 1 or 2 puffs in the evening of the canister in the run-in kit with the 
exception of the morning of the next clinic visit (Visit 2). Subject will be also instructed 
to take albuterol as rescue if necessary. 
-
An electronic diary will be dispensed. Subject must complete the Diary each day, until 
Visit 2. It is important to ensure good compliance of the subject to the use of the diary 
during the run-in period.
-
An appointment for the day before Visit 2 (in order to place the 24hr Holter) will be 
scheduled.
-
An appointment for Visit 2 will be made within 2 weeks (+2 days) time from Visit 1, in the 
morning (at approximately the same time of the day) before 9:00 am. Subjects will be 
instructed:
Not to take albuterol or caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from all non-permitted medications in accordance with section 
5.2 unless absolutely necessary.
For those subjects prescribed QVAR® : Not to take background ICS medication 
(QVAR®) in the morning of the next visit.
To bring back the run-in and rescue medications (in their boxes), and the electronic 
Diary. 
7.1.3 Visit 2 (Randomization/ Start of Treatment Period /Week 0)
Reminder:  Subject must visit clinic one day prior to Visit 2, in order to have the ambulatory 
24-hour digital Holter placed and activated.  On Visit 2, the Holter recording will continue for 


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24-hours after morning study drug administration (until the following morning).  Subject will 
return to the clinic the day after Visit 2 in order to have the Holter removed.
The Visit 2 will start in the morning (before 9:00 am).
If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, the 
washout for non-permitted medications has not been respected, or run-in ICS medication (QVAR®) 
has been taken in the morning of the visit (prior to spirometry), the visit needs to be re-scheduled to 
take place within 2 days. Only one re-scheduling is allowed. If any of these relevant washouts is not 
respected again on the morning of the re-scheduled visit, the subject will be discontinued and 
recorded as screen failure in the IRT and eCRF.
The following pre-dose procedures will be performed:
-
The BDI questionnaire will be completed and BDI focal score will be assessed. Only 
subjects with a BDI focal score ≤ 10 are eligible (see section 7.2.1).
-
The COPD Assessment Test (CAT) will be completed to evaluate if the subject’s burden of 
COPD symptoms (see section 7.2.3). Subjects at screening with a CAT score ≥10 are 
eligible. 
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, background ICS medication (QVAR®) or study drug 
administration, after 5 minutes of rest, in resting position (see section 7.2.4).
-
12-lead ECG will be measured before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.6)
-
Changes of concomitant medications being taken by the subject will be recorded. In case of 
intake of any non-permitted concomitant medication, the subject will be withdrawn from the 
study and recorded as screen failure in the IRT. (see section 5.2).
-
A urine pregnancy test in women with childbearing potential will be performed.
-
Changes of smoking status will be recorded; pharmacological smoking cessation therapies 
started during the study will be recorded as concomitant medications.
-
Background ICS medication dispensed for the run-in period (QVAR®) will be collected.
-
The investigator will check the electronic Diary to confirm compliance.  In case of lack of 
compliance, instructions on how to complete the diary will be given again to the subject 
(see section 7.2.11).
-
The occurrence of COPD exacerbations will be evaluated (see section 7.2.12) and data 
recorded in the eCRF. In case of exacerbation during the run-in, the subject will not be 
randomized (see also sections 5) and recorded as screen failure in the IRT.
-
The occurrence of other adverse events will be checked and recorded if any.
-
The proper use of pressurized metered dose inhaler will be checked and subject will be 
retrained on the usage of the pMDI using the Training kit previously assigned at Visit 1 (see 
section 6.2.4).
-
Eligibility criteria will be rechecked: (Inclusion criteria # 6-8 and Exclusion criteria # 1, 3, 
4, 5, 10 and 11). At the discretion of the investigator, a subject who fails to meet all 
inclusion/exclusion criteria (screening failure) at V2 may be re-screened again, up to one 


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additional time, after 1 month from the date of the initial screening failure. A re-screened 
subject will be treated as a new subject.  
For eligible subjects:
-
The subject will be randomized and the study treatment will be allocated according to the 
central randomization system. Investigator will access IRT in order to obtain the appropriate 
kit number for the first 3-week treatment period. 
-
Pre-dose spirometry: pre-dose spirometry measurements will then be performed to assess 
FEV1, FVC and IC at -45 min and to assess FEV1 and FVC also at -15 min prior to first 
dose of study drug. These measurements will constitute the baseline values (see section 
7.2.8). 
-
For subjects randomized to receive open-label SPIRIVA® HandiHaler®, the Investigator 
will instruct subjects on how to use SPIRIVA® by reading together and showing the FDA-
approved Patient Information Leaflet to the subjects, in accordance with section 6.2.4.
-
The administration of the 1st dose of study drug will take place at the clinic visit (before 
10:00 am) under supervision of the Investigator. The corresponding tear-off labels will be 
placed in the dispensation tracking form and the kit number will be recorded in the 
corresponding electronic CRF (eCRF). The use-by-date must be filled-in on the labels. Drug 
administration will be done according to section 6.2.3. For those receiving background ICS, 
the morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at Visit 1.
-
Post-dose Vital signs (SBP and DBP) will be measured after 5 minutes of rest at 30 minutes, 
1.5h, 3.5h, 7h, 11h post-dose (see section 7.2.4).
-
Post-dose 12-lead ECG will be measured after 5 minutes of rest at 1.5h post-dose (see 
section 7.2.6)
-
Post-dose spirometry (FEV1, FVC) will be performed at T15’, T30’, T45’, T1h, T2h, T3h 
T4h, T6h, T8h, T10h, T11.5h, T12h. For each time point, spirometry consists of three 
acceptable maneuvers (see sections 7.2.8).
Before discharge
-
Study drug will be dispensed to the subject together with instructions for use. Drug 
administration will be done according to section 6.2.3. Subject will be instructed to take 
albuterol as rescue if necessary. Investigator will also dispense albuterol if needed.
-
The electronic Diary will be returned to the subject. Subject will be reminded to continue 
to complete the electronic Diary each day until Visit 3.
-
An appointment for Visit 3 will be made at 3 weeks (±2 days) from Visit 2 (at 
approximately the same time as Visit 2, before 9:00 am). The subject will be instructed:
To bring back the study drug (in the box) and the Diary at the next visit.
Not to take albuterol or caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from all non-permitted medications in accordance with section 
5.2 unless absolutely necessary. 
Not to take the morning dose of the study drug before coming to the next clinic visit 
(it will be administered at the clinic visit).


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For those subjects prescribed QVAR® at Visit 1: Not to take the morning dose of 
QVAR® before coming to the next clinic visit (it will be administered at the clinic visit, 
immediately after the dose of study drug).
-
The Investigator will access IRT in order to record completion of the study visit.
7.1.4 Visit 3 (Week 3 of Treatment Period)
The Visit 3 will start in the morning (before 9:00 am).
If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, or the 
washout for non-permitted medications has not been respected or the study drug has been taken on 
the morning of the visit (prior to spirometry), the visit needs to be re-scheduled to take place within 
2 days. Only one re-scheduling is allowed. If any of these relevant washouts is not respected  again 
on the morning of the re-scheduled visit, the visit will be performed anyway and the time of the 
intake and the number of puffs of rescue medication or of the medication with washout not 
respected will be recorded in the eCRF.
The following pre-dose procedures will be performed:
-
The TDI questionnaire will be completed (see section 7.2.2).
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, background ICS medication (QVAR®) or study drug 
administration, after 5 minutes of rest, in resting position (see section 7.2.4).
-
12-lead ECG will be measured before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.6)
-
Changes of concomitant medications being taken by the subject will be recorded. In case of 
intake of any non-permitted concomitant medication, the subject will be withdrawn from the 
study and recorded as Early Termination in the IRT (see section 5.2).
-
A urine pregnancy test in women with childbearing potential will be performed (see section 
7.2.10).
-
Pre-dose spirometry:  pre-dose spirometry measurements will be then performed to assess 
FEV1, FVC and IC at -45 min and to assess FEV1 and FVC also at -15 min prior to morning 
dose of study drug (see section 7.2.8). 
-
Changes of smoking status will be recorded; pharmacological smoking cessation therapies 
started during the study will be recorded as concomitant medications.
-
The investigator will check in the e-diary to confirm compliance.  In case of lack of 
compliance, instructions on how to complete the diary will be given again to the subject 
(see section 7.2.11).
-
The investigator will collect study drug dispensed at Visit 2 and perform accountability.
-
The occurrence of COPD exacerbations will be evaluated (see section 7.2.12) and data 
recorded in the eCRF. In case a COPD exacerbation occurs post-randomization, the subject 
will be discontinued from the study and an Early Termination visit performed and recorded 
in the eCRF and the IRT.
-
The occurrence of other adverse events will be checked and recorded if any.


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-
The morning dose of study medication will be administered at the clinic (before 10:00 
am) under supervision of the Investigator from the kit dispensed at Visit 2. For those 
subjects prescribed QVAR® at Visit 1: morning dose will be administered at the clinic visit, 
immediately after the dose of study drug.
-
The Investigator will access IRT to record completion of the study visit.
Before discharge
-
Study drug (Visit 3 kit) will be dispensed to the subject together with instructions for use. 
Subject will be instructed to take albuterol as rescue if necessary.  For administration of 
study medications, subject will be given the same instructions as the ones given at Visit 2. 
-
The electronic Diary will be returned to the subject. Subject must continue to complete 
the e-diary each day until Visit 4.
-
An appointment for the day before Visit 4 (in order to place the 24hr Holter) will be 
scheduled.
-
An appointment for Visit 4 will be made within 3 weeks from Visit 3 (at approximately the 
same time as other visits, before 9:00 am). The time window should not exceed 6 weeks 
(±2 days) from Visit 2.
The subject will be instructed:
To bring back the study drug (in the box), and the e-diary at the next visit.
Not to take albuterol or caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from all non-permitted medications in accordance with section 
5.2 unless absolutely necessary. 
Not to take the morning dose of the study drug before coming to the clinic visit (it 
will be administered at the clinic visit).
For those subjects prescribed QVAR® at Visit 1: Not to take the morning dose of 
QVAR® before coming to the next clinic visit (it will be administered at the clinic visit, 
immediately after the dose of study drug).
To fast overnight (at least 10 hours) for the next visit in order to perform blood sampling 
(only water is allowed).
7.1.5 Visit 4 (Week 6 of Treatment Period)
Reminder:  Subject must visit clinic one day prior to Visit 4, in order to have the ambulatory 
24-hour digital Holter placed and activated.  Monitoring will continue for 24-hours until the 
following morning (Visit 4 date) when  subject will have the Holter removed.
The Visit 4 will start in the morning (before 9:00 am). 
If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, or the 
washout for non-permitted medications has not been respected or the study drug has been taken on 
the morning of the visit (prior to spirometry), the visit needs to be re-scheduled to take place within 
2 days.  Only one re-scheduling is allowed. If any of these relevant washouts is not respected again 
on the morning of the re-scheduled visit, the visit will be performed anyway and the time of the 


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intake and the number of puffs of rescue medication or of the medication with washout not 
respected will be recorded in the eCRF.
The following pre-dose procedures will be performed:
-
The TDI questionnaire will be filled in by the subject and TDI score will be assessed before 
the study treatment dose intake (see section 7.2.2). 
-
Pre-dose vital signs (SBP and DBP) will be measured, before spirometry, bronchodilator, 
background ICS medication (QVAR®) or study drug, after 5 minutes of rest (see section 
7.2.4).
-
12-lead ECG will be measured before before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest, in resting 
position
-
Pre-dose spirometry: pre-dose spirometry measurements will then be performed to assess 
FEV1, FVC and IC at -45 min and to assess FEV1 and FVC also at -15 min prior to last dose 
of study drug (see section 7.2.8). 
-
Changes of concomitant medications being taken by the subject will be recorded. 
-
A full physical examination will be performed including assessment of oral candidiasis.
-
Changes of smoking status will be recorded; pharmacological smoking cessation therapies 
started during the study will be recorded as concomitant medications.
-
The investigator will check the e-diary to confirm compliance, and assess adverse events.  
-
The study drug (in the box) provided at Visit 3 will be collected. 
-
The occurrence of COPD exacerbations and other adverse events will be evaluated and 
recorded in the eCRF (if any) (see section 7.2.12). 
-
A blood sample will be collected prior to study drug administration and after an overnight 
fasting for the assessments of (see section 7.2.9): 
standard hematology and blood chemistry;
a serum -HCG test will be performed in women of childbearing potential.
The blood sample must be collected after the vital signs and 12-lead ECG recording.
In case of non-interpretable data, another determination must be performed as soon as 
possible.
-
The 24hr Holter device will be disconnected (but the dual snap leads kept until completion 
of post-dose ECGs). 
-
The morning dose of study medication will be administered at the clinic (before 10:00 
am) under supervision of the Investigator from the kit dispensed at Visit 3.  This will 
be the last dose of study drug. Subjects maintained on QVAR® since Visit 1 will also 
receive their last dose at the clinic visit, immediately after the dose of study drug.
-
Post-dose vital signs (SBP and DBP) will be measured at 30 minutes, 1.5h, 3.5h, 7h, 11h 
post-dose, after 5 minutes of rest (see section 7.2.4).
-
Post-dose 12-lead ECG will be measured at 1.5hr post dosing, after 5 minutes of rest, in 
resting position (see section 7.2.6)
-
Post-dose spirometry (FEV1, FVC) will be performed T15’, T30’, T45’,T1h, T2h, T3h, T4h, 
T6h, T8h, T10h, T11.5h, T12h. For each time point, spirometry consists in three acceptable 
maneuvers (see sections 7.2.7).
-
 Investigator will access IRT in order to record completion of the study visit. 


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Before discharge at Visit 4
-
All study material (study drug, background ICS treatment (QVAR®), rescue 
medications, e-diary) will be collected.
-
The investigator will prescribe each subject an appropriate treatment or restore their initial 
therapy or refer them to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
7.1.6 Follow-up Phone Call (Visit 5)
A safety follow up phone call will be performed by the investigator or designated staff no later than 
1 week after the final visit (Visit 4) or Early Termination Visit to check the status of unresolved 
AEs and to record any COPD exacerbation or new AEs that may have occurred after Visit 4, as well 
as related concomitant medications. Investigator will access IRT in order to record completion of 
the study visit.
7.1.7 Early Termination Visit
If a subject prematurely discontinues the study after randomization, all efforts will be made to 
perform an Early Termination visit which will include the following assessments, providing there 
are no safety issues for the subject and in accordance with the subject’s agreement:
-
All study material (Study and rescue medications, subject diary) will be collected
-
Site to update IRT
-
The TDI questionnaire will be completed.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, or study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.4).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, or study drug 
administration, after 5 minutes of rest (see section 7.2.6). 
-
The investigator will check in the electronic diary portal whether subject has been 
transmitting data daily since previous visit. 
-
Changes of smoking status will be recorded; pharmacological smoking cessation therapies 
started during the study will be recorded as concomitant medications.
-
Changes of concomitant medications being taken by the subject will be recorded. 
-
A full physical examination will be performed, including assessment of oral candidiasis.
-
A blood sample will be collected, after an overnight fasting (at least 10h, when possible), for 
the assessments of (see section 7.2.9):
standard hematology and blood chemistry;
a serum -HCG test in women of childbearing potential.
The blood samples must be collected after vital signs and 12-lead ECG recording.
-
The occurrence of COPD exacerbation or other adverse events will be checked and recorded 
if any.
-
Pre-dose spirometry: pre-dose spirometry measurements will then be performed to assess 
FEV1, FVC and IC at -45 min and to assess FEV1 and FVC also at -15 min prior to the 


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expected time for the morning dose of study drug (at approximately the same time as done 
on V2). 
-
The investigator will prescribe each subject an appropriate treatment or restore their initial 
therapy or refer them to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
7.2 Investigations (by order of conduct):
7.2.1 BDI Questionnaire
The Baseline Dyspnea Index (BDI)[61] is a validated, interviewer-administered rating of severity of 
dyspnea. It provides a multidimensional measurement of dyspnea that evokes dyspnea in activities 
of daily living, in symptomatic individuals during the last 2 weeks. The BDI consists of 24 items 
divided into 3 domains: Functional Impairment, Magnitude of Task, and Magnitude of Effort.  Each 
category is rated on a 5-point scale from 0 (very severe) to 4 (no impairment), with a total score 
ranging from 0-12. 
The same investigator or designee will interview the subject for the BDI and TDI during the study 
period. BDI will be assessed at V1 and the morning of V2. 
7.2.2 TDI Questionnaire
The Transitional Dyspnea Index (TDI) is a validated,[62] interviewer-administered questionnaire 
that measures changes in dyspnea severity from the baseline established by the BDI.  TDI consists 
of the same 24 items and 3 domains as the BDI, with the same 2-week recall period.  Each category 
is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total 
score ranging from -9 to +9. The MCID is considered a change of ≥1 unit [63]. 
The same investigator or designee will interview the subject for the BDI and TDI during the study 
period. TDI will be assessed at V3, V4 and Early Termination. 
7.2.3 COPD Assessment Test (CAT™)
The CAT is a subject-completed validated questionnaire [64][65] to measure the global impact of 
COPD on a subject’s life in an objective way and to monitor changes over time. It consists of 8 
items scored on a scale of 1 to 5, with a total score range of 0-40. A higher score denotes a more 
severe impact of COPD on the subject’s life. No target score represents the best achievable 
outcome.  Although an MCID has not been determined, mapping to the SGRQ suggests a group-
level MCID of 1.6 units.  Experts also have suggested that a score < 10 = low impact; 10-20 = 
medium impact, 21-30 = high impact, and > 30 a very high impact. 
The CAT has been used in the GOLD 2011 and GOLD 2017 Reports.  A CAT score of ≥ 10 points 
is considered an indicator of a high symptom burden (GOLD category B & D)[2] and a threshold 
for initiating regular treatment of COPD symptoms including dyspnea.[66] 
The subject will complete the CAT at V1 and V2.  


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7.2.4 Vital Signs 
Systolic and diastolic blood pressure will be measured before spirometry, bronchodilator, QVAR® 
or study drug administration, after 5 min rest in resting position. At Visit 2 and Visit 4, the 
measurements will be done pre-dose and at 30 mins, 1.5h, 3.5h, 7h and 11h post-dose. At Visit 1, 
Visit 3 and Early Termination, the measurements will be done before the expected time of study 
drug administration. SBP and DBP have to be assessed twice with at least 2 minutes elapsing 
between the two measurements. The final SBP and DBP values to be considered are the means of 
the two measurements respectively. These measurements will be repeated at all visits at the same 
time.
7.2.5 Physical Exam and assessment of oral candidiasis
A full physical examination will be performed at V1, V4 and Early Termination, including an 
assessment of oral candidiasis. 
Oropharyngeal candidiasis is a condition commonly associated with the use of ICS, and is cause by 
the Candida fungus. This side effect may be attributed to the topical effects of these medications on 
the oral mucosa.[26] Generalized immunosuppressive and anti-inflammatory effects of steroids are 
thought to play a major role in the pathogenesis of candidiasis.[67] Asthmatics who are using β-2 
agonists show a decreased salivary flow rate, which in turn can be associated with higher oral 
Candida counts.[68]
The subject’s mouth and throat will be visually inspected by the investigator at every study visit to 
look for the presence of characteristic-looking white lesions / oral thrush. If deemed necessary by 
the investigator to confirm the diagnosis, the suspected lesion should be swabbed/scraped with a 
sterile cotton and the tissue sample sent to a laboratory for microscopic and culture identification.  
Appropriate treatment of oropharyngeal thrush (e.g. using topical rinses and oral anti-fungal agents) 
can be prescribed at the discretion of the study investigator as deemed necessary throughout the 
study.
7.2.6 12-lead ECG
A 12-lead ECG will be performed at visits 1, 2, 3 and 4 to verify the subject’s cardiac safety 
parameters and his/her eligibility. At Visit 2 and Visit 4, the ECG will be done prior to study drug 
intake and at 1.5h post-dose. At V1, V3 and Early Termination, the ECG will be done before the 
expected time of study drug administration. Subjects will receive instructions to refrain from intake 
of caffeinated beverages or foods past midnight before the visit date. Prior to recording, the subject 
should be at rest for at least 5 minutes. 
Safety ECGs (10-sec strip) will be taken using the site’s own instrument. Standard electrode 
placement will be used for these ECGs, including placing the limb leads; dual snap electrodes will 
be used for the precordial leads. The ECG will be evaluated by the investigator/sub-investigator on-
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The QTc interval value will be calculated using the Fridericia formula (Fridericia-corrected QTc=
). It will be calculated automatically by the ECG recorder. Heart rate (HR), PR and QRS 
𝑄𝑇
3 𝑅𝑅
interval values will be also evaluated from ECG at all visits.
ECGs with computerized protocol interpretation are considered normal if: 
-
40 ≤ Heart rate ≤ 110 bpm, 
-
120 ms ≤ PR interval ≤ 210 ms 
-
QRS interval ≤ 120 ms
For eligible subjects, QTcF values must be QTcF ≤ 450 (for males) and 470 ms (for females) (as 
per Exclusion Criterion #11).
In case of relevant ECG abnormalities, the inclusion of the subject will be judged by the 
investigator. If there are any doubts the Investigator may consult the study’s medical monitor. The 
final decision for enrolment would be documented in the Medical File of the subject.  Clinically 
significant abnormalities at Visit 1 not due to a pre-existing condition or clinically 
significant changes at the following visits, in the medical opinion of the investigator, will be 
reported as adverse events in the eCRF.
7.2.7 24-hour digital ECG Holter Recorder
Subjects will have an ambulatory 24-hour digital Holter recording for 24 hours before and 24 hours 
after the 1st dose of study drug (Visit 2) and for 24 hours before the last dose of study drug (Visit 4). 
Two sets of analysis will be conducted for this trial: arrhythmia and electrocardiographic analysis.
For the arrhythmia analysis, the 12-lead Holter recording will be scanned for the presence or 
absence of arrhythmia including, but not limited to:

Atrial fibrillation,

Sinus Pauses,

PACs,

SVT,

PVCs,

Ventricular tachycardia,

AV Blocks.
Details of arrhythmia analysis and how the Holter variables are calculated will be provided in the 
Holter Analysis Plan.
The ECGs database will be made from discrete 12-lead ECGs (10-sec recording duration each) that 
will be extracted from the Holter recording. To facilitate data quality, the subject will be asked to 
assume a supine posture and remain quiet, but awake, beginning at 10 minutes before the nominal 
extraction time and then for five minutes afterward. For each subject, there will be:

3 nominal extraction times in the day before Visit 2 (time-matched with the post-study drug 
extraction times on Visit 2); 

3 extraction times at +5min, +55min, and +2.5h after 1st dose of study drug on Visit 2; and

3 extraction times at +5min, +55min, and +2.5h after the morning dose of study drug on the 
day before Visit 4. 


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ECGs taken from the Holter recording will have the limb leads placed on the torso. At each nominal 
timepoint, ECGs will be extracted in triplicate, separated by 30-second intervals.
In addition, HR will be extracted and the average calculated on hourly basis during each 24 hour 
monitoring period.
A detailed description and training on the 24hr Holter procedure will be provided by 
 
(
).
7.2.8 Pulmonary Function Test
All pulmonary function tests including FEV1 and FVC will be performed in accordance with 
ATS/ERS spirometry criteria,[69] using standardized equipment provided by a Contract Research 
Organization.  The specific procedures for centralized spirometry will be provided to the 
investigator by the centralized spirometry company (
). The investigator 
and/or qualified delegate will be trained by 
 on the calibration and testing procedures for the 
spirometer prior to the scheduled first subject’s visit.
 
Pulmonary function measurements will be done with subjects in sitting position with the nose 
clipped after at least 10 minutes rest. Calibration of the spirometer must be performed by the same 
investigator or deputy (to the extent possible) at each visit prior to any spirometry maneuvers and 
the reports must be kept with the source study documents.
Throughout the study (after randomization), the clinic visits and the lung function measurements 
will start in the morning between 7:00 and 9:00 a.m. preferably, approximately at the same time of 
the day for each subject.
The following parameters will be recorded at Visits 1, 2, 3 and 4 or Early Termination Visit:
Forced Expiratory Volume in the 1st second (FEV1, L)
o
The volume exhaled during the first second of a forced expiratory maneuver starting 
from the level of total lung capacity. FEV1 is decreased in obstructive lung diseases.
Forced Vital Capacity (FVC, L)
o
The maximal volume of gas that can be exhaled from full inhalation by exhaling as 
forcefully and rapidly as possible.
The following parameter will be recorded at Visits 2, 3 and 4 or Early Termination Visit:
Inspiratory Capacity (IC, L)
o
The volume of air that can be inspired without hesitation, after a normal, relaxed 
expiration. It is the sum of the tidal volume and the inspiratory reserve volume. It 
equates to the difference between the Total Lung Capacity (TLC) and Functional 
Residual Capacity (FRC, or the amount of gas remaining at the end of normal quiet 
respiration). IC is decreased in obstructive lung diseases. 
The following parameter will be recorded at Visit 1:


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FEV1/FVC also called Tiffeneau-Pinelli index, is a calculated ratio used in the diagnosis of 
obstructive and restrictive lung disease. It represents the proportion of a person's vital 
capacity that they are able to expire in the first second of forced expiration.[70]
Note: some additional standard parameters (for instance PEF, FEF25-75%) will be assessed by the 
spirometer during the visit only for the investigator’s information purpose.
Predicted normal value for FEV1 will be calculated using the Third National Health and Nutrition 
Examination Survey (NHANES III) reference equations.[71]
Subjects should be relaxed (shoulders down and relaxed) and asked to breathe regularly for several 
breaths until the end expiratory lung volume is stable (this usually requires at least three tidal 
maneuvers). They are then urged to take a deep breath to TLC (Total Lung Capacity) with no 
hesitation. FEV1 and FVC will be recorded at each clinic visit from a forced vital capacity 
maneuver. The highest FVC and the highest FEV1 (values corrected for BTPS) will be selected after 
examining the data from all of the usable spirograms, even if they do not come from the same 
maneuver. An adequate test requires a minimum of 3 acceptable FVC maneuvers.
Acceptable repeatability is achieved when the difference between the largest and the next largest 
FEV1 and FVC is ≤ 150mL (≤ 100 mL when FVC is < 1L).[72] If these criteria are not met in 3 
maneuvers, additional trials should be attempted, up to, but usually no more than 8. 
IC will be assessed at -45 min pre-dose at V2, V3, V4 and Early Termination using the Slow Vital 
Capacity (SVC) maneuver. The average of at least 3 acceptable slow vital capacity (SVC) 
maneuvers will be recorded. Acceptable IC repeatability is considered when the coefficient of 
variation for all IC values is ≤ 6%. The SVC maneuvers must be performed before the FVC 
maneuvers used to assess FEV1.
In the rare event where a subject shows a progressive decline in FEV1 or FVC with a 
cumulative drop exceeding 20% of start value, the test procedure should be terminated in the 
interest of subject safety.
The rescue medication (albuterol) must be withheld as much as possible for at least 6 hours prior to 
starting the pre-dose assessment at each visit. If the subject requires rescue medication within this 
timeframe, the visit should be rescheduled once within the three next days.
During the serial 12-hour spirometry, rescue medication (albuterol) use should be avoided as much 
as possible, and administered only under investigator’s oversight. The serial measurements may 
continue after rescue treatment intake, if there is no safety risk to the subject. Details including 
exact time of the intake of rescue medication during the study visits must be recorded in the eCRF. 
The run-in medication (QVAR®) or the study drug should not be taken on the morning of the visit. 
If taken, the measurements should be deferred (i.e. the visit needs to be re-scheduled to take place 
within 2 days). Repeated failure (more than once) to meet the washout window at Visit 1 and Visit 
2 will result in a screening failure and the subject’s permanent discontinuation from the study. All 
efforts need to be taken to respect the washout periods for Visit 3 and Visit 4.


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To optimize the treatment response in this study, subjects will be required to demonstrate a 
bronchodilator response (airway reversibility) to ipratropium at Visit 1. Baseline (pre-
bronchodilator) spirometry will be assessed before administration of the bronchodilator, and 
reversibility (post-bronchodilator) will be assessed with triplicate FVC maneuvers (as described 
above) at 30-45 minutes after administration of 4 separate doses of ATROVENT® HFA 
(ipratropium bromide HFA) Inhalation Aerosol (21µg/ actuation, total dose = 84µg) at 30-sec 
intervals.[73][74][75] The following inclusion criteria must be met at Visit 1:

A post-bronchodilator FEV1/FVC ratio of < 0.7, and

a post-bronchodilator FEV1 ≥40% and <80% of the predicted normal value.

An increase in FEV1 of ≥5% from pre-bronchodilator value constitutes a positive 
reversibility test.[59][76] In case the reversibility threshold is not met at screening, the test 
can be performed once before randomization. 
At Visit 2, Visit 3, and Visit 4, spirometry will be conducted at 45 and 15 minutes pre-morning 
dose. At Visit 2 and Visit 4, spirometry will be conducted also at 15, 30, 45 minutes, 1h, 2h, 3h, 4h, 
6h, 8h, 10h, 11.5h and 12h post-morning dose. Time excursions for serial spirometry assessments 
should be avoided and kept to a minimum as follows: ±5 min for assessments done pre-dose and 
during the first hour post-dose; ±10 min during hours 2-6 and 11.5 – 12 post-dose; and ±15 min 
during hours 8-10 post-dose.
At the Early Termination Visit, spirometry will be conducted at 45 and 15 minutes before the 
expected time of dosing (the subject will not be dosed) only.
7.2.9 Blood Hematology and Chemistry
Blood samples of approximately 12 mL will be collected for hematology and serum chemistry at 
Visit 1 (screening), Visit 4 and Early Termination in the morning, after an overnight fasting of at 
least 10 hours (only water is allowed during the night). The blood withdrawal should be performed 
after vital signs and 12-lead ECG recording and before administration of ipratropium, QVAR® or 
study drug.  An additional blood sample will be collected for serum pregnancy test in women of 
childbearing potential at these Visits.
The following evaluations will be performed using a central laboratory:

Hematology test: red blood cells count (RBC), white blood cells count (WBC) and 
differential, total hemoglobin (Hb), hematocrit (Hct), and platelets count (PLT).

Serum chemistry test: blood urea nitrogen (BUN), cholesterol, triglycerides, creatinine, uric 
acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma-glutamyl 
transpeptidase (γ-GT), total bilirubin, alkaline phosphatases, albumin, total proteins, and 
electrolytes (sodium, potassium, calcium, and chloride). 

Fasting blood glucose

Serum pregnancy test (serum β-hCG) in women of child-bearing potential.
Blood collection and sample preparation will be performed according to procedures provided by the 
laboratory which will be in charge to transmit the results to the Investigator. In case of clinically 
significant abnormality, findings will be reported in the medical history (if occurred at Visit 1), or 
as an Adverse Event (if occurred after Visit 1). 
 


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7.2.10 Urine Pregnancy Test
A urine pregnancy test will be administered using a commercial urine hCG pregnancy test strip. 
This test kit is used to obtain a quick (within a few minutes), visual, qualitative result for the early 
detection of pregnancy at Visit 1, Visit 2 and Visit 3.
7.2.11 Daily Subject Diary
Daily symptom assessments offers several potential advantages over periodic assessments, 
including 1) reduced recall bias, providing a prospective, daily account of symptom severity, 2) 
information on day-to-day symptom variability, 3) analytical flexibility, allowing the evaluation of 
symptoms over various time intervals.
To date, however, there is no standardized method for evaluating respiratory symptoms of stable 
COPD.[77][78] Formerly known as the EXACT-Respiratory Symptoms Scale, the Evaluating 
Respiratory Symptom in COPD (E-RS™: COPD) instrument uses 11 respiratory symptom items 
from the 14-item questionnaire, and has been shown to be a reliable, valid and responsive measure 
of respiratory symptom severity in stable COPD, suitable for use in clinical trials. The E-RS total 
score quantifies respiratory symptom severity and 3 domains: breathlessness, cough and sputum, 
and chest symptoms. 
 
 
Higher E-RS scores indicate more severe symptoms and a declining 
total score indicates health improvement. 
Using the electronic diary dispensed at V1, subjects will be instructed to enter once daily a record of 
their COPD symptom scores and for each 24h period as follows: 

Subjects are instructed to complete the E-RS diary each evening just prior to bedtime, 
reflecting back on their experiences “today”.[79]  

Enter daily number of study drug doses taken.  

Enter daily number of albuterol rescue doses taken.

Record daily all doses of QVAR® (only for subjects on background ICS).
7.2.12 Handling of COPD Exacerbations:
Subjects who experience a moderate or severe COPD exacerbation any time after screening (V1) as 
defined below will be instructed to visit the site as soon as possible for an Early Termination Visit 
and will be withdrawn permanently from the study. The Adverse Event form will be completed and 
appropriate medical management of the COPD exacerbation according to standard medical practice 
will be ensured by the study investigator, with the aim to preserve the research subject’s wellbeing 
at all times.
A COPD exacerbation is defined as “a sustained worsening of the subject’s condition (increased 
dyspnoea, cough, wheeze, sputum purulence/volume), from the stable state and beyond normal day-
to-day variations, that is acute in onset and necessitates a change in regular medication including 
prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalization.”
The exacerbations will be classified as:


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
Moderate exacerbations will be defined as worsening symptoms of COPD necessitating 
treatment with SABD plus oral corticosteroids and/or antibiotics;

Severe exacerbations will be similar events that necessitate visits to the emergency room, 
require hospital admission or result in death. Severe exacerbations may also be associated 
with acute respiratory failure.[2][80] 
8. EFFICACY ASSESSMENTS
Primary efficacy variable

Change from baseline in FEV1 AUC0-12h normalized by time at Week 6
Secondary efficacy variables

Change from baseline in FEV1 AUC0-12h normalized by time at Day 1

Change from baseline in FEV1 AUC0-4h normalized by time and in FEV1 peak0-4h  at Day 1 
and Week 6

Change from baseline in FVC AUC0-12h normalized by time, in FVC AUC0-4h normalized by 
time and in FVC peak0-4h  at Day 1 and Week 6

Time to onset of action (change from baseline in post-dose FEV1 ≥ 100 mL[15][81]) at Day 
1 

Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) 
at Week 3 and Week 6

Change from baseline in pre-dose morning IC at Week 3 and Week 6

TDI focal score at Week 3 and Week 6

TDI response (TDI focal score ≥ 1) at Week 3 and Week 6

Change from baseline in percentage of rescue medication-free days during inter-visit periods 
and entire treatment period

Change from baseline in average use of rescue medication (number of puffs/day) during 
inter-visit periods and entire treatment period

Change from baseline in average E-RS total score and domain scores during inter-visit 
periods and entire treatment period
9. SAFETY ASSESSMENTS

Adverse Events (AEs) and Adverse Drug Reactions (ADRs)

Vital signs (systolic and diastolic blood pressure) 

24-hour digital Holter ECG parameters (HR, QTcF, QRS, PR)

24-hour HR average, minimum and maximum and hourly average HR

24-hour Holter ECG abnormal findings 

Standard blood chemistry and hematology
10. ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event is “any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment”.


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An adverse event can therefore be any unfavorable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.
An Adverse Drug Reaction is an “untoward and unintended responses to an investigational 
medicinal product related to any dose administered”.
All adverse events judged by either the reporting Investigator or the Sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression “reasonable 
causal relationship” means to convey in general that there are facts (evidence) or arguments meant 
to suggest a causal relationship.
The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.
A Serious Adverse Event (SAE)/Serious Adverse Drug Reaction (SADR) is any untoward 
medical occurrence or effect that at any dose falls in one or more of the following categories:
-
Results in death
Death is not an adverse event but an outcome. It is the cause of death that should be regarded as the 
adverse event. The only exception to this rule is “sudden death” where no cause has been 
established; in this latter instance, “sudden death” should be regarded as the adverse event and 
“fatal” as its reason for being serious.
-
Is life-threatening
Life-threatening refers to an event in which the subject was at risk of death at the time of the event 
(e.g., aplastic anemia, acute renal failure, and anaphylaxis). The term does not refer to an event 
which hypothetically might have caused death if it were more severe.
-
Requires hospitalization or prolongation of existing hospitalization
Hospitalization refers to a situation whereby an AE is associated with unplanned formal overnight 
admission into hospital, usually for purpose of investigating and/or treating the AE. Hospitalization 
for the treatment of a medical condition that occurs on an “elective” or “scheduled” basis or for a 
pre-existing condition that did not worsen during the study should not necessarily be regarded as an 
AE. Complications that occur during the hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. Emergency room visits that do not result in a formal admission 
into hospital should be evaluated for one of the other seriousness criteria (e.g., life-threatening; 
persistent or significant disability or incapacity; medically significant).
-
Results in persistent or significant disability or incapacity.
The term significant disability should be viewed as any situation whereby an AE has a clinically 
important effect on the subject’s physical or psychological well-being to the extent that the subject 
is unable to function normally.
-
      Is a congenital anomaly or birth defect
-
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This criterion allows for any situations in which important adverse events/reactions that are not 
immediately life-threatening or do not result in death or hospitalization may jeopardise the subject’s 
health or may require intervention to prevent one of the above outcomes.  Examples of such events 
are: intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse.
Medical and scientific judgment should be exercised in deciding whether an event is serious 
because medically significant.
Any suspected transmission via a medicinal product of an infection agent in also considered a 
serious adverse reaction.
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event or 
adverse drug reaction that does not meet the criteria listed above for a serious adverse event/serious 
adverse drug reaction.
10.2 Expectedness
An expected adverse reaction is an adverse reaction, the nature or severity of which is consistent 
with the applicable reference safety  information (Investigator’s Brochure for CHF 5259 pMDI or 
US-FDA approved Product Information for SPIRIVA® HANDIHALER®), otherwise it is 
considered unexpected. 
Reports which add significant information on specificity or severity of a known, already 
documented serious adverse drug reaction constitute unexpected events. For example, an event 
more specific or more severe than described in the Investigator’s Brochure would be considered as 
“unexpected”. Examples of such events are: (a) acute renal failure as a labeled ADR with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.
In the event an exacerbation is interpreted as due to lack of efficacy, it should not be classified as 
drug related.
10.3 Intensity of Adverse Event
Each Adverse Event must be rated on a 3-point scale of increasing intensity:
Mild:  The event causes a minor discomfort, or does not interfere with daily activity of the 
subject, or does not lead to either modification of test treatment dosage or establishment of a 
correcting treatment.
Moderate: The event perturbs the usual activity of the subject and is of a sufficient severity 
to make the subject uncomfortable. The event leads to a diminution of dosage of the test 
treatment, or a temporary interruption of its administration or to the establishment of a 
correcting treatment.
Severe:  The event prevents any usual routine activity of the subject and causes severe 
discomfort. It may be of such severity to cause the definitive interruption of test treatment.


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10.4 Causality Assessment
The following “binary” decision choice will be used by the Investigator to describe the causality 
assessment:
Reasonable possibility of a relatedness
No reasonable possibility of relatedness
The expression “reasonable possibility of relatedness” is meant to convey, in general, that there are 
facts (evidence) or arguments meant to suggest a causal relationship.
The Investigator will be asked to consider the following before reaching a decision on causality 
assessment:
Time relationship between study drug intake and event’s onset;
Dechallenge (did the event abate after stopping drug?);
Rechallenge (did the event reappear after reintroduction?);
Medical history;
Study drug(s);
Mechanism of action of the study drug;
Class effects;
Other treatments-concomitant or previous;
Withdrawal of study drug(s);
Lack of efficacy/worsening of existing condition;
Erroneous treatment with study drug (or concomitant);
Protocol related process.
10.5 Action taken with the study drug due to the AE 
Dose not changed
Drug withdrawn
Drug interrupted
Not applicable
Unknown
10.6  Other actions taken
Specific therapy/medication
Concomitant procedure
Not applicable
10.7 Outcome
Each Adverse Event must be rated by choosing among:
Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered with sequelae/resolved with sequelae
Fatal
Unknown


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10.8 Recording Adverse Events
All Adverse Events occurring during the course of the study must be documented in the Adverse 
Event page of the electronic Case Report Form (eCRF). Moreover, if the Adverse Event is serious, 
the Serious Adverse Event Form must also be completed. 
It is responsibility of the Investigator to collect all adverse events (both serious and non-serious) 
derived by spontaneous, unsolicited reports of subjects, by observation and by routine open 
questionings.  The recording period for Adverse Events is the period starting from the Informed 
Consent signature until the subject’s study participation ends.
Clinically significant abnormalities detected at Visit 1 not due to a pre-existing condition or 
clinically significant changes at the following visits in the medical opinion of the investigator must 
be reported as adverse events in the eCRF.
If a clinically significant abnormal laboratory finding or other abnormal assessment meets the 
definition of an AE, then the AE eCRF page must be completed, as appropriate. A diagnosis, if 
known, or clinical signs and symptoms if diagnosis is unknown, rather than the clinically significant 
abnormal laboratory finding, should be reported on the AE eCRF page. If no diagnosis is known 
and clinical signs and symptoms are not present, then the abnormal finding should be recorded.
For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as 
completely and practically as possible their nature and/or causality until resolution of all queries, 
clinical recovery is complete, laboratory results have returned to normal, stable condition is reached 
or until the subject is lost to follow-up. Follow-up may therefore continue after the subject has left 
the study. In this case, the follow-up will continue with no timelines for related SAEs, while for 
unrelated SAEs the type and extent of follow-up undertaken will be determined for each individual 
case and will depend upon the nature (e.g. events with poor prognosis or which do not resolve), 
severity and medical significance of the event. 
10.9 Reporting Serious Adverse Events to Chiesi
The Investigator must report all Serious Adverse Events to the 
 Safety Contact 
listed below within 24 hours of awareness. The information must be sent by providing the 
completed Serious Adverse Event form. At a later date, the 
 Safety Contact will 
report all information to Chiesi Global Pharmacovigilance, the Clinical Project Manager and the 
Clinical Research Physician. 
Name and Title
Telephone no.
Fax no.
Safety E-mail
 (office)
 (mobile)
 
 


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Reporting of SAEs from the investigator site is from the time of subject’s signature of 
informed consent and until the subject’s study participation ends.  After this date, even if no 
active monitoring of subjects is required, SAEs occurring to a subject should be reported if 
the investigator becomes aware of them.
Up to the closure of the site, SAE reports should be reported to the 
 Safety 
Contact.  New serious adverse event occurring after the site is closed should be reported 
directly to the Chiesi Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB
The Sponsor or designated CRO will report adverse events to the regulatory authorities in 
compliance with the timelines and standards of reporting according to local regulations (Guidance 
for industry and Investigators-Safety Reporting Requirements for INDs and BA/BE studies, 
December 2012). All suspected unexpected serious adverse reactions (SUSARs), which occur with 
the investigational medicinal product or marketed active comparator, within or outside the 
concerned clinical trial, will be reported by the Sponsor or designated CRO to regulatory 
authorities, as required, as well as to the Investigators and Central IRB, if applicable, by 
MedWatch/CIOMS form. The Investigator (or Sponsor/CRO where required) must inform the IRB 
per Sponsor instruction upon receipt of the SUSAR notification. An IND and/or NDA Safety 
Report will be submitted to regulatory authorities unblinded. Participating Investigators and IRB 
will receive a blinded IND Safety Report, unless otherwise specified.
With regard to regulations in force for Pharmacovigilance, the Investigator must fulfil his/her 
obligation according to the law in force in his country. 
10.11 General Notes
In case of death, a comprehensive narrative report of the case should be prepared by the 
Investigator and sent to the 
/Chiesi Safety Contact together with the Serious 
Adverse Event form, retaining a copy on site.
If an autopsy is performed, copy of autopsy report should be actively sought by the 
Investigator and sent to the 
/Chiesi Safety Contact as soon as available, 
retaining a copy on site. 
In case of pregnancy, the subject will be immediately withdrawn from the study and she will 
be followed with due diligence until the outcome of the pregnancy is known. The pregnancy 
must be reported by the investigator within 24 hours by fax/e-mail/via Monitor to the 
/Chiesi Safety Contact using the paper Pregnancy Report Form. The 
Safety Contact will inform Chiesi of the pregnancy within one working day 
of being notified. 
The first two pages of the Pregnancy Report Form should be completed by the investigator 
with all the available information and sent to the 
/Chiesi Safety Contact. The 
third page will be completed as soon as the investigator has knowledge of the pregnancy 
outcome together with a follow-up of the first two pages, if necessary (e.g. an update in the 
medication received during pregnancy by the mother). If it meets the criteria for immediate 
classification of a SAE (e.g. spontaneous or therapeutic abortion, stillbirth, neonatal death, 
congenital anomaly, birth defect) the Investigator should follow the procedure for reporting 
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If it is the partner, rather than the subject, who is found to be pregnant, the same procedure 
regarding pregnancy reporting is to be followed and the Pregnancy Report Form should be 
completed. 
If the pregnancy is discovered before taking any dose either of study drug or of the run-in 
/rescue medication, the pregnancy does not need to be reported; it is only required that the 
subject is immediately withdrawn from the study.
11. DATA MANAGEMENT
An electronic CRF (eCRF) will be filled-in by the Investigator and/or his/her designee. All subjects 
who sign the informed consent will be databased. For subjects who are screened but not 
randomized, a minimum set of information is required: date of informed consent signed, 
demography, assessment of inclusion/exclusion criteria when applicable, primary reason for not 
continuing, prior medications, adverse events and concomitant medications if any.  Subject’s 
questionnaire (BDI, TDI, CAT) answers will be databased.
Front-end edit checks will run at the time of data collection and back-end edit checks will be used 
by the Data Manager to check for discrepancies and to ensure consistency and completeness of the 
data. 
Medical history, Concomitant Procedures and Adverse Events will be coded using the MedDRA 
dictionary; medications will be coded using the WHO Drug dictionary and Anatomical Therapeutic 
Chemical classification (ATC).
External data (IRT, Spirometry, Holter ECG, electronic Diary, Central Laboratory) will be 
processed centrally and reconciled against data recorded in the eCRF as part of cleaning activities.  
After cleaning of data, a review meeting will be held to determine the occurrence of any protocol 
violation and to define the subject populations for the analysis. Once the database has been declared 
to be complete and accurate, it will be locked, the randomization codes will be opened and the 
planned statistical analysis will be performed. Only authorised and well-documented updates to the 
study data are possible after database lock. 
At the study conclusion, a complete copy of the study data will be created for archival purposes at 
Chiesi. The investigators will receive copies of the subject data for retention at the investigational 
sites.
12. STATISTICAL METHODS
12.1 Sample Size
The sample size has been calculated to evaluate the superiority of CHF 5259 pMDI at different 
doses over placebo in terms of change from baseline in FEV1 AUC0-12h normalized by time at Week 
6.
A total of 594 evaluable subjects (99 per group) will provide 80% power to detect a mean 
difference of 120 mL between each dose of CHF 5259 pMDI and placebo [51][52] at a two-sided 
significance level of 0.0125 (since 4 dose levels will be tested, the Bonferroni adjustment has been 
taken into account: 0.0125 = 0.05/4), assuming a standard deviation of 250 mL.


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Since four dose levels will be tested, the Edwards and Berry method will be used to control the 
family-wise Type I error rate at the 0.05 (two-sided) level. In the sample size calculation, the 
Bonferroni adjustment of the significance level has been taken into account (0.0125 = 0.05/4). This 
will ensure the required power for each test, since the Edwards and Berry method is uniformly more 
powerful than the Bonferroni procedure.
Considering a non-evaluable rate of 15%, a total of approximately 702 subjects (117 per group) will 
be randomized.
12.2 Populations for Analysis
Safety population: all randomized subjects who receive at least one dose of study drug.
Intention-to-Treat population (ITT): all randomized subjects who receive at least one dose of 
the study drug and with at least one available evaluation of efficacy (primary or secondary 
efficacy variables) after the baseline.
Per-protocol population (PP): all subjects from the ITT population without any major 
protocol deviation (i.e., wrong inclusions, poor compliance, non-permitted medications). Exact 
definition of major protocol deviations will be discussed by the study team during the blind 
review of the data and described in the Data Review Report.
Since the superiority of CHF 5259 pMDI at different doses over placebo will be tested, the primary 
efficacy analysis will be based on the ITT population. The primary efficacy analysis will be also 
performed on the PP population for sensitivity purposes. 
The secondary efficacy variables will be analyzed in the ITT population.
The safety variables will be analyzed in the Safety population. 
In case of deviation between randomized treatment and treatment actually received, the treatment 
actually received will be used in the safety analyses (i.e. an as-treated analysis will be performed).
12.3 Statistical Analysis
A detailed statistical analysis plan will be described in a separate document. The plan might be 
reviewed and updated as a result of the blind review of the data and will be finalized before 
breaking the blind. 
12.3.1 Descriptive Statistics 
Descriptive statistics will be provided in summary tables by treatment group according to the type 
of variable summarized.
Descriptive statistics for quantitative variables will include n (the number of non-missing values), 
mean, SD, median, minimum and maximum values. 
Categorical variables will be summarized by using frequency count and percent distribution.


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12.3.2 Missing data
For the primary efficacy analysis, a linear mixed model for repeated measures will be used to 
handle missing data. Under the Missing At Random (MAR) assumption, this model provides an 
unbiased estimate of the treatment effect that would have been observed if all subjects had 
continued on treatment for the full study duration. This approach addresses efficacy (or de jure) 
hypotheses, estimating the causal effects of the initially randomized drug if taken as directed 
(in contrast with effectiveness, or de facto, hypotheses, evaluating the effect of the drug as 
actually taken) [82]. The efficacy estimand is considered appropriate in the context of a phase 
II study aiming at characterising dose-response.[83][84][85] 
If one of the spirometry measurements at 45 min and 15 min pre-dose is not available, then the 
non-missing measurement will be taken as the pre-dose value (corresponding to time 0 for the 
calculation of AUC). If no measurement is available, then the pre-dose value will be considered 
as missing.
In the calculation of AUC normalized by time, missing values will be replaced as follows:
o If the pre-dose value is not available, the entire curve will be considered as missing;
o Single, isolated missing values (not pre-dose or last value) will be replaced by linear 
interpolation using the adjacent values;
o If the value at 12 h post-dose is missing, it will be replaced by the value at 11.5 h;
o In case of two or more consecutive missing values or more than three missing values, the 
entire curve will be missing.
In case of rescue medication intake during the serial spirometry (from pre-dose to 12 h post-
dose), all spirometry data recorded from the time of rescue medication intake onwards for 6 
hours will be excluded from the analysis of primary efficacy endpoint on PP population.
In case of less than three missing values among post-dose spirometry measurements at 45 min, 
1h, 2h, 3h, 4h, the peak value will be calculated as the maximum of the available post-dose 
values over the time interval considered (4h). In case of three or more missing values, the peak 
value will be considered as missing.
In case of at least one post-dose timepoint with change from baseline in FEV1 ≥ 100 mL, then 
Time to onset of action will be equal to the first post-dose timepoint with change from baseline 
in FEV1 ≥ 100 mL in the time interval considered (12 h). In case of no timepoint with change 
from baseline in FEV1 ≥ 100 mL, and less than four missing values among post-dose 
spirometry measurements at 15 min, 30 min, 45 min, 1h, 2h, 3h and 4h, then Time to onset of 
action will be equal to the last available post-dose timepoint with non-missing data and the 
subject will be considered as censored in the analysis.
A minimum of 7 days with available measurements will be required for each inter-visit period 
(including run-in period) to consider the following variables as non-missing: percentage of 
rescue medication-free days, average use of rescue medication, average E-RS total score and 
domain scores.
The BDI and the TDI focal scores will be considered as missing if at least one response will be 
included among the following: “W”, “X”, “Y”, “Z”.
In the responder analysis, subjects with missing data at the relevant visit will be considered as 
non-responders.
Further details on dealing with missing data, along with the handling of possible outliers, will be 
described in the SAP. Other critical missing data, if any, will be discussed during the review of the 
data. Decisions will be fully documented in the Data Review Report.


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12.3.3 Subject demographics and baseline characteristics
The following variables will be summarized by treatment group on the ITT population (and on the 
Safety or PP populations, if relevant): demographic characteristics, medical history and concomitant 
diseases, previous and concomitant medications, efficacy and safety parameters at screening and/or 
at baseline. 
12.3.4 Primary efficacy variables
Change from baseline in FEV1 AUC0-12h normalized by time will be analyzed using a linear mixed 
model for repeated measurements including treatment, visit, treatment by visit interaction, US 
regions and smoking status at screening as fixed effects, and the baseline value (average of the pre-
dose FEV1 measurements on Day 1) and baseline by visit interaction as covariates. An unstructured 
covariance matrix will be assumed. 
The adjusted means in each treatment group, the adjusted mean difference between treatments and 
their 95% Confidence Intervals (CIs) will be estimated by the model. The CIs and the p-values of 
the comparisons between each dose of CHF 5259 pMDI and placebo at Week 6 will be adjusted for 
multiplicity. The adjustment will be based on the parametric simulation method by Edwards and 
Berry.[86] At each dose level, the superiority of CHF 5259 pMDI will be demonstrated by a 
statistically significant difference (adjusted p-value < 0.05) favouring CHF 5259 pMDI.
All the other comparisons between treatments will be performed as secondary efficacy analyses 
with no multiplicity adjustment.
12.3.5 Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy analyses.
For change from baseline in FEV1 AUC0-12h normalized by time at Day 1, the adjusted means 
in each treatment group and the adjusted mean differences between treatments at Day 1 will be 
estimated with their 95% CIs and p-values by the same model used for the primary efficacy 
analysis.
Change from baseline in FEV1 AUC0-4h normalized by time and in FEV1 peak0-4h at Day 1 and 
Week 6 and change from baseline in pre-dose morning FEV1 at Week 3 and Week 6 will be 
analyzed using the same model as for the primary efficacy variable.
Change from baseline in FVC AUC0-12h normalized by time, in FVC AUC0-4h normalized by 
time and in FVC peak0-4h at Day 1 and Week 6 will be analyzed using a similar model as the 
one used for the primary efficacy analysis.
Time to onset of action (i.e., change from baseline in post-dose FEV1 ≥ 100 mL[15][81]) at 
Day 1 will be analyzed using a Cox proportional hazard model including treatment, US regions 
and smoking status at screening as fixed effects, and baseline (average of the pre-dose FEV1 
measurements on Day 1) as covariate. A Kaplan-Meier plot will be presented. 
Change from baseline in pre-dose morning IC at Week 3 and Week 6 will be analyzed using a 
similar model as the one used for the primary efficacy analysis. 
TDI focal score at Week 3 and Week 6 will be analyzed using a similar model as the one used 
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TDI response at Week 3 and Week 6 will be analyzed using a logistic regression model 
including treatment, US regions and smoking status at screening as fixed effects and baseline 
(BDI [Baseline Dyspnea Index] focal score assessed on Day 1) as a covariate.
Change from baseline to each inter-visit period in percentage of rescue medication-free days, in 
average use of rescue medication and in average E-RS total score and domain scores will be 
analyzed using a similar model as the one used for the primary efficacy analysis. The inter-visit 
period will be considered instead of visit in the model. Comparison between treatments over 
the entire treatment period will also be derived from this model.
12.3.6 Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake will be classified as 
Treatment Emergent Adverse Events (TEAEs). Any adverse event started after the informed 
consent signature and before the time of first study drug intake will be classified as pre-treatment 
adverse event. Pre-treatment adverse events will be listed only.
The number of TEAEs and the number and percentage of subjects who experienced at least one 
TEAE will be presented by treatment for all AEs, ADRs, serious AEs, serious ADRs, severe AEs, 
AEs leading to study discontinuation and AEs leading to death. Summaries will be presented 
overall and by system organ class and preferred term based on the MedDRA dictionary. 
Vital signs
Vital signs (systolic and diastolic blood pressure) and their changes from baseline (pre-dose on Day 
1) and from pre-dose on Week 6 will be summarized by treatment using descriptive statistics and 
the 95% CI of the mean.
Holter
ECG parameters extracted from Holter (HR, QTcF, QRS and PR) and their changes from baseline 
(time-matched on day before V2) will be summarized for all timepoints on Day 1 and Week 6 by 
treatment using descriptive statistics and the CI of the mean (95% CI for absolute values and 90% 
CI for the changes from baseline). 
Change from baseline (time-matched on day before V2) in ECG parameters extracted from Holter 
(HR, QTcF, QRS and PR) will be analyzed using a linear mixed model for repeated measurements 
including treatment, timepoint, treatment by timepoint interaction, US regions and smoking status at 
screening as fixed effects, and the baseline value (time-matched on day before V2), baseline by 
timepoint interaction and time-averaged baseline as covariates. An unstructured covariance matrix 
will be assumed. 
The number and the percentage of subjects with a 
o QTcF >450 ms (males only), >470 ms (females only) or >480 ms (males only) and >500 ms 
(males and females)
o change from baseline (time-matched on day before V2) in QTcF >30 ms and >60 ms
at each post-dose timepoint and at any post-dose timepoint will be presented by treatment group.


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24-hour HR average, minimum and maximum extracted from the Holter and their changes from 
baseline (day before V2) will be summarized by treatment using descriptive statistics and the 95% 
CI of the mean. 
Change from baseline (day before V2) in 24-hour HR average, minimum and maximum extracted 
from Holter will be analyzed using a linear mixed model for repeated measurements including 
treatment, visit, treatment by visit interaction, US regions and smoking status at screening as fixed 
effects, and the baseline value (day before V2) and baseline by visit interaction as covariates. An 
unstructured covariance matrix will be assumed. 
Hourly average HR will be summarized by treatment using descriptive statistics and the 95% CI of 
the mean. 
The number and the percentage of subjects with abnormal findings (including supraventricular 
arrhythmias, ventricular arrhythmias and non-sustained ventricular tachycardia) in the 24-hour 
Holter will be summarized by treatment group.
Laboratory parameters
Shift tables from screening to the end of treatment, based on normal ranges, will be presented by 
treatment group for the laboratory parameters.
12.3.7 Interim analysis
Interim analysis not planned.
13. ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the United States FDA regulations, the ICH E6 GCP guidelines, the 
Declaration of Helsinki, and other local regulations as applicable.
14. INFORMED CONSENT
Written informed consent will be obtained from all subjects as per IRB guidelines before any study-
related procedures (including any pretreatment procedures) are performed. The investigator has 
both ethical and legal responsibility to ensure that each subject being considered for inclusion in 
this study is given a full explanation of the protocol. This shall be documented on a written 
informed consent form, which shall be approved by the same IRB or IEC responsible for approval 
of this protocol. Each informed consent form shall include the elements required by ICH, Part E6, 
Section 4.8, and any applicable local regulations. The investigator agrees to obtain approval from 
the Sponsor of any written informed consent form used in the study, preferably prior to submission 
to the IRB or IEC.
Once the appropriate essential information has been provided to the subject and fully explained by 
the investigator (or a qualified designee) and it is felt that the subject understands the implications 
of participating, the subject and the investigator (or designee) shall sign the IRB- or IEC-approved 
written informed consent form. The subject shall be given a copy of the signed informed consent 
form, and the original shall be filed appropriately, according to the institution. A second copy may 
be filed in the subject’s medical record, if allowed by the institution.


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15. INSTUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITTEE
This protocol, the written informed consent form, and any materials presented to the subject shall be 
submitted to the IRB or IEC identified with this responsibility. Notification in writing of approval 
must come from the IRB or IEC chairman or secretary to the investigator, either as a letter or as a 
copy of the appropriate section of the IRB or IEC meeting minutes where this protocol and 
associated informed consent form were discussed. The investigator will not participate in the 
decision. If the investigator is an IRB or IEC member, the written approval must indicate such non-
participation in the voting session. The investigator will submit status reports to the IRB or IEC as 
required by the governing body. The IRB or IEC must be notified by the investigator in writing of 
the interruption and/or completion of the study; the investigator must promptly report to the IRB or 
IEC all changes in research (protocol amendments), and will not make such changes without IRB or 
IEC approval, except where necessary to eliminate apparent immediate hazards to human subjects. 
In cases where it is necessary to eliminate immediate hazards to subjects, the IRB or IEC must then 
be notified of the change as per local requirements. The investigator is required to maintain an 
accurate and complete record of all written correspondence to and received from the IRB or IEC 
and must agree to share all such documents and reports with the Sponsor.
16. DIRECT ACCESS TO SOURCE DOCUMENTS/DATA
The 
Investigators 
or 
designee 
must 
permit 
trial-related 
monitoring, 
audits, 
Ethics 
Committee/Institutional Review Board review or regulatory inspection, providing direct access to 
source data/documents.
17. STUDY MONITORING
Monitoring will be performed by 
 who has been designated by Chiesi.  It is 
understood that the monitor(s) will contact and visit the Investigator/center before the study, 
regularly throughout the study and after the study had been completed, and that they will be 
permitted to inspect the various study records: case reports form, Investigator study file and source 
data (source data is any data that is recorded elsewhere to the case report forms), provided that 
subject confidentiality is respected.
The purposes of these visits are:
to assess the progress of the study;
to review the compliance with the study protocol;
to discuss any emergent problem;
to check the eCRFs for accuracy and completeness;
to validate the contents of the eCRFs against the source documents;
to assess the status of drug storage, dispensing and retrieval;
Prior to each monitoring visit, the Investigator or staff will record all data generated since the 
last visit on the case report forms. The Investigator and/or study staff will be expected to be 
available for at least a portion of the monitoring visit to answer questions and to provide any 
missing information;
It is possible that the Investigator site may be audited by Sponsor personnel or national and/or 
international regulatory agencies during and after the study has been completed.


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18. QUALITY ASSURANCE
The R&D Quality Assurance Department of Chiesi may perform an audit at any time according to 
the Sponsor’s Standard Operating Procedures, in order to verify whether the study is being 
conducted in agreement with Good Clinical Practices. 
19. INSURANCE AND INDEMNITY 
Chiesi holds and will maintain an adequate insurance policy covering damages arising out of 
Chiesi’s sponsored clinical research studies.  Chiesi will indemnify the Investigator and hold 
him/her harmless for claims for damages arising out of the investigation, in excess of those covered 
by his/her own professional liability insurance, providing that the drug was administered under 
his/her or deputy’s supervision and in strict accordance with accepted medical practice and with the 
study protocol.
The Investigator must notify Chiesi immediately upon notice of any claims or lawsuits. 
20. CONFIDENTIALITY
All study documents are provided by the Sponsor in confidence to the Investigator and his/her 
appointed staff. None of this material may be disclosed to any party not directly involved in the 
study without written permission from Chiesi.  The Investigator must assure the subject’s 
anonymity will be maintained. The Investigator will keep a separate list with at least the initials, the 
subject’s study numbers, names, and addresses and telephone numbers. The Investigator will 
maintain this for the longest period of time allowed by his/her own institution and, in any case, until 
further communication from Chiesi.
21. PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should 
this be necessary, the procedures for an early termination or temporary halt will be arranged after 
consultation by all involved parties.  The Sponsor should submit a written notification to the 
Regulatory Authority concerned and Ethics Committee/Institutional Review Board providing the 
justification of premature ending or of the temporary halt.
22. CLINICAL STUDY REPORT
At the end of the trial a summary of the clinical study report will be provided, as required, to all 
Ethics Committees/Institutional Review Boards, to the Competent Authority of the EU Member 
State or US concerned and to Investigators.
23. RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an orderly 
manner by the Investigator in a secure study file. 
Regulations require that essential documents must be retained for at least two years after the final 
marketing approval in an ICH region or until two years have elapsed since the formal interruption 
of the clinical development of the product under study.


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It is the responsibility of the Sponsor to inform the Investigator of when these documents can be 
destroyed. The Investigator must contact Chiesi before destroying any trial-related documentation. 
In addition, all subjects’ medical records and other source documentation will be kept for the 
maximum time permitted by the institution.
24. PUBLICATION OF RESULTS
Chiesi is entitled to publish and/or present any results of this study at scientific meetings, and to 
submit the clinical trial data to national and international Regulatory Authorities. Chiesi 
furthermore reserves the right to use such data for industrial purposes. In the absence of a Study 
Steering Committee, Investigators will inform Chiesi before using the results of the study for 
publication or presentation, and agree to provide the Sponsor with a copy of the proposed 
presentation. Data from individual study sites must not be published separately.  Negative as well as 
positive results should be published or otherwise made publicly available. 
25. REFERENCES
[1]
Lozano R, Mohsen N, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional 
mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic 
analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-128.
[2]
Global Initiative for Chronic Obstructive Lung Disease, Inc. Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2017 
Report. 2017.
[3]
Tilert T, Dillon C, Paulose-Ram R, Hnizdo E, Doney B. Estimating the U.S. prevalence of 
chronic obstructive pulmonary disease using pre- and post-bronchodilator spirometry: the 
National Health and Nutrition Examination Survey (NHANES) 2007-2010. Respir Res. 
2013;14(1):103. doi: 10.1186/1465-9921-14-103. 
[4]
Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease 
heterogeneity. Chest. 2002 May;121(5 Suppl):121S-126S.
[5]
Tonnesen P. Smoking cessation and COPD. Eur Respir Rev. 2013 Mar 1;22(127):37-43. 
doi : 10.1183/09059180.00007212.
[6]
van Eerd EA, van der Meer RM, van Schayck OC, Kotz D. Smoking cessation for people 
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APPENDIX I
A 6-week, 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 (glycopyrronium bromide) 
in subjects with Chronic Obstructive Pulmonary Disease (COPD)
Product: CHF 5259 pMDI (glycopyrronium bromide)
Pharmaceutical Form: Spray aerosol via pMDI HFA-134a propellant
Approval of Clinical Study Protocol by the Principal Investigator: 
I have carefully read this protocol and I agree that it contains all the necessary information required 
to conduct the study and I agree to conduct it as described.
I understand that this trial will not be initiated without Ethics Committee/Institutional Review 
Board approvals and that the administrative requirements of the governing body of the institution 
will be fully complied with.
Informed written consent will be obtained from all participating subjects and appropriately 
documented, prior to their enrollment in the study. 
The undersigned agrees that the trial will be carried out in conformity with the Code of Federal 
Regulations (21 CFR 50) and the Declaration of Helsinki (as applicable, with attention being drawn 
to Section concerning freely given consent), Good Clinical Practices and with all the other local 
laws and regulations relevant to the use of new and approved therapeutic agents in subjects.
Principal Investigator’s Name:   
,MD
Center No.: 
Signature
     Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy


-Clinical Study Protocol-
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APPENDIX II
MINIMUM LIST OF SOURCE DATA REQUIRED
The following list should be considered as an example (not exhaustive list): 
-
Subjects demography file
-
Subjects medical file
-
Study number
-
Subject identity/number
-
Randomization number
-
Medical and surgery history
-
Previous and concomitant medications
-
Weight, height
-
Date of informed consent signature
-
Date of specific study visits
-
Labels of study drugs
-
Examination or assessments carried out during the study
-
Laboratory reports
-
Adverse events / serious adverse events
-
If subject is withdrawn, reason for withdrawal

SAP_001.pdf: 
Page 1 of 70 
CHIESI 
GLIMMER 
A 6-WEEK, 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 (GLYCOPYRRONIUM BROMIDE) IN SUBJECTS WITH CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE (COPD) 
Protocol: CCD-05993AA3-02 
IND No: 133681 
Statistical Analysis Plan 
Version 1.0 
Final  
 20 SEP 2018 
Author: 
 
 
ClinicalTrials.gov ID: NCT03084796 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 2 of 70 
 
Table of Contents 
1 SOPs to be followed ............................................................................................................................. 5 
2 Abbreviations ....................................................................................................................................... 6 
3 Protocol / Clinical Investigation Plan ................................................................................................... 8 
3.1 Study Objectives .................................................................................................. 8 
3.2 Study Design ........................................................................................................ 8 
3.3 Study Schedule .................................................................................................... 9 
3.4 Randomization................................................................................................... 10 
3.5 Sample Size Calculation ..................................................................................... 10 
3.6 Efficacy and Safety Variables ............................................................................. 10 
3.7 Interim Analyses ................................................................................................ 11 
3.8 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol .................................................................................................................. 11 
4 General Definitions ............................................................................................................................ 12 
4.1 Report Language ............................................................................................... 12 
4.2 Analysis Software .............................................................................................. 12 
5 Data Preparation ................................................................................................................................. 13 
5.1 Data Handling and Medical Coding .................................................................... 13 
5.1.1 Data Handling ................................................................................................ 13 
5.1.2 Coding ........................................................................................................... 13 
5.2 CDISC ............................................................................................................... 13 
5.3 SAS-Programming Quality Level ....................................................................... 13 
5.4 Data from third parties ...................................................................................... 14 
6 Analysis Populations and Subgroups ................................................................................................. 15 
6.1 Analysis Populations .......................................................................................... 15 
6.2 Treatment Misallocation .................................................................................... 15 
6.3 Subgroup Definitions ......................................................................................... 16 
7 Definition of Time Points and Analysis Variables ............................................................................. 17 
7.1 Definition of Time Points .................................................................................... 17 
7.2 Baseline and Derived Analysis Variables ............................................................ 19 
7.2.1 Demographic Characteristics ............................................................................ 20 
7.2.2 COPD History and Pre-Study Smoking Habits ................................................... 20 
7.2.3 Baseline Subject Characteristics ....................................................................... 20 
7.2.4 Spirometry Performed at Screening .................................................................. 20 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 3 of 70 
 
7.2.5 Medications.................................................................................................... 21 
7.2.6 Procedures ..................................................................................................... 21 
7.2.7 Treatment Exposure and Compliance – Background Medication .......................... 22 
7.2.8 Treatment Exposure and Compliance - Study Drug Administration ...................... 24 
7.2.9 Compliance with the use of e-Diary .................................................................. 26 
7.2.10 Efficacy Variables ......................................................................................... 27 
7.2.11 Safety Variables ............................................................................................ 33 
8 Analysis Methods ............................................................................................................................... 38 
8.1 General Methods ............................................................................................... 38 
8.1.1 Rules for Handling Missing Data ...................................................................... 39 
8.2 Specific Methods for Efficacy Analyses ............................................................... 41 
8.2.1 Statistical/Analytical Issues .............................................................................. 47 
8.3 Specific Methods for Safety Analyses .................................................................. 47 
9 Interim analyses .................................................................................................................................. 49 
10 Overview of Tables, Listings and Figures ........................................................................................ 49 
10.1 Disposition of Subjects ..................................................................................... 49 
10.2 Protocol Deviations .......................................................................................... 50 
10.3 Analysis Sets .................................................................................................... 50 
10.4 Demographic and Other Baseline Characteristics ............................................. 50 
10.4.1 Demographic Characteristics, COPD History and Smoking Habits ..................... 50 
10.4.2 Medical History ............................................................................................ 50 
10.4.3 Baseline Subject Characteristics ..................................................................... 50 
10.4.4 Previous, Maintained and Concomitant Medications ......................................... 50 
10.5 Study drug / Investigational Medicinal Product ................................................ 51 
10.5.1 Background medication ................................................................................. 51 
10.5.2 Study drug .................................................................................................... 51 
10.6 Efficacy Results ................................................................................................ 52 
10.6.1 Primary efficacy variable ............................................................................... 52 
10.6.2 Secondary efficacy variables .......................................................................... 52 
10.6.3 Other efficacy variables ................................................................................. 55 
10.7 Safety Analyses ................................................................................................ 55 
10.7.1 Adverse Events ............................................................................................. 55 
10.7.2 Vital Signs ................................................................................................... 56 
10.7.3 ECGs ........................................................................................................... 56 


 
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10.7.4 Clinical Laboratory Evaluation ....................................................................... 58 
10.8 Early Termination and Unscheduled Visits ....................................................... 59 
11 Table of Contents for the Tables, Listings and Figures .................................................................... 61 
12 References ........................................................................................................................................ 67 
APPENDIX I: EXACT-PRO QUESTIONNAIRE ............................................................................... 68 
 
 
 
 


 
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1 SOPs to be followed 
The statistical analysis will be carried out according to the following 
 SOPs: 
 
SOP Number SOP Title  
Effective Date & 
Version Number  
 
or Sponsor  
SOP_ST_03 
Statistical Analysis Plan 
3.0 01AUG2015 
 
SOP_ST_04  
SAS Programming, QC and 
Validation 
3.0 21DEC2015 
 
SOP_ST_06 
Study Unblinding for Analysis 
3.0 12JUN017 
 
SOP_ST_07  
Statistical Report 
3.0 26JUN2017 
 
SOP_ST_08 
Trial Statistics File* 
2.0 15APR2014 
 
* TSF SOP in combination with the ToC of Chiesi. 


 
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2 Abbreviations 
Abbreviation 
Description 
ADAM 
Analysis Data Model 
ADR  
Adverse Drug Reaction  
AE  
Adverse Event  
AUC 
Area Under the Curve 
BDI 
Baseline Dyspnea Index 
BID 
Bis in die (twice a day)  
BMI 
Body Mass Index 
CAT 
COPD Assessment Test 
CDISC 
Clinical Data Interchange Standards Consortium 
Cm 
Centimeters 
COPD 
Chronic Obstructive Pulmonary Disease 
CSR 
Clinical Study Report 
DBP  
Diastolic Blood Pressure 
ECG  
ElectroCardioGram  
eCRF  
Electronic Case Report Form  
E-RS 
EXACT-Respiratory Symptom 
FEV1  
Forced Expiratory Volume in the 1st second  
FVC 
Forced Vital Capacity 
GB  
Glycopyrronium Bromide  
H 
Hours 
HR  
Heart Rate  
IC 
Inspiratory Capacity 
ICS 
Inhaled Corticosteroid 
IRT  
Interactive Response Technology  
ITT  
Intention-to-Treat (analysis population) 
Kg 
Kilograms 
L 
Liters 
LABA 
Long-Acting β2-adrenergic receptor Agonist 
LAMA  
Long Acting Muscarinic Antagonist  
µg 
Micrograms 
M 
Meters 
ms 
Milliseconds 
MedDRA  
Medical Dictionary for Regulatory Activities  
min 
Minute 
mL 
Milliliter 
PEF 
Peak Expiratory Flow 
pMDI  
Pressurized Metered Dose Inhaler  
PP  
Per-Protocol (analysis population) 
PR 
PR Interval width (ECG) 
PT 
Preferred Term (MedDRA) 
QC 
Quality Control 
Qd 
Once a day 
Abbreviation 
Description 


 
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QRS 
QRS interval width (ECG) 
QTcF 
QT interval width corrected according to Fridericia (ECG) 
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SBP  
Systolic Blood Pressure 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class (MedDRA) 
SOP  
Standard Operating Procedure 
TDI 
Transitional Dyspnea Index 
TEAE 
Treatment Emergent Adverse Event 
WHO  
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 


 
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3 Protocol / Clinical Investigation Plan 
This document presents the statistical analysis plan (SAP) for Chiesi Farmaceutici S.p.A., 
Protocol No. CCD-05993AA3-02: A 6-week, 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 (glycopyrronium bromide) in subjects with Chronic Obstructive Pulmonary 
Disease (COPD). This analysis plan is based on the final protocol (version 2.0) dated 19 MAY 
2017 and the final electronic case report form (eCRF) (version 3.0) dated 28 JUL 2017. Text 
copied from Protocol is reported in this document in Italics to avoid unnecessary alterations to 
text approved in the Protocol. 
The SAP provides the description of the final analyses. In case of deviations from the SAP, 
explanations will be provided in the Clinical Study Report (CSR). 
3.1 Study Objectives 
The primary objective of this clinical trial is  
• To evaluate the efficacy of CHF 5259 pMDI by comparison with placebo in terms 
of change from baseline in FEV1 AUC0-12h normalized by time at Week 6. 
There are 2 secondary objectives: 
• To evaluate the effect of CHF 5259 pMDI on other lung function parameters and 
clinical outcome measures. 
• To assess the safety and the tolerability of the study treatments. 
3.2 Study Design 
The study is a Phase II multi-center, randomized, double-blind, placebo and active-controlled, 
parallel group, dose ranging study. Subjects will be randomized into 1 of 6 treatment groups 
presented below. 
• Treatment A*: GB 12.5μg Total Daily Dose (GB 6.25μg per inhalation, 1 inhalation 
bid) 
• Treatment B*: GB 25μg Total Daily Dose (GB 12.5μg per inhalation, 1 inhalation bid) 
• Treatment C: GB 50μg Total Daily Dose (GB 12.5μg per inhalation, 2 inhalations bid) 
• Treatment D: GB 100μg Total Daily Dose (GB 25μg per inhalation, 2 inhalations bid) 
• Treatment E: Matched placebo (2 inhalations bid) 
• Treatment F (open-label): SPIRIVA® HANDIHALER® (Tiotropium bromide 
inhalation powder) 18μg capsule (2 inhalations qd)  
 
*An adequate number of inhalations from Placebo inhalers will be performed to maintain a 
double blind design. 
Background Medication for the Run-in and Treatment Periods 
At the screening visit (Visit 1), all eligible subjects who have been receiving an ICS in 
combination with a LABA or LAMA will be switched to an equipotent dose of QVAR® as run-
in / background therapy: QVAR® 80μg (HFA beclomethasone dipropionate - Teva Respiratory, 
LLC). The dose will be 1-2 inhalations twice per day (Total daily dose: beclomethasone 
dipropionate 160-320μg). 


 
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This treatment will be maintained at a stable dose and regimen (160-320μg daily) throughout 
the study from screening until the end of the study. 
3.3 Study Schedule 
 
 
Pre-
Screening 
Screening 
Treatment period 
Follow-
Up 
ET 
Visits 
V0 
V1 
V2 
V3 
V4 
V5 
Time (Weeks) 
 
-2 
0 
3 
6 
7 
Early 
Termination 
Window (days) 
 
 
±2 
±2 
±2 
±2 
 
 
Informed consent form 
 
 
 
 
 
 
 
IRT – visit confirmation call 
 
 
 
 
 
 
 
Demographic data 
 
 
 
 
 
 
 
BDI questionnaire 
 
 
 
 
 
 
 
TDI questionnaire 
 
 
 
 
 
 
 
COPD Assessment Test (CAT) 
 
 
 
 
 
 
 
Vital signs (SBP/DBP) a 
 
 
 
 
 
 
 
Weight and Height 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
Medical history/Previous medication 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
Smoking Status 
 
 
 
 
 
 
 
12-lead ECG b 
 
 
 
 
 
 
 
Spirometry (pre & post BD) c 
 
 
 
 
 
 
 
Pre-dose spirometry d 
 
 
 
 
 
 
 
Post-dose serial spirometry 12h e 
 
 
 
 
 
 
 
Hematology and Blood Chemistry 
 
 
 
 
 
 
 
Serum pregnancy test f 
 
 
 
 
 
 
 
Urinary pregnancy test f 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
 
 
 
 
 
 
 
Eligibility recheck g 
 
 
 
 
 
 
 
Training for use of pMDI Inhalers and e-diary 
 
 
 
 
 
 
 
Dispensation of rescue albuterol h 
 
 
 
 
 
 
 
24-hour holter recording  i 
 
 
 
 
 
 
 
Schedule next visit 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
e-diary completion 
 
 (daily) 
 
 
Study drug dispensation (D) / Return (R) and 
Accountability 
 
 
D 
D/R 
R 
 
R 
Subject diary dispensation (D) /return (R) 
 
D 
D/R 
D/R 
R 
 
R 
Dispensation (D) of background ICS (QVAR®) j / 
return (R) 
 
D 
D/R 
D/R 
R 
 
R 
Adverse Events assessment 
 
 
 
 
 
 
 
Check for COPD Exacerbations 
 
 
 
 
 
 
 
a At V2 and V4: SBP/DBP will be measured within 1h pre-dose and at 30 mins, 1.5h, 3.5h, 7h and 11h post-dose. At V1 and Early 
Termination: SBP/DBP will be measured within 1h before the expected time of study drug administration. At V3: SBP/DBP will be 
measured within 1h pre-dose. 
b At V2 and V4: Local 12-lead ECG will be done within 1h prior to study drug intake and at 1.5h post-dose. At V1 and Early Termination: 
Local 12-lead ECG will be done within 1h before the expected time of study drug administration. At V3: Local 12-lead ECG will be done 
within 1h prior to study drug intake. 
c  Spirometry (FVC maneuver) will be carried out 15 min before bronchodilator and 30 to 45 minutes after the inhalation of 84µg of 
ipratropium pMDI at V1. 
d  Pre-dose FEV1, FVC: T -45’and T -15’ before the expected time of study drug administration. IC will be measured only once at T-45’ using 
SVC maneuver, before the FVC maneuver. 
e  Post-dose serial spirometry (FEV1, FVC): T15’, T30’, T45’, T1h, T2h, T3h, T4h, T6h, T8h, T10h, T11.5h, T12h 
f  In women of childbearing potential only. 
g  Eligibility recheck only for exclusion criteria #1, 3, 4, 5, 10, 11 and inclusion criteria # 6-8. 
h One commercial albuterol HFA MDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1, 
and resupplied as needed at V2-V3 based on assessment of doses used between visits. 
i At V2: the 24h digital device will be placed the day before the visit and will be removed the day after the visit. At V4: the 24-hour digital 
device will be placed the day before the visit and will be removed upon arrival to the site (before any assessment). 
j all subjects who have been receiving an ICS in combination with a LABA or LAMA at V1 will be switched to an equipotent dose of 
QVAR® and continued on same dose until V4 or Early Termination. 
 
 


 
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3.4 Randomization 
A balanced block randomization scheme stratified by US Region (based on US Census Bureau 
Regions: West, Midwest, South, Northeast) will be prepared via a computerized system. 
Subjects will be centrally assigned to one of the six treatment arms at the end of the run-in 
period through an IRT system (Interactive Response Technology) with a 1:1:1:1:1:1 ratio.  
The IRT will allocate the subject to a certain treatment group using a list-based randomization 
algorithm and will assign the study drug kit number corresponding to the treatment group 
assigned to the subject. The IRT will also generate a confirmation after every IRT transaction 
is performed.  
The Investigator will call the IRT at each visit (from pre-screening to follow-up call) to record 
the subject number at pre-screening, to enroll and randomize the subject, to obtain the 
medication kit numbers and to register the subject status in the system. Detailed instructions 
for use of IRT will be provided to the site. 
3.5 Sample Size Calculation 
The sample size has been calculated to evaluate the superiority of CHF 5259 pMDI at different 
doses over placebo in terms of change from baseline in FEV1 AUC0-12h normalized by time at 
Week 6. 
A total of 594 evaluable subjects (99 per group) will provide 80% power to detect a mean 
difference of 120 mL between each dose of CHF 5259 pMDI and placebo at a two-sided 
significance level of 0.0125 (since 4 dose levels will be tested, the Bonferroni adjustment has 
been taken into account: 0.0125 = 0.05/4), assuming a standard deviation of 250 mL. 
Since four dose levels will be tested, the Edwards and Berry method will be used to control the 
family-wise Type I error rate at the 0.05 (two-sided) level. In the sample size calculation, the 
Bonferroni adjustment of the significance level has been taken into account (0.0125 = 0.05/4). 
This will ensure the required power for each test, since the Edwards and Berry method is 
uniformly more powerful than the Bonferroni procedure. 
Considering a non-evaluable rate of 15%, a total of approximately 702 subjects (117 per group) 
will be randomized. 
3.6 Efficacy and Safety Variables 
Primary Efficacy Variable 
Change from baseline in FEV1 AUC0-12h normalized by time at Week 6. 
 
Secondary Efficacy Variables 
The protocol defines 14 unique secondary efficacy variables but groups them into 8 bullet points 
in Section 12.3.5 of the protocol and 11 bullet points in Section 8. The variable numbering 
below is not meant to reflect a hierarchical ordering. Rather, the numbering is meant to allow 
the listing of all 14 unique secondary efficacy variables but provide the traceability back to the 
8 bullet points as outlined in the protocol: 
• 1: Change from baseline in FEV1 AUC0-12h normalized by time at Day 1 
• 2a: Change from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Week 6 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• 2b: Change from baseline in FEV1 peak0-4h at Day 1 and Week 6 
• 2c: Change from baseline in pre-dose morning FEV1 at Week 3 and Week 6 
• 3a: Change from baseline in FVC AUC0-12h normalized by time at Day 1 and Week 6 
• 3b: Change from baseline in FVC AUC0-4h normalized by time at Day 1 and Week 6 
• 3c: Change from baseline in FVC peak0-4h at Day 1 and Week 6 
• 4: Time to onset of action (change from baseline in post-dose FEV1 ≥ 100 mL) at Day 
1 
• 5: Change from baseline in pre-dose morning IC at Week 3 and Week 6 
• 6: TDI focal score at Week 3 and Week 6 
• 7: TDI response (TDI focal score ≥ 1) at Week 3 and Week 6 
• 8a: Change from baseline in percentage of rescue medication-free days during inter-
visit periods and entire treatment period 
• 8b: Change from baseline in average use of rescue medication (number of puffs/day) 
during inter-visit periods and entire treatment period 
• 8c: Change from baseline in average E-RS total score and domain scores during 
inter-visit periods and entire treatment period 
Safety Assessments 
The list of safety assessments presented below is from Section 8 of the protocol.  Additional 
details regarding the safety variables collected during this clinical trial are presented in 
Section 12.3.6 of the protocol. 
• Adverse Events (AEs) and Adverse Drug Reactions (ADRs) 
• Vital signs (systolic and diastolic blood pressure) 
• 24-hour digital Holter ECG parameters (HR, QTcF, QRS, PR) 
• 24-hour HR average, minimum and maximum and hourly average HR 
• 24-hour digital Holter ECG abnormal findings 
• Standard blood chemistry and hematology 
3.7 Interim Analyses 
No interim analyses are planned for this clinical investigation. 
3.8 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol 
No changes in conduct between the Statistical Analysis Plan (SAP) and the study protocol 
have been noted. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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4 General Definitions 
4.1 Report Language 
The output of the analyses will be prepared in (USA) English. 
4.2 Analysis Software 
The statistical analysis will be performed using the SAS® statistical software package (Version 
9.3). 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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5 Data Preparation 
5.1 Data Handling and Medical Coding 
5.1.1 Data Handling 
For data quality control, please refer to the Data Management Plan (Version 1.0 from 22 JUN 
2017) including the Data Validation Plan (Version 3.0 from 28 JUL 2017). 
5.1.2 Coding 
The following dictionaries will be used for coding in the analysis: 
Medical History, Concomitant Diseases, Surgeries and Procedures 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, version 20.0. 
Prior and Concomitant Medications 
World Health Organization Drug Dictionary (WHO-DD version January 2017. 
Adverse Events 
Medical Dictionary for Regulatory Activities (MedDRA) coding system, version 20.0. 
5.2 CDISC 
All output as defined in the SAP will be generated based on CDISC ADaM datasets. 
Specifications for the ADaM datasets (as well as SDTM datasets) are described in a separate 
document. 
5.3 SAS-Programming Quality Level 
The following quality level of programming deliverables will be applied: 
All statistical output will receive a tailored Quality Control (QC) approach by: 
• Full independently double programmed reproduction (QC) of results of  
o CDISC ADaM datasets 
o Unique Tables and Graphs  
o All tables and figures reporting inferential analyses results  
• Listings will not be double programmed.  The programming to generate the listings will 
be reviewed in accordance with the
 procedure for all SAS programs. 
• All tables, listings, and graphs will undergo comparison with specifications (i.e. SAP 
and templates), cross checking with other tables, listings and graphs, the individual logs 
from the SAS programs will be reviewed to ensure all errors, warnings, and uninitialized 
variable messages have been rectified.  
• A Senior Review will also be performed by a reviewer independent of the study team. 
The reviewer studies all tables, listings and graphs for consistency and correctness, and 
pre-empts customer comments. This allows points of interest to be highlighted and 
discussed at customer hand-over. 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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All SDTM datasets, ADaM datasets, and tables, listings, and figures will be QC’ed by 
independent programmers, the study biostatistician, and a senior review as per the 
 SOP (
) SAS Programming, Validation, and QC version 3.0. 
 
5.4 Data from third parties 
Data provided by third parties, not contained in the clinical database, will be included in the 
SAS data repository. These third parties are: 
• 
: central laboratory data. 
• 
: Holter/ECG data, drug intake details, PEF values, compliance values, spirometry 
data, rescue medication and EXACT-Respiratory Symptom (RS) scores. 
• 
: supplies the randomization numbers and treatment codes to 
 
• 
: randomization data from the IRT system. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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6 Analysis Populations and Subgroups 
6.1 Analysis Populations 
• All Enrolled Subjects 
 
• All Randomized subjects  
 
• Safety population: all randomized subjects who receive at least one dose of study drug.  
 
• Intention-to-Treat population (ITT): all randomized subjects who receive at least one 
dose of the study drug and with at least one available evaluation of efficacy (primary or 
secondary efficacy variables) after the baseline. 
 
• Per-protocol population (PP): all subjects from the ITT population without any major 
protocol deviation (i.e., wrong inclusions, poor compliance and non-permitted 
medications). Exact definition of major protocol deviations will be discussed by the 
study team during the blind review of the data and described in the Data Review Report.  
 
Since the superiority of CHF 5259 pMDI at different doses over placebo will be tested, the 
primary efficacy analysis will be based on the ITT population. The primary efficacy analysis 
will be also performed on the PP population for sensitivity purposes.  
All 3 populations (Safety, ITT, and PP) will be used for the presentation of demographics, 
COPD history and smoking, and spirometry and reversibility.   
The medical history/concomitant diseases and exposure/compliance to treatment results will be 
presented using the ITT and Safety populations.  Exposure/compliance to background 
medication will be presented using the ITT population. 
Medications, CAT score, BDI, compliance with the use of e-diary, and protocol deviations will 
be reported using the ITT population.   
The safety data will be summarized and reported using the Safety population.   
6.2 Treatment Misallocation 
In case of deviation between the as-randomized treatment and the treatment actually received, 
the treatment actually received will be used in the safety analyses (i.e. an as-treated analysis 
will be performed). The following rules will be applied in the construct of the populations: 
• Subjects randomized but not treated will be excluded from the Safety, ITT and PP 
populations.  
• Subjects treated but not randomized will be excluded from the ITT and PP population, 
given there will be no randomized treatment. These subjects will be summarized based 
on the treatment they received and will be counted in the Safety population. 
• Subjects who were randomized, but took the incorrect study drug for the duration of the 
study, will be summarized based on their randomized treatment for the ITT population 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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and excluded from the PP population. These subjects will be summarized based on the 
treatment that they received for the safety analyses.   
• Subjects who were randomized, but took the incorrect study drug for part of the study 
(e.g. the subject began the study by taking the incorrect study drug at Visit 2 but 
switched to randomized study drug at Visit 3) will be discussed during the Blind Data 
Review Meeting, and the decisions will be agreed prior to unblinding, and documented 
in the Data Review Report prior to unblinding. 
6.3 Subgroup Definitions 
There are no specific subgroups that are planned for analysis. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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7 Definition of Time Points and Analysis Variables 
7.1 Definition of Time Points 
For each visit, the date recorded by the Investigator in the eCRF (variable SVSTDTC in the 
SDTM SV dataset) will be considered as the visit date in all the algorithms and the listings.  
Start/End of the Randomized Treatment Period  
Since many algorithms used in the statistical analyses require the start and/or the end of the 
randomized treatment period to be identified, ad-hoc variables specifying these dates will be 
defined. The date of start/end of randomized treatment period will be set according to the 
following rule:  
• The date of Start of the Randomized Treatment Period should coincide with the date 
of Visit 2, the randomization date and the date of first randomized study drug intake. 
However, discrepancies between these dates may arise and the most appropriate date to 
be used in such situations requires a case-by-case evaluation. The date of the start of the 
randomized treatment period will be initially set equal to the date of first randomized 
study drug intake for all subjects. The need for deviations from this rule in single cases 
will be evaluated during the data review and documented in the Data Review Report. 
As a consequence, the distinction between diary data from the run-in and the treatment 
period will not be based on the EPOCH variable included in the SDTM datasets, but on 
the algorithms defined in the SAP.   
• 
If Visit 4 or Early Termination visit was completed, then he date of End of the 
Randomized Treatment Period will be defined as Date of Visit 4/ Early Termination 
Visit.  Otherwise, the date of End of Randomized Treatment Period  will be defined as 
the maximum of [Date of Last Study Drug Intake, date of last clinic visit during 
treatment period (excluding Visit 5 and any unscheduled visits after last dose)].   
 
Period durations (days) 
Day 1 is defined as the date of first dose of randomized study drug.  The day prior to Day 1 is 
Day -1.  There is no Day 0. 
Periods used in the analysis of this study are:  
• Run-in Period: Morning of Visit 1 through the evening of the day before the date of 
Start of the Randomized Treatment Period. 
Run-in duration = date of the day before the date of the Start of the Randomized 
Treatment Period – date of Visit 1 + 1 day 
 
• Treatment Period: (End of the Randomized Treatment Period minus Start of the 
Randomized Treatment Period) + 1 day 
Inter-visit periods will be used in the analysis of the percentage of rescue medication-free days, 
the average number of rescue medication-puffs per day, and the average E-RS total score and 
domain scores.  The periods used in these analyses are: 
• Run-in Period: The Run-In Period starts at Visit 1 and runs through the day 
before the date of Start of the Randomized Treatment Period  


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• Inter-visit Period 1: Inter-visit Period 1 starts on the date of the Start of the 
Randomized Treatment Period and runs through the day before the subject returns 
to the clinic at Visit 3. 
If the subject withdraws prematurely after Visit 2 and before Visit 3 any value 
collected until the End of Randomized Treatment Period will be considered for the 
inter-visit period 1. By default inter-visit period 2 is missing. 
• Inter-visit Period 2: Inter-visit Period 2 starts on the day the subject returns to the 
clinic at Visit 3 and runs through End of the Randomized Treatment Period.   
If the subject withdraws prematurely after Visit 3,any value collected until the End 
of the Randomized Treatment Period will be considered for the inter-visit period 2.  
 
Date of first/last study drug intake  
Date of first randomized study drug intake is derived as the minimum of ‘Date/Time of 
administration’ between the 2 inhalations (puffs) of the Morning Dose collected on the ‘Study 
drug administration at the clinic’ eCRF page.  While subjects randomized to open-label label 
SPIRIVA® will only receive 1 inhaler (and only 1 date/time of inhalation is recorded), patients 
are required to take 2 inhalations of the content of 1 inhaler.  For these patients, no minimum is 
required, since only 1 time is recorded. 
Note: The date and time of drug administration at each visit are mandatory variables to be 
reported in the eCRF; no missing or partial data can be accepted.  Only eCRF data will be 
considered for the date of first randomized study drug intake. 
Date of last randomized study drug intake is derived as ‘Date/Time of last intake of study drug’ 
variable collected on the ‘Study Termination form’ eCRF page. If the date of the last intake of  
study drug is missing or partially missing, but the date of at least one dose of the study drug is 
recorded in the diaries or at the clinic, the date of the last randomized study drug intake will be 
imputed using the following rule: 
 max [date of last study drug intake in the diaries, date of last study drug intake at the clinic 
visits] 
The need for deviations from these rules in single cases will be evaluated during the data review 
and documented in the Data Review Report. 
 
 
Time to discontinuation from the study 
Time to discontinuation will be calculated for all randomized subjects, including subjects who 
complete the study.  For subjects randomized but not treated, the time to discontinuation from 
the study will be imputed as 0.  Subject disposition data will be collected on the ‘Study 
Termination form’ eCRF page, which provides information about study completion status of a 
subject. Study discontinuation is recorded along with the main reason for withdrawal. The 
primary reason for discontinuation could be early withdrawal or lost to follow up.  Patients 
completing the study will be censored at the Date of Completion.  Patients lost to follow up will 
be considered as having an event at the date of Discontinuation recorded on the ‘Study 
Termination” eCRF page.   


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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The time to completion/discontinuation from the study (weeks) is defined as: 
(date of completion/discontinuation - date of start of randomized treatment period ) / 7 
 
Baseline definitions 
  
For FEV1 and FVC, the baseline value is defined as the average of the pre-dose measurements 
on Visit 2 (45 min and 15 min pre-dose). For IC, the measurement recorded at 45 minutes pre-
dose at Visit 2 will be used as the baseline.   
From Section 12.3.2 of the protocol: If one of the spirometry measurements at 45 min and 15 
min pre-dose is not available, then the non-missing measurement will be taken as the pre-dose 
value. If no measurement is available, then the pre-dose value will be considered as missing. 
This rule applies to FEV1 and FVC. 
The analysis models of TDI will use the BDI focal score at Visit 2 as the baseline value. 
The baseline used in the analysis of rescue medication use and E-RS score is based on the data 
recorded during the Run-in Period. Depending on the structure of the specific variable, this may 
be an average value or a percentage.  
For vital signs, baseline values are those recorded pre-dose at Visit 2.  
For laboratory the baseline values are the ones collected at Visit 1.   
Subjects will have ambulatory 24-hour digital Holter recording for 24 hours before and 24 hours 
after the 1st dose of study drug (Visit 2) and for 24 hours before the last dose of study drug (Visit 
4). The time-matched values recorded during the 24 hours before the 1st dose of study drug on 
Visit 2 will serve as the baseline for the Holter-extracted ECG parameters (HR, QTcF, QRS 
and PR).  The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m 
and +2.5h.   
To facilitate data quality, the subject will be asked to assume a supine position and remain 
quiet, but awake, beginning at 10 minutes before the nominal extraction time and then for 5 
minutes afterward. For each subject, there will be: 
• 3 nominal extraction times in the day before Visit 2 (time-matched with the post-study 
drug extraction times on Visit 2) 
• 3 extraction times at +5 min, +55 min, and +2.5h after 1st dose of study drug on Visit 
2; and  
• 3 extraction times at +5 min, +55 min, and +2.5h after the morning dose of study drug 
on the day before Visit 4. 
For 24-hour average, minimum and maximum HR the baseline values are those derived from 
the Holter recording during the 24 hours before the 1st dose of study drug on Visit 2. 
 
7.2 Baseline and Derived Analysis Variables 
The purpose of this section is to describe the calculation of all derived variables. All other 
variables that are obtained directly from the eCRF system with no derivation are not described 
in this section. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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7.2.1 Demographic Characteristics 
• 
Age of the subject will be calculated by the IVRS system based on the date of birth and 
date of Pre-Screening (Visit 0) entered into the system. 
7.2.2 COPD History and Pre-Study Smoking Habits 
• 
The time since first COPD diagnosis (months) will be calculated as the (Visit 1date - date 
of first diagnosis)/30.4375.   
• Age at First COPD Diagnosis (years) will be calculated in SAS using the following formula:  
floor(yrdif(date of birth, date of first diagnosis, 'AGE')).    
The Duration of Smoking (years) will be calculated using the start/stop date of smoking and 
is calculated differently for current and ex-smokers:  
o For ex-smokers: (smoking stop date - smoking start date + 1)/365.25 
o For current smokers: (Visit 1 date - smoking start date + 1)/365.25 
 
Only the month and the year (not the day) is recorded on the eCRF for Date of first diagnosis 
and smoking start/stop date. The first day of the month will be assumed for these dates in order 
to calculate time duration variables.  
In order to calculate the duration, the following rules will be applied for the partial dates: if the 
month is missing, January 1st will be assumed. When the start date is completely missing, the 
time duration variable will not be calculated. 
7.2.3 Baseline Subject Characteristics 
• The Baseline Dyspnea Index (BDI) Focal Score will be calculated within the eCRF from 
the three individual domain scores (Functional Impairment, Magnitude of Task, and 
Magnitude of Effort).   
• The COPD Assessment Test (CAT) is an assessment containing 8 elements, each scored 
on a scale from 0 to 5. A score of 0 describes the best possible status and a score of 5 
describes the worst possible status. These scores will be summed in the eCRF to 
calculate the CAT Total Score. 
• Medical/Surgical History and Concomitant Diseases will be collected during Visit 1.  
All conditions that are not indicated as ongoing will be considered as medical/surgical 
history, while conditions indicated as ongoing will be considered as concomitant 
diseases. 
• Body Mass Index (kg/m2) is calculated as Weight (kg) / [Height (m)]² 
 
7.2.4 Spirometry Performed at Screening 
Spirometry (FVC maneuver) will be carried out 15 minutes before bronchodilator and 30 to 45 
minutes after the inhalation of 84μg of ipratropium pMDI at Visit 1 (screening). The 
reversibility parameters ΔFEV1 (mL) and % ΔFEV1 will be calculated in the eCRF.  
If the reversibility test of Visit 1 is repeated in a (pre-randomization) rescheduled visit (called 
Visit 1.1 in the eCRF), then all spirometry values of the rescheduled visit will be considered as 
the Visit 1 assessment in the analysis. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Page 21 of 70 
 
 
7.2.5 Medications 
Medications will be split into four categories: 
• Previous medications are those medications started and stopped prior to the initial 
exposure to the study drug (medication start date < date of first study drug intake and 
medication stop date ≤ date of first study drug intake). 
• Maintained medications are all medications started before initial exposure to the study 
drug and ongoing at initial exposure to the study drug (medication start date < date of 
first study drug intake and medication stop date > date of date of first study drug intake). 
• Concomitant medications are all medications started during the treatment period (date 
of first study drug intake <= medication start date < date of last study drug intake). 
• Post-treatment medications are all medications started on or after the last dose of study 
drug (medication start date >= date of last study drug intake) 
In case of missing or incomplete dates not directly allowing allocation to any of the four 
categories of medications, a worst-case allocation will be performed according to the available 
parts of the start and the stop dates. The medications will be allocated to the first category 
allowed by the available data, according to the following order: 
1. concomitant medication; 
2. maintained medication; 
3. post-treatment medication; 
4. previous medication. 
Information on concomitant medications is retrieved from the ‘Prior and Concomitant 
medications’ eCRF page. 
7.2.6 Procedures 
Medications will be split into two categories: 
• Previous procedures are all procedures started and stopped prior to the initial exposure 
to the study drug (procedures start date < date of first study drug intake and procedures 
stop date ≤ date of first study drug intake). 
• Maintained procedures are all procedures started before initial exposure to the study 
drug and ongoing at initial exposure to the study drug (procedures start date < date of 
first study drug intake and procedures stop date > date of date of first study drug intake). 
• Concomitant procedures are all procedures started during the treatment period (date 
of first study drug intake <= procedures start date < date of last study drug intake). 
• Post-treatment procedures are all procedures started on or after the last dose of study 
drug (procedures start date >= date of last study drug intake) 
In case of missing or incomplete dates not directly allowing allocation to the two categories of 
procedures, a worst-case allocation will be performed according to the available parts of the 
start and the stop dates. The procedures will be allocated to the first category allowed by the 
available data, according to the following order: 
1. concomitant procedures; 
2. maintained procedures; 
3. post-treatment procedures; 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
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Page 22 of 70 
 
4. previous procedures. 
Information on concomitant procedures is retrieved from the ‘Concomitant procedures’ eCRF 
page. Procedures will be listed only. 
7.2.7 Treatment Exposure and Compliance – Background Medication 
Run-In Period / Exposure and Compliance 
Since only subjects receiving prior ICS treatment will be provided with QVAR at V1, treatment 
exposure and compliance with background ICS medication (QVAR) can only be performed on 
subjects provided with QVAR at V1.  The Run-In Period starts at Visit 1 and runs through the 
day before Day 1 (Day -1).  Exposure during the Run-in Period is based on actual dosing 
date/times and not visit dates.  
Exposure will be calculated as the date of last dose of the Run-in Period – date of first dose of 
the Run-in Period + 1 day. 
Compliance to background medication during the run-in period is based on eCRF and diary 
data. If, on a visit day, information is available from both eCRF and diaries, data entered by the 
investigator in the eCRF will be taken into account. 
The evaluation of compliance will be based on the number of puffs following the formula 
presented below: 
 
Total number of administered puffs (as recorded in the Subject Diary 
and / or Background Medication Administration eCRF page)
Total number of scheduled puffs
𝑥𝑥 100% 
 
The total number of scheduled puffs per day is the sum of the ‘Number of puffs the subject 
has been instructed to take: Morning puffs’ plus ‘Evening puffs’ as recorded on the Screening 
‘COPD Background Medication Administration’ eCRF page. 
The total scheduled number of puffs during the Run-in Period is defined as: 
[Run-in period duration (days)] x [scheduled number of puffs per day] 
The approach above defined for the calculation of compliance assumes no intake of the 
background medication in case of missing data. 
 
Treatment Period / Exposure and Compliance 
Compliance to background medication during the treatment period should be calculated 
considering data recorded from date of start of randomized treatment period to date of end 
randomized treatment period.  
Exposure to background medication during treatment period (days) will be calculated as date 
of last background medication intake - date of first background medication intake + 1 day.   
Compliance to background medication during the treatment period is based on eCRF and diary 
data. If on a visit day information is available from both eCRF and diaries, data entered by the 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
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Page 23 of 70 
 
investigator in the eCRF will be taken into account.  In the case that eCRF data is available for 
unscheduled visits within the Treatment period, it will also be considered. 
Date of last background medication will be collected in the ‘COPD Background medication 
administration’ eCRF page of Visit 4. If the subject discontinued the study before Visit 4 or the 
date of the last background medication is missing or partially missing, but the date of at least 
one dose of the study drug is recorded in the diaries or at the clinic, the date of the last 
background medication will be imputed using the following rule: 
 max [date of last background drug intake in the diaries, date of last background drug intake at 
the clinic visits]. 
The evaluation of compliance will be based on the number of puffs following the formula 
presented for Run-in period. 
The total scheduled number of puffs during the Treatment Period is defined as: 
– For subjects who had their last background medication dose on the last scheduled 
dosing day in the period [i.e. the “Week 6 visit”] the scheduled number of puffs = 
Treatment exposure (days) x [scheduled puffs per day] minus [scheduled evening 
puffs on the last scheduled dosing day]  
 
– For subjects who had their last background medication dose on any day before the 
last scheduled dosing day in the period [i.e. an  early discontinuation] the 
scheduled number of puffs = Treatment exposure (days) x [scheduled puffs per day] 
 
If the date of the last dose of  Background treatment = date of first dose of Background  
treatment, the scheduled number of puffs will be 1 day * [scheduled puffs per day].  
The approach above defined for the calculation of compliance assumes no intake of the 
background medication in case of missing data. 
Any level of compliance in the interval [65%; 135%] is considered as satisfactory after 
randomization. Therefore, the following categories will be presented: 
• 
Treatment compliance < 65% 
• 
65% ≤ Treatment compliance ≤ 135% 
• 
Treatment compliance > 135%. 
The compliance will also be summarized using the following categories for the Run-in Period 
and also for the Treatment period: 
• [0%-10%] 
• (10%-20%] 
• (20%-30%] 
• (30%-40%] 
• (40%-50%] 
• (50%-60%] 
• (60%-70%] 
• (70%-80%] 
• (80%-90%] 
• (90%-100%] 
• (100%-110%] 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• (110%-120%] 
• (120%-130%] 
• (130%-140%] 
• >140% 
 
7.2.8 Treatment Exposure and Compliance - Study Drug Administration 
The actual date and time of study drug administration will be used to calculate exposure.  For 
Treatment Arms A, B, C, D and E, the following dosing schedule will be followed for the 6-
week treatment period; study drug will be administered twice-a-day (in the morning and in the 
evening), except for the last day of treatment (Visit 4) when only the morning dose is 
administered: 
Morning administration (between 8-10 am): 
One inhalation from the inhaler numbered 1 
One inhalation from the inhaler numbered 2 
 
Evening administration (between 8-10 pm):  
One inhalation from the inhaler numbered 1 
One inhalation from the inhaler numbered 2 
 
If the settings in the electronic diary are incorrect at randomization for a subject (e.g., Run-in 
period settings are applied during the treatment period), such that data is not collected for study 
drug administration during some days during the treatment period, then compliance  will not be 
calculated for that subject for days on which the settings were incorrect.  Instead, compliance 
will be calculated based on days during which the settings were correct.  The information 
recorded at the study clinic will always be considered in the calculation (i.e. day will be 
considered in calculation if exposure is recorded at clinic in a day where diary has an incorrect 
setting). For these subjects, the duration of the treatment period (as used for calculation of 
scheduled puffs) will be reduced by the number of days during which the settings were 
incorrect.  In other words, days with incorrect diary settings will be excluded from the 
numerator and denominator of the compliance calculation for these subjects.  If the diary 
settings were incorrect during the entire treatment period, then compliance  will not be 
calculated for the subject.  To be considered as incorrect, diary data should be nonmissing and 
questions answered consistent with a different period. For example (I=incorrect questions, 
C=correct questions, M=missing data): 
• Day 1: I 
• Day 2: I 
• Day 3: M 
• Day 4: M 
• Day 5: C. 
In this case, the last “incorrect day” is Day 2. 
For Treatment Arm F (Open Label arm), there will be 1 morning administration (between 8-10 
am): two inhalations of the powder contents of a single SPIRIVA® capsule (18µg) once daily. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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The first and last dosing occasions for study drug are expected to be taken during the visit dates, 
however exposure and compliance are based on actual dosing date/times and not visit dates. 
See Section 7.1 for the definition of the study periods and period durations (days). 
For the calculation of the number of administered and scheduled puffs, the dosing occasions 
from the first to the last study drug intake will be taken into account (i.e. any study drug 
recorded in the Subject Diary after the Date of last intake of study drug (as recorded on the 
‘Study Termination’ eCRF page) will be ignored for study drug compliance calculations).  
If Date of last intake of study drug (as recorded on the ‘Study Termination’ eCRF page) is 
missing or partially missing, dosing occasions of the study drug recorded in the diaries or at the 
clinic will be taken into account until the ‘last randomized study drug intake’ as defined in 
Section 7.1. 
Exposure will be calculated as the Date of last intake of study drug – date of first intake of study 
drug + 1 day. 
The evaluation of compliance is done using the following formula: 
 
Total number of administered puffs (as recorded in the Subject Diary 
and / or Study Drug Administrationat the Clinic eCRF page)
Total number of scheduled puffs
 𝑥𝑥 100% 
 
 
The total number of administered puffs will be calculated by adding up the number of puffs 
taken during the Treatment period, as recorded in the Subject Diary or ‘Study Drug 
Administration at the Clinic’ eCRF page. 
It should be noted that 2 puffs should be taken twice a day (for treatments A-E) and 2 puffs 
should be taken once daily (for treatment F) during the Treatment period (from  Day 1 (V2) 
until the day before V4) and 2 puffs should be taken once at V4 for all treatment arms [On the 
Week 6 visit day, the morning dose occurs in the clinic and there is no evening dose]. 
The total number of scheduled puffs is defined during the treatment period as:  
• For subjects who had their last study drug dose on the last scheduled dosing day [i.e. 
the “Week 6 visit”], the scheduled number of puffs = Treatment exposure (days) x 
[scheduled puffs per day] minus [scheduled evening puffs on the last scheduled dosing 
day] 
 
• For subjects who had their last study drug dose on any day before the last scheduled 
dosing day [i.e. an early discontinuation], the scheduled number of puffs = Treatment 
exposure (days) x [scheduled puffs per day]. 
 
• If a subject is randomized into the study and discontinues the same day, then the subject 
was included in the study for 1 day.  Hence, the expected number of puffs would be 1 
day * [scheduled puffs per day] 
 
Information on study drug intake is retrieved from the eCRF (on visit days) and subject diaries. 
If on a visit day information is available from both eCRF and diaries, data entered by the 
investigator in the eCRF will be taken into account. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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The approach above defined for the calculation of compliance assumes no intake of the study 
drug in case of missing data. 
Any level of compliance in the interval [65%; 135%] is considered as satisfactory after 
randomization. Therefore, the following categories will be discerned for Treatment Period: 
• Treatment compliance < 65% 
• 65% ≤ Treatment compliance ≤ 135% 
• Treatment compliance > 135%. 
The compliance will also be summarized as per following categories: 
• [0%-10%] 
• (10%-20%] 
• (20%-30%] 
• (30%-40%] 
• (40%-50%] 
• (50%-60%] 
• (60%-70%] 
• (70%-80%] 
• (80%-90%] 
• (90%-100%] 
• (100%-110%] 
• (110%-120%] 
• (120%-130%] 
• (130%-140%] 
• >140% 
 
7.2.9 Compliance with the use of e-Diary 
If the setting in the electronic diary are incorrect for a subject (e.g., Run-in settings applied 
during treatment period or vice-versa), then compliance with use of e-Diary will still be 
considered.   
  In these cases, if any questions were answered, the day will count as “data recorded in the 
 device”.   
 See Section 7.1 for the definition of the study periods and period durations (days).  Period 
duration will be calculated differently for completed subjects and discontinued subjects as 
defined in Section 7.1.  Since diary data is not expected on the date of Visit 4, Period durations 
for periods including that date will be shortened by 1 day.  If diary data is received for date of 
Visit 4, it will also be excluded from the numerator of the compliance calculation. 
The evaluation of compliance per period (Run-in/Treatment Period) is done using the following 
formula: 
 
Total number of days in the treatment period with data recorded in the 
 device
Period duration
 𝑥𝑥 100% 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Page 27 of 70 
 
The following categories will be discerned for compliance: 
•  [0%-10%] 
• (10%-20%] 
• (20%-30%] 
• (30%-40%] 
• (40%-50%] 
• (50%-60%] 
• (60%-70%] 
• (70%-80%] 
• (80%-90%] 
• (90%-100%] 
 
7.2.10 Efficacy Variables 
● Overview 
All spirometry results will be graded by an independent reviewer at 
. The grades after the 
Best Test Review are: U = Unacceptable, A = Acceptable, and B = Borderline Acceptable.  All 
spirometry values, including the values scored with a grade “Unacceptable”, will be considered 
in the statistical analyses.  This follows the approach recommended by the paper by Hankinson 
et al., where it was concluded that quality assessment regarding the acceptability of individual 
blows should be primarily used as an aid to good quality during testing rather than a reason to 
subsequently disregard data.  
Spirometry data together with the time of scheduled time points are imported from external 
 data. 
In addition, the spirometry values excluded from the analysis based on the decisions taken 
during the Blind Data Review Meeting (e.g., due to technical issues) will be considered to be 
missing prior to the calculation of the derived variables. In the listings, these assessments will 
be shown and flagged, to highlight their exclusion from the analyses. 
 
● Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in FEV1 AUC0-12h normalized by 
time at Visit 4. The baseline value is the average of the pre-dose FEV1 measurements on Day 
1.  FEV1 is a continuous variable derived from spirometry data (
). FEV1 AUC0-12h will be 
calculated at Week 6. AUC normalized by time will be calculated based on the actual times 
using the linear trapezoidal rule:  
 ൝෍[(𝐭𝐭𝐢𝐢−𝐭𝐭𝐢𝐢−𝟏𝟏)(𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐢𝐢+ 𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐢𝐢−𝟏𝟏)/𝟐𝟐]
𝐢𝐢
ൡ𝐭𝐭𝐭𝐭𝐭𝐭𝐭𝐭
ൗ
 
where: 
for t0, FEV10 is the pre-dose average of T -45’ and T -15’ before study drug administration at 
that visit  
t0 is the actual time of the administration of the first morning dose of study drug, 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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for i = 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h and 12h, FEV1i is the actual 
FEV1 value at each time point and ti is the actual time of sample i. 
time is the actual elapsed time from t0 until t12.   
 
For the calculation, all valid measurements i are taken and, in addition, the following imputation 
rules apply: 
• If one of the spirometry measurements at 45 min and 15 min pre-dose is not available, 
then the non-missing measurement will be taken as the pre-dose value (corresponding 
to time 0 for the calculation of AUC). If no measurement is available, then the pre-dose 
value will be considered as missing. 
• If the pre-dose value is not available, the entire curve will be considered as missing 
• The linear trapezoidal rule will allow AUC0-12h to be calculated if a single, isolated 
missing value (not pre-dose or last value) exists. This is akin to replacing the missing 
value by linear interpolation using the adjacent values 
• If the value at 12h post-dose is missing, it will be replaced by the value at 11h30; the 
time will be replaced with the planned 12h post-dose time . 
• If two or more consecutive post-dose time points have a missing observation, the entire 
FEV1 AUC0-12h for that day will be missing. 
• If in total more than three of the post-dose time points have missing values, the FEV1 
AUC0-12h for that day will be missing. 
• In case of missing actual time, the theoretical or planned time is used. 
If a subject uses rescue medications within the 6-hour wash-out period prior to dosing or during 
the 12-hour period during which the FEV1 measurements are obtained at Week 6, then all FEV1 
measurements will be used in the calculation of the FEV1 AUC0-12h and analyzed as part of the 
ITT Population with no exception.  In case of rescue medication intake during the serial 
spirometry (from pre-dose to 12 h post-dose) or during the 6 h wash-out pre-dose, cases will be 
reviewed during the DRM and documented in the DRR.  As a general rule, all spirometry data 
recorded from the time of rescue medication intake onwards for 6 hours will be excluded from 
the analysis of primary efficacy endpoint for the PP population. 
 
Secondary Efficacy Variables 
If a subject uses rescue medications within the 12-hour period/4-hour period during which 
spirometry measurements are obtained or during the 6 hour wash out period prior to spirometry 
then all spirometry  measurements will be used and analyzed as part of the ITT Population with 
no exception.   
• 1: Change from baseline in FEV1 AUC0-12h normalized by time at Day 1 
FEV1 is a continuous variable derived from spirometry data (
).  FEV1 AUC0-12h will be 
calculated on Day 1. The baseline value is the average of the T-45 and T-15 min pre-dose FEV1 
measurements on Day 1.  The calculation of the FEV1 AUC0-12h on Day 1 will follow in the 
same manner as the calculation outlined above for the primary efficacy variable.  
 
• 2a: Change from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Week 6 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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The baseline value is the average of the pre-dose FEV1 measurements on Day 1.  The change 
from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Week 6 will be calculated 
using the following equation: 
 
൝෍[(𝐭𝐭𝐢𝐢−𝐭𝐭𝐢𝐢−𝟏𝟏)(𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐢𝐢+ 𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐅𝐢𝐢−𝟏𝟏)/𝟐𝟐]
𝐢𝐢
ൡ𝐭𝐭𝐭𝐭𝐭𝐭𝐭𝐭
ൗ
 
Where: 
for t0, FEV10 is the pre-dose average of T -45’ and T -15’ before the time of study drug 
administration at that visit  
t0 is the actual time of the administration of the first morning dose of study drug, 
for i = 15 min, 30 min, 45 min, 1h, 2h, 3h and 4h, FEV1i is the actual FEV1 value at each time 
point and ti is the actual time of sample i. 
time is the actual elapsed time from t0 until t4.   
 
For the calculation, all valid measurements i are taken and, in addition, the following imputation 
rules apply: 
• If one of the spirometry measurements at 45 min and 15 min pre-dose is not available, 
then the non-missing measurement will be taken as the pre-dose value (corresponding 
to time 0 for the calculation of AUC). If no measurement is available, then the pre-dose 
value will be considered as missing. 
• If the pre-dose value is not available, the entire curve will be considered as missing 
• The linear trapezoidal rule will allow AUC0-4h to be calculated if a single, isolated 
missing value (not pre-dose or last value) exists. This is akin to replacing the missing 
value by linear interpolation using the adjacent values 
• If the value at 4h post-dose is missing, it will be replaced by the value at 3h. 
• If two or more consecutive post-dose time points until 4h have a missing observation, 
the entire FEV1 AUC0-4h for that day will be missing. 
• If in total three or more post-dose time points until 4h have missing values, the FEV1 
AUC0-4h for that day will be missing. 
• In case of missing actual time, the theoretical or planned time is used. 
 
• 2b: Change from baseline in FEV1 peak0-4h at Day 1 and Week 6 
FEV1 peak0-4h at Day 1 and Week 6 will be calculated using the following formula: 
Maximum value of all FEV1 values at the time points 15 min, 30 min, 45 min, 1h, 2h, 3h, and 
4h of the respective day.  If 3 or more missing values are reported among the post-dose 
spirometry measurements at 45 min, 1h, 2h, 3h, 4h, , the FEV1 peak0-4h for that day will be 
missing. 
 
• 2c: Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 
measurements) at Week 3 and Week 6 
If one of the spirometry measurements at 45 min and 15 min pre-dose is not available, then the 
non-missing measurement will be taken as the pre-dose value. If no measurement is available, 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 30 of 70 
 
then the pre-dose value will be considered as missing. The baseline value is the average of the 
pre-dose FEV1 measurements on Day 1. 
In case of rescue medication intake during the 6 hours wash-out pre-dose, all spirometry data 
recorded will be considered. 
 
• 3a: Change from baseline in FVC AUC0-12h normalized by time at Day 1 and Week 6 
FVC is a continuous variable derived from spirometry data (
). The baseline value is the 
average of the pre-dose FVC measurements on Day 1. FVC AUC0-12h will be calculated on Day 
1 and Week 6. The calculation of the FVC AUC0-12h will follow in the same manner as the 
calculation outlined above for the primary efficacy variable.  
 
• 3b: Change from baseline in FVC AUC0-4h normalized by time at Day 1 and Week 6 
FVC AUC0-4h will be calculated on Day 1 and Week 6. The baseline value is the average of the 
pre-dose FVC measurements on Day 1. The calculation of the FVC AUC0-4h will follow in the 
same manner as the calculation outlined above for FEV1 AUC0-4h.  
 
• 3c: Change from baseline FVC peak0-4h at Day 1 and Week 6 
FVC peak0-4h at Day 1 and Week 6 will be calculated using the following formula: 
Maximum value of all FVC values at the time points 15 min, 30 min, 45 min, 1h, 2h, 3h, and 
4h of the respective day. If 3 or more missing values are reported among the post-dose 
spirometry measurements at 45 min, 1h, 2h, 3h, 4h, the FVC peak0-4h for that day will be 
missing.  
 
• 4: Time to onset of action (change from baseline in post-dose FEV1 ≥ 100 mL) at Day 1 
In case of at least one post-dose timepoint with change from baseline in FEV1 ≥ 100 mL, then 
Time to onset of action will be equal to the first post-dose timepoint with change from baseline 
in FEV1 ≥ 100 mL in the time interval considered (12 h). Time to onset of action will be 
calculated as the difference in minutes from the actual spirometry time and the time of first drug 
intake.  In case of no timepoint with change from baseline in FEV1 ≥ 100 mL, and less than 
four missing values among post-dose spirometry measurements at 15 min, 30 min, 45 min, 1h, 
2h, 3h and 4h, then the subject will be considered as censored at the last available post-dose 
timepoint.  Subjects with 4 or more of these data points missing will be excluded from the 
analysis of time to onset of action. 
 
• 5: Change from baseline in pre-dose morning IC at Week 3 and Week 6 
IC will be measured at V2, V3 and V4 only once at T-45’ pre-dose using the SVC maneuver, 
before the FVC maneuver. If either a baseline (V2) or a post-baseline value is missing, then the 
change from baseline in IC value will be considered as missing at that visit.   
 
• 6: TDI focal score at Week 3 and Week 6 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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The TDI  Focal Score will be calculated within the eCRF from the three individual domain 
scores (Functional Impairment, Magnitude of Task, and Magnitude of Effort).  The BDI and 
the TDI focal scores will be considered as missing if at least one response is included among 
the following: “W = Amount Uncertain”, “X = Unknown”, “Y = Impaired for Reasons other 
than Shortness of Breath” or “Z = Further Impairment for Reasons other than Shortness of 
Breath”.  
 
• 7: TDI response (TDI focal score ≥ 1) at Week 3 and Week 6 
  A TDI response occurs if the TDI focal score is ≥ 1. Subjects with missing data at the relevant 
visit will be considered as non-responders. 
 
• 8a: Change from baseline in percentage of rescue medication-free days during inter-visit 
periods and entire treatment period 
Information on rescue medication use is collected in the subject-completed e-diary. A patient 
is assumed to have used rescue medication if the answer to either of the following questions is 
>0:   
• How many inhalations of rescue medication did you take since last evening?  
• How many times did you take rescue medication since last evening?  
In case of duplicates information reported at clinic and in diary, the greatest information will 
be used. The change from baseline in the percentage of rescue medication-free days is a 
continuous variable.  The percentage of rescue medication-free days is calculated in each period 
as 
Number of rescue medication −free days
Number of days with available data
𝑥𝑥100% 
 
A minimum of 7 days with available measurements will be required for each inter-visit period 
(including the run-in period) to consider the percentage of rescue medication-free days as non-
missing.  The percentage of rescue medication-free days of the entire treatment period will be 
derived only if both inter-visit period are non-missing. See Section 7.1 for the definition of the 
inter-visit periods. 
 
• 8b: Change from baseline in average use of rescue medication (number of puffs/day) during 
inter-visit periods and entire treatment period 
The change from baseline in the average use of rescue medication is a continuous variable.  The 
average use of rescue medication is calculated in each period as 
∑Number of puffs of rescue medication taken
Number of days with available data
 
In case of duplicates information reported at clinic and in diary, the greatest information will 
be used. A minimum of 7 days with available measurements will be required for each inter-
visit period (including run-in period) to consider the average use of rescue medication as non-
missing.  The percentage of rescue medication-free days of the entire treatment period will be 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 32 of 70 
 
derived only if both inter-visit period are non-missing. See Section 7.1 for the definition of the 
inter-visit periods. 
 
8c: Change from baseline in average E-RS total score and domain scores during inter-visit 
periods and entire treatment period.   
Formerly known as the EXACT-Respiratory Symptom Scale (E-RS), the Evaluating 
Respiratory Symptoms of COPD measure (E-RS™:COPD) uses 11 respiratory symptom items 
from the 14-item EXACT. The E-RS total score quantifies respiratory symptom severity and 3 
domains: breathlessness, cough and sputum, and chest symptoms. 
 
 
 
 
The E-RS Total score will be 
calculated for each day of diary collection. 
: 
• 
 
• 
 
. 
E-RS domain scores will be calculated for each day of diary collection.  
 
• 
 
• 
 
• 
 
 
• 
  
• 
 
 
Higher E-RS scores indicate more severe symptoms and a declining total score indicates health 
improvement.  
 
  The 
average score will be calculated as the sum of the scores for the interval being summarized, 
divided by the number of scores in the interval. 
The average E-RS total and domain scores will be calculated as the average of the total/domain 
scores for subjects with ≥7 days of measurements. A minimum of 7 days with available 
measurements will be required for each inter-visit period (including run-in period) to consider 
the average E-RS total/domain score as non-missing.  The percentage of rescue medication-free 
days of the entire treatment period will be derived only if both inter-visit period are non-
missing. Section 7.1 for the definition of the inter-visit periods. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 33 of 70 
 
7.2.11 Safety Variables 
There are 6 sets of safety variables identified in the protocol. A description of each variable, 
and the timing of the recording of the information is presented below.   
 
• 1: Treatment Emergent Adverse Events (TEAEs)  
Three categories of AEs will be presented: Pre-Treatment, Treatment Emergent, and Post-
Study.  An AE will be classified as: 
• pre-treatment AE: if AE starts before the first randomized study medication intake (AE 
onset date < date of first randomized study medication intake).   
• Treatment emergent AEs (TEAEs): all adverse events starting on or after the first study 
drug intake, up to study completion/discontinuation. TEAEs are defined as AEs with 
date of first randomized study drug intake ≤ AE onset date ≤ date of study 
completion/discontinuation.  
• post-study AE: if AE starts after the date of completion/discontinuation (AE onset date 
> date of completion/discontinuation).   
 
Additional variables to define an adverse event include the following: 
• Serious AE (SAE) is defined as any AE that has the question “Is the AE serious?” 
marked as “Yes” on the eCRF.  
• ADR is defined as any AE that has the question “Is the AE Related to Study Drug?” 
marked as “Yes” on the eCRF.  
• Serious ADR is defined as any ADR that are also SAE   
• Severe AE, defined as any AE that has intensity marked as “Severe” on the eCRF. 
• AE leading to study drug discontinuation, defined as a TEAE where the action taken 
on the eCRF is marked as “Drug withdrawn”.  
• AE leading to death, defined as a TEAE where the outcome is marked as “Fatal” on 
the eCRF. 
• Relative day of AE onset, defined as  the AE onset date – Date of first study drug intake 
+ 1 if the AE onset date is greater or equal to date of first study drug intake.  For pre-
treatment AEs, the relative day is defined as the AE onset date – Date of first study drug 
intake.  Relative day will not be calculated in case of partial/missing date of AE onset. 
• Duration of AE, defined as the AE end date – AE onset date + 1 when the AE is resolved.  
If the AE is not resolved, the duration is defined as study completion/discontinuation 
date – AE onset date + 1 and the duration will be reported as “>x” in the listings.  AE 
duration will not be calculated in the case of a partial/missing date of AE onset. 
In case of missing or incomplete AE date not directly allowing allocation to any of the 
categories of AEs, a worst-case allocation will be done according to the available parts of the 
start and the stop date. The AE will be allocated to the first category allowed by the available 
data, according to the following order: 
1. treatment emergent; 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Final Version 1.0, 20SEP2018 
 
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2. post-study; 
3. pre-treatment. 
 
• 2: Vital signs (systolic and diastolic blood pressure) 
On Day 1 and at Week 6, vital signs (systolic and diastolic blood pressure) will be measured 
within 1hr pre-dose and at 30 mins, 1.5, 3.5, 7 and 11h post-dose.  Blood pressure measurements 
are continuous variables and recorded in mmHg.  At Screening and Early Termination, blood 
pressure will be measured within 1h before the expected time of study drug administration. At 
Week 3, blood pressure will be measured within 1h pre-dose. Change from baseline will be 
calculated using the pre-dose assessment on Day 1 as the baseline value.  Change from pre-
dose at Week 6 will be calculated using the pre-dose assessment at Week 6. 
 
• 3: 24-hour digital Holter ECG parameters (HR, QTcF, QRS, PR) 
 
Subjects will have an ambulatory 24-hour digital Holter recording for 24 hours before and 24 
hours after the 1st dose of study drug (Day 1) and for 24 hours before the last dose of study drug 
(Week 6).  
The changes from baseline will be based on the pre-dose assessment on Day 1, and the results 
will also be matched by time for 24 hours before and 24 hours after the 1st dose of study drug 
(Day 1) and for 24 hours before the last dose of study drug (Week 6). For each visit involving 
Holter, sites will begin the Holter at approximately the same time of day to allow for consistency 
of data collected at various time points across visits.  Results will be presented for each time 
point.  Change from baseline for a given time point will use the corresponding time point at 
baseline as reference.  (e.g., If Visit 2 dosing occurs at 9:30 AM, and the “+55min” ECG on V2 
occurs at 10:25 AM, then the +55 minute ECG on V2 will be “matched” to the corresponding 
pre-dose assessment which occurred on or around 10:25 AM on the day prior to Visit 2.  
Therefore, change from baseline to “Visit 2 +55 minutes” will be calculated as value at “Visit 
2 +55 minutes”  – value at “Day prior to V2 10:25 AM”). 
The following ECG parameters will be recorded: HR, QTcF, QRS and PR.  
For each subject, there will be: 
• 3 nominal extraction times in the day before Visit 2 (time-matched with the post-study 
drug extraction times on Visit 2) 
• 3 extraction times at +5 min, +55 min, and +2.5h after 1st dose of study drug on Visit 
2; and  
• 3 extraction times at +5 min, +55 min, and +2.5h after the morning dose of study drug 
on the day before Visit 4. 
For each extraction time, ECG parameters will be obtained in triplicate, separate by 30-second 
intervals. The average of the triplicate will be used in the descriptive statistics and analysis of 
the Holter ECG results for each extraction time. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 35 of 70 
 
 
• 4: 24-hour HR average, minimum and maximum and hourly average HR using the 24-
hour digital Holter ECG monitoring 
Three distinct 24-hour monitoring periods will be collected. The first 24-hour monitoring period 
will start on the day prior to Visit 2. The Holter recordings will be started approximately 30 
minutes prior to expected dosing time on the day before Visit 2 and continue until 
approximately 30 minutes prior to actual dosing time on Visit 2 (Day 1). The second 24-hour 
monitoring period will start approximately 30 minutes prior to dosing on Visit 2 and continue 
for 23 hours and 30 minutes after dosing on Visit 2. The third and final 24-hour monitoring 
period will start on the day prior to Visit 4. The Holter recordings will be started approximately 
30 minutes prior to dosing on the day before Visit 4 and continue until approximately 30 
minutes prior to dosing on Visit 4. 
For 24 hour Holter assessments, records covering <18 hours will not be considered in the 
analysis.  
Hourly heart rate:  First and last hour are often <60 minutes.  In these cases, if <30 mins are 
available, the record will not be used.  If >=30 minutes are available, then it will be used. 
For each of the distinct 24-hour digital Holter monitoring periods, the recordings for HR will 
be used to derive the 24-hour HR average, minimum and maximum HR (bpm). In addition, the 
average HR will be calculated on an hourly basis during each 24-hour monitoring period.  
The following parameters will also be obtained from the 24 hour Holter monitor results: 
• Longest Tachycardia Duration (min); 
• Longest Tachycardia Maximum HR (bpm); 
• Fastest Tachycardia Duration (min); 
• Fastest Tachycardia Maximum HR (bpm); 
• Longest Bradycardia Duration (min); 
• Longest Bradycardia Minimum HR (bpm); 
• Slowest Bradycardia Duration (min); 
• Slowest Bradycardia Minimum HR (bpm); 
• Time in Atrial Fibrillation Percentage; 
• Atrial Fibrillation Peak Average Rate (bpm); 
• Supraventricular Total; 
• Ventricular Total; 
• RR > 2 sec (yes/no: yes if number of RR > 2 sec > 0, no if number of RR > 2 sec = 0). 
 
• 5: 24-hour digital Holter ECG abnormal findings 
The number and percentage of subjects exhibiting arrhythmia will be summarized.  The Holter 
ECG recordings will be scanned for the presence or absence of arrhythmia including, but not 
limited to: 
• Atrial fibrillation, 
• Sinus Pauses, 
• PACs, 
• SVT, 
• PVCs, 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 36 of 70 
 
• Ventricular tachycardia, 
• AV Blocks. 
For 24 hour Holter assessments, records covering <18 hours will not be considered in the 
analysis.  All abnormal findings will be listed. 
 
• 6: Standard blood chemistry and hematology 
Blood samples will be collected for hematology and serum chemistry at Screening, Week 6 and 
Early Termination in the morning.   
The following evaluations will be performed using a central laboratory: 
• Hematology test: red blood cells count (RBC), white blood cells count (WBC) and 
differential, total hemoglobin (Hb), hematocrit (Hct), platelets count (PLT). 
• Serum chemistry test: blood urea nitrogen (BUN), cholesterol, triglycerides, creatinine, 
uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma-
glutamyl transferase (γ-GT), total bilirubin, alkaline phosphatases, albumin, total 
proteins, and electrolytes (sodium, potassium, calcium, and chloride).  
• Fasting blood glucose 
• Serum pregnancy test (serum β-hCG) in women of child-bearing potential; results will 
be presented as positive or negative.  Urine β-hCG from visits 1, 2, and 3 will also be 
presented as positive or negative. 
 
Complete Blood Count (abbreviation followed by the full name and units) 
HCT:  
Hematocrit (L/L) 
HGB:  
Hemoglobin (g/L) 
PLATE: 
Platelets (10^9/L) 
RBC:  
Erythrocytes (10^12/L) 
WBC:  
Leucocytes (10^9/L) 
 
Differential (abbreviation followed by the full name and units)  
BASO: 
Basophil (10^9/L) and (%) 
EOSIN:  
Eosinophil (10^9/L) and (%) 
LYMPH: 
Lymphocyte (10^9/L) and (%) 
MONO: 
Monocyte (10^9/L) and (%) 
NEUT:  
Neutrophil (10^9/L) and (%) 
 
Blood Chemistry (abbreviation followed by the full name and units) 
ALB:  
Albumin (g/L) 
ALKPH: 
Alkaline Phosphatase (U/L) 
ALT:  
ALT (U/L) 
AST:  
AST (U/L) 
BUN:  
Blood Urea Nitrogen (mmol/L) 
BILDIR: 
Direct Bilirubin (μmol/L) 
CA: 
 
Calcium (mmol/L) 
CHOL: 
Cholesterol (mmol/L) 
CL:  
 
Chloride (mmol/L) 
CREAT: 
Creatinine (μmol/L) 
GGT:  
Gamma-GT (U/L) 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
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GLUC:  
Fasting Serum Glucose (mmol/L) 
K: 
 
Potassium (mmol/L) 
NA: 
 
Sodium (mmol/L) 
PROT:  
Total Protein (g/L) 
TRIG:  
Triglycerides (mmol/L) 
URATE: 
Urate (μmol/L) 
 
Results from the central laboratory will include the out of range flag based on the lower and 
upper limits of normal range. Categories will be  
• Low CS 
• Low NCS 
• Normal 
• High NCS 
• High CS, and 
• Missing.   
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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8 Analysis Methods 
8.1 General Methods 
Hypothesis testing will be carried out at the alpha = 0.05 level (two-sided). Statistical 
significance will be declared if the p-value is less than 0.05, with p-values for the primary 
efficacy analysis adjusted for multiplicity as described in Section 8.2.1.4.  
For continuous variables, summary statistics will include the number of non-missing 
observations, mean, standard deviation, 95% (or otherwise) confidence interval of the mean 
(only in the efficacy and safety analyses, unless otherwise specified), minimum, median and 
maximum.    
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing 
data per category will be the default summary presentation, and where appropriate and present, 
the number of missing values as a “Missing” category. Unless otherwise specified, the 
denominator for each percentage will be the number of non-missing observations within the 
analysis set and treatment group. 
 
General rules to be used for reporting the number of decimal places for derived variables in the 
listings (in the analyses rounding will not be performed): 
• BMI, treatment exposure (days): whole numbers; 
• Time to discontinuation (weeks), duration of smoking (years), time since first COPD 
diagnosis (years), compliance, average use of rescue medication (number of puffs/day), 
percentage of rescue medication-free days, average E-RS scores: 1 decimal place; 
• Change from baseline/pre-dose: same as the variable considered. 
 
The following rules on decimal places will be considered for the results of the analyses (if the 
analyses are performed on derived variables, the level of precision of the actual data is derived 
from the previous list): 
• min, max: same as actual data; 
• mean and its confidence limits (unadjusted and adjusted), adjusted difference between 
means and its confidence limits, SD, median: actual data + 1 decimal place; 
• percentage: 1 decimal place; 
• Kaplan-Meier percentiles estimates and confidence limits: actual data + 1 decimal place 
(3 decimal places for probabilities). 
• hazard ratio and its confidence limits, odds ratio and its confidence limits: 2 decimal 
places; 
• P-values: 3 decimal places; if the p-value is less than 0.001, it will be presented as 
<0.001. 
 
In general, additional to the analysis model results presented in TLFs, the full SAS output 
generated for all the analyses will be presented to the sponsor as a standalone document. SAS 
output results will be generated only after DB lock. 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Page 39 of 70 
 
8.1.1 Rules for Handling Missing Data 
Handling of missing data for the statistical analysis is described below:  
For the primary efficacy analysis, a linear mixed model for repeated measures will be used to 
handle missing data. Under the Missing At Random (MAR) assumption, this model provides an 
unbiased estimate of the treatment effect that would have been observed if all subjects had 
continued on treatment for the full study duration. This approach addresses efficacy (or de jure) 
hypotheses, estimating the causal effects of the initially randomized drug if taken as directed 
(in contrast with effectiveness, or de facto, hypotheses, evaluating the effect of the drug as 
actually taken). The efficacy estimand is considered appropriate in the context of a phase II 
study aiming at characterizing dose-response. 
In the TDI responder analysis, subjects with missing data at the relevant visit will be considered 
as non-responders. In order to avoid any exclusion from the responder analysis, for subjects 
with missing baseline value (i.e., with baseline value still missing after having applied ad-hoc 
rules potentially defined in the Data Review Report), the baseline value will be imputed as the 
overall (i.e., calculated jointly considering all treatment groups) mean baseline BDI focal score 
value calculated on subjects with available data on ITT population.  
The specific methods to deal with missing data, in particular with partial or missing dates (e.g., 
of medication use), missing spirometry data and missing questionnaire data, are laid out in detail 
in the description of the variable derivation in the subsections under Section 7.2. 
Other critical missing data, if any, will be discussed during the blind review of the data. 
Decisions will be fully documented in the Data Review Report. 
 
 
Calculation of adjusted means (least squares means): 
The approach described below will ensure that the least squares means calculated by SAS will 
be based on: 
– coefficients for classification effects (i.e., the effects of categorical covariates) 
proportional to the margins observed in the group of subjects analysed; 
– effects of quantitative covariates set equal to their mean values in the group of subjects 
analysed. 
The analysis is based on the following steps: 
1. generate a dataset by selecting: 
– in case of repeated post-randomisation measurements (e.g., FEV1 at each 
visit, analysed using a linear mixed model for repeated measures): all the 
post-randomization records for subjects with at least one available and valid 
post-randomisation measurement and no missing covariates; 
2. in case of repeated post-randomisation measurements, add to the dataset generated in 
step 1 the records for missing post-randomisation visits of the subjects included in 
the dataset. In the added records the value of the response variable will be missing, 
but the full information on covariates has to be included; 
3. use the dataset obtained as the input dataset for the MIXED or the GENMOD procedure, 
specifying the following options in the LSMEANS statement: 
– in case of repeated post-randomisation measurements: OM AT MEANS; 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Final Version 1.0, 20SEP2018 
 
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– in case of single post-randomisation measurement: OM. 
Example: analysis of change from baseline (Visit 2) at all visits (Visits 3 to 5) based on a 
mixed model for repeated measures including the effects of treatment, visit (categorical 
variable), treatment by visit interaction, baseline and another covariate. Visit 1 represents 
the screening visit. 
Original dataset (X = available value, . = missing or invalid value): 
Patient 
Treatment Covariate 
Baseline 
Visit Change from baseline 
1 
A 
X 
X 
1 
. 
1 
A 
X 
X 
2 
. 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
1 
. 
2 
B 
X 
X 
2 
. 
2 
B 
X 
X 
3 
X 
3 
A 
X 
X 
1 
. 
3 
A 
X 
X 
2 
. 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
4 
B 
X 
X 
1 
. 
4 
B 
X 
X 
2 
. 
5 
A 
. 
X 
1 
. 
5 
A 
. 
X 
2 
. 
5 
A 
. 
X 
3 
X 
 
Step 1 (visits 1 and 2 not selected since pre-randomisation, subject 4 not selected due to missing 
post-randomisation measurements, subject 5 not selected due to missing covariate): 
Subject Treatment Covariate Baseline Visit 
Change from baseline 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
3 
X 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
 
Step 2 (added records in italic): 
Subject Treatment Covariate Baseline Visit 
Change from baseline 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
3 
X 
2 
B 
X 
X 
4 
. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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2 
B 
X 
X 
5 
. 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
8.2 Specific Methods for Efficacy Analyses 
Analyses Based on Mixed Models 
Primary efficacy endpoint 
The change from baseline in FEV1 AUC0-12h normalized by time at week 6 will be analyzed 
using a linear mixed model for repeated measurements including treatment, visit, treatment by 
visit interaction, US regions and smoking status at screening as fixed effects, and the baseline 
value (average of the pre-dose FEV1 measurements on Day 1) and baseline by visit interaction 
as covariates. An unstructured covariance matrix will be assumed; the generic code for the 
model is presented below.   
 
proc mixed data = <xxx>; 
  class subject treatment visit usregion smoking; 
  model <response> = treatment  visit  treatment*visit  usregion  smoking  fev1base  fev1base*visit / 
DDFM=KR;  
  repeated  visit / subject=subject  type=UN; 
  lsmeans treatment*visit / cl OM AT MEANS; 
  lsmestimate treatment*visit ‘Trt A vs Placebo week 6’ 0  1  0  0  0  0  0  0  0  -1  0  0, 
                      ‘Trt B vs Placebo week 6’ 0  0  0  1  0  0  0  0  0  -1  0  0,  
                      ‘Trt C vs Placebo week 6’ 0  0  0  0  0  1  0  0  0  -1  0  0, 
                      ‘Trt D vs Placebo week 6’ 0  0  0  0  0  0  0  1  0  -1  0  0 / cl adjust = simulate (seed = 12311980 
acc = 0.0001); 
  lsmestimate treatment*visit ‘Trt D vs Trt A week 6’ 0  -1  0  0  0  0  0  1  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt D vs Trt B week 6’ 0  0  0  -1  0  0  0  1  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt D vs Trt C week 6’ 0  0  0  0  0  -1  0  1  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt A week 6’ 0  -1  0  0  0  1  0  0  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt B week 6’ 0  0  0  -1  0  1  0  0  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt B vs Trt A week 6’ 0  -1  0  1  0  0  0  0  0  0  0  0/cl; 
  lsmestimate treatment*visit ‘Trt F vs Placebo week 6’ 0 0  0  0  0  0  0  0  0  -1  0  1/cl; 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• visit is the visit variable (Visit 2 [Day 1], and Visit 4 [week 6]) 
• treatment*visit is the treatment by visit interaction 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• fev1base is the baseline FEV1 result 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 42 of 70 
 
• fev1base*visit is the baseline FEV1 result by visit interaction. 
 
The adjusted means in each treatment group, the adjusted mean difference between treatments 
and their 95% Confidence Intervals (CIs) will be estimated by the model.  In addition, the p-
values for each of the factors in the model will be provided. 
The CIs and the p-values of the comparisons between each dose of CHF 5259 pMDI and 
Placebo at Week 6 will be adjusted for multiplicity. For the primary endpoint, the adjustment 
will be based on the parametric simulation method by Edwards and Berry (adjust=simulate in 
the MODEL statement). The random number seed will be set equal to 12311980, and 0.0001 
will be used for the target accuracy radius gamma (i.e. ACC=0.0001). At each dose level, the 
superiority of CHF 5259 pMDI will be demonstrated by a statistically significant difference 
(adjusted p-value < 0.05) favoring CHF 5259 pMDI.  
The model will include also pairwise comparisons of treatment A through treatment D, 
comparing each dose with a lower dose, and treatment F versus Placebo. The CIs and the p-
values of the comparisons between those pairwise comparisons at Week 6 will not be adjusted 
for multiplicity.  
Kenward Rogers method will be used to approximate denominator degrees of freedom 
(/DDFM=KR in the MODEL statement); OM and AT MEANS in LSMEANS statement will 
be used to account for unbalanced population (see details in 8.1). 
 
Sensitivity analysis: 
Primary analysis will be repeated for sensitivity analysis excluding the subject that has been 
randomized few seconds after another subjects receiving the same random number. 
On 
, two subjects 
 and 
, were assigned the same Randomization 
Number (Rand ID), 
. Both subjects were randomized between 
 and 
 on 
 
. 
The Subject report shows Rand ID 
 assigned to both subjects. However, the Subject 
Randomization report shows ID 
 being assigned to subject 
 and not to subject 
. Subject 
 does not appear on the Subject Randomization report. 
The subject 
 will be excluded from the sensitivity analysis for ITT population. 
Secondary efficacy endpoints 
For additional secondary efficacy analyses (FEV1 AUC0-12 at Day 1, FEV1 AUC0-4, FEV1 peak 
0-4, Pre-dose morning FEV1, FVC AUC0-12, FVC AUC0-4, FVC peak 0-4, Pre-dose morning IC 
at week 3 and week 6, TDI focal score, Percentage of rescue medication free-days, Average use 
of rescue medication and E-RS total score and domain score) all the comparisons between 
treatments will be performed with no multiplicity adjustment.  
The adjusted means in each treatment group, the adjusted mean difference between treatments 
and their 95% Confidence Intervals (CIs) and p-values will be estimated by the model.   In 
addition, the p-values for each of the factors in the model will be provided. 
Kenward Rogers method will be used to approximate denominator degrees of freedom 
(/DDFM=KR in the MODEL statement); OM and AT MEANS in LSMEANS statement will 
be used to account for unbalanced population. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 43 of 70 
 
 
The SAS code for the secondary efficacy endpoints using the same model as the primary 
efficacy analysis will be as below. 
 
proc mixed data = <xxx>; 
  class subject treatment visit usregion smoking; 
  model <response> = treatment  visit  treatment*visit  usregion  smoking  base  base*visit / DDFM=KR;  
  repeated  visit / subject=subject  type=UN; 
  lsmeans treatment*visit   / cl OM AT MEANS; 
  lsmestimate treatment*visit ‘Trt A vs Placebo day 1’ 1  0  0  0  0  0  0  0  -1  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt B vs Placebo day 1’ 0  0  1  0  0  0  0  0  -1  0   0  0 /cl; 
  lsmestimate treatment*visit ‘Trt C vs Placebo day 1’ 0  0  0  0  1  0  0  0  -1  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt D vs Placebo day 1’ 0  0  0  0  0  0  1  0  -1  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt D vs Trt A day 1’     -1  0  0  0  0  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt D vs Trt B day 1’     0  0  -1  0  0  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt D vs Trt C day 1’     0  0  0  0  -1  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt A day 1’     -1  0  0  0  1  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt B day 1’     0 0  -1  0  1  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt B vs Trt A day 1’     -1  0  1  0  0  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment*visit ‘Trt F vs Placebo day 1’ 0  0  0  0  0  0  0  0  -1  0  1  0 /cl; 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• visit is the visit variable (Visit 2 [Day 1] <if applicable>, Visit 3 [week 3] <if 
applicable>,  and Visit 4 [week 6]) 
• treatment*visit is the treatment by visit interaction 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• base is the baseline result, as defined in Section 7 per each variable. 
• base*visit is the baseline result by visit interaction. 
 
In the sas code model reported above, the LSMESTIMATE statement shows comparisons of 
the treatments at Day 1 for a variable assessed at Day 1 and Week 6. This statement will be 
adapted for week 3 or week 6 as appropriate for each secondary variables. 
For the change from baseline in FEV1 AUC0-12h normalized by time at Day 1, the adjusted 
means in each treatment group and the adjusted mean differences between treatments at Day 1 
will be estimated with their 95% CIs and p-values by the model outlined above for the 
secondary efficacy endpoints. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 44 of 70 
 
Change from baseline in FEV1 AUC0-4h normalized by time and in FEV1 peak0-4h at Day 1 and 
Week 6 and change from baseline in pre-dose morning FEV1 at Week 3 and Week 6 will be 
analyzed using the model outlined above for the secondary efficacy endpoints. 
Change from baseline in FVC AUC0-12h normalized by time, in FVC AUC0-4h normalized by 
time and in FVC peak0-4h at Day 1 and Week 6 will be analyzed using the model outlined above 
for the secondary efficacy endpoints.  
The change from baseline in pre-dose morning IC at Week 3 and Week 6 will be analyzed using 
the model outlined above for the secondary efficacy endpoints. 
TDI focal score at Week 3 and Week 6 will be analyzed using the model outlined above for the 
secondary efficacy endpoints. 
The change from baseline to each inter-visit period in percentage of rescue medication-free 
days, in average use of rescue medication and in average E-RS total score and domain scores 
will be analyzed using a similar model outlined above for the secondary efficacy endpoints. 
The inter-visit period will be considered instead of visit in the model. Comparison between 
treatments over the entire treatment period will also be derived from this model. In this 
comparison, equal weights will be assigned to the two inter-visit periods. The SAS code will 
be as below. 
proc mixed data = <xxx>; 
  class subject treatment inter_visit usregion smoking; 
  model <response> = treatment  inter_visit treatment*inter_visit usregion  smoking  base  base*inter_visit / 
DDFM=KR;  
  repeated  inter_visit / subject=subject  type=UN; 
  lsmeans treatment  treatment*inter_visit / cl OM AT MEANS; 
  lsmestimate treatment  "Trt A vs Placebo entire tmt period"  1 0 0 0 -1 0  /cl; 
  lsmestimate treatment  "Trt B vs Placebo entire tmt period"  0 1 0 0 -1 0  /cl; 
  lsmestimate treatment  "Trt C vs Placebo entire tmt period"  0 0 1 0 -1 0  /cl; 
  lsmestimate treatment  "Trt D vs Placebo entire tmt period"  0 0 0 1 -1 0  /cl; 
  lsmestimate treatment  "Trt B vs Trt A entire tmt period"    -1 1 0 0 0 0  /cl; 
  lsmestimate treatment  "Trt C vs Trt A entire tmt period"    -1 0 1 0 0 0  /cl; 
  lsmestimate treatment  "Trt D vs Trt A entire tmt period"    -1 0 0 1 0 0  /cl; 
  lsmestimate treatment  "Trt C vs Trt B entire tmt period"    0 -1 1 0 0 0  /cl; 
  lsmestimate treatment  "Trt D vs Trt B entire tmt period"    0 -1 0 1 0 0  /cl; 
  lsmestimate treatment  "Trt D vs Trt C entire tmt period"    0 0 -1 1 0 0  /cl; 
  lsmestimate treatment  "Trt F vs Placebo entire tmt period"  0 0 0 0 -1 1  /cl; 
  lsmestimate treatment*inter_visit ‘Trt A vs Placebo period 1’ 1  0  0  0  0  0  0  0  -1  0  0  0 /cl; 
  lsmestimate treatment*inter_visit ‘Trt B vs Placebo period 1’ 0  0  1  0  0  0  0  0  -1  0   0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Placebo period 1’ 0  0  0  0  1  0  0  0  -1  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt D vs Placebo period 1’ 0  0  0  0  0  0  1  0  -1  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt D vs Trt A period 1’     -1  0  0  0  0  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt D vs Trt B period 1’     0  0  -1  0  0  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt D vs Trt C period 1’     0  0  0  0  -1  0  1  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Trt A period 1’     -1  0  0  0  1  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Trt B period 1’     0 0  -1  0  1  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt B vs Trt A period 1’     -1  0  1  0  0  0  0  0  0  0  0  0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt F vs Placebo period 1’ 0  0  0  0  0  0  0  0  -1  0  1  0 /cl; 
 lsmestimate  treatment* inter_visit "Trt A vs Placebo period 2" 0 1    0  0    0  0    0  0   0 -1   0 0 /cl; 
 … 
 lsmestimate treatment* inter_visit  "Trt F vs Placebo period 2" 0 0    0  0    0  0    0  0   0  -1   0 1 /cl; 
run; 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 45 of 70 
 
Analyses Based on the Time to Onset 
A Cox proportional hazards model will be utilized to analyze the time to onset of action in 
FEV1. The Cox proportional hazards model will include treatment, US Region and smoking 
status at screening as fixed effects, and baseline (average of pre-dose FEV1 measurements on 
Day 1) as a covariate. The generic code for the Cox model is: 
proc phreg data=<xxx>; 
   class  treatment  usregion  smoking; 
   model time*censor(0) = treatment usregion smoking fev1base / risklimits ties=exact; 
   contrast “Treatment A vs Placebo" treatment      1 0 0 0 -1  /estimate=exp; 
   contrast “Treatment B vs Placebo" treatment       0 1 0 0 -1  /estimate=exp; 
   contrast “Treatment C vs Placebo" treatment       0 0 1 0 -1  /estimate=exp; 
   contrast “Treatment D vs Placebo" treatment       0 0 0 1 -1  /estimate=exp; 
   contrast “Treatment D vs Treatment A" treatment -1 0 0 1 0  /estimate=exp; 
   contrast “Treatment D vs Treatment B" treatment 0 -1 0 1 0  /estimate=exp; 
   contrast “Treatment D vs Treatment C" treatment 0 0 -1 1 0  /estimate=exp; 
   contrast “Treatment C vs Treatment A" treatment -1 0 1 0 0  /estimate=exp; 
   contrast “Treatment C vs Treatment B"  treatment 0 -1 1 0 0  /estimate=exp; 
   contrast “Treatment B vs Treatment A" treatment -1 1 0 0 0  /estimate=exp; 
   contrast “Treatment F vs Placebo "         treatment 0 0 0 0 -1 /estimate=exp; 
run; 
 
The generic code for the Kaplan-Meier plot is: 
proc lifetest data=<xxx>; 
      time time*censor(0); 
      strata treatment; 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South, and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• fev1base is the baseline FEV1 result 
 
A censor variable value of 0 will be used for subjects who do not experience the onset of action 
in FEV1. If the option ties=exact requires a considerable amount of computer resources, the 
Efron approximation will be used (ties=efron). 
The 1st quartile, median, and 3rd quartile for the time to onset of action in FEV1 will be provided 
along with the number and percentage of subjects who were censored.  The hazard ratios, 95% 
confidence intervals for the hazard-ratios, and p-values comparing treatment groups will be 
provided. P-values will not be adjusted for multiplicity. In addition, the p-values for each of the 
factors in the model will be provided. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 46 of 70 
 
The Kaplan-Meier plot will be repeated also for time to discontinuation from study. 
 
Analyses Based on logistic regression model 
A multiple logistic regression model will be utilized to analyze TDI Response (TDI Focal Score 
≥ 1). The logistic regression model will model the probability of a subject successfully 
achieving the TDI Response. The model will include treatment, US Region, and smoking status 
as fixed effects and the Baseline Dyspnea Index (BDI) as a covariate. The logistic regression 
model will be based on the results from the Week 3 and Week 6 time points separately. The 
generic code for the model is: 
 
proc genmod data = <xxx>; 
  class treatment usregion smoking; 
  model TDI_focal_response = treatment usregion smoking BDI / dist=binomial wald type3; 
   lsmestimate treatment  “Treatment A vs. Placebo" 1 0 0 0 -1 0/ exp cl; 
  lsmestimate treatment  “Treatment B vs. Placebo" 0 1 0 0 -1 0/ exp cl; 
  lsmestimate treatment  “Treatment C vs. Placebo" 0 0 1 0 -1 0/ exp cl; 
  lsmestimate treatment  “Treatment D vs. Placebo" 0 0 0 1 -1 0/ exp cl; 
  lsmestimate treatment “Treatment D vs. Treatment A" -1 0 0 1 0 0/ exp cl; 
  lsmestimate treatment “Treatment D vs. Treatment B " 0 -1 0 1 0 0/ exp cl ; 
  lsmestimate treatment “Treatment D vs. Treatment C "0 0 -1 1 0 0/ exp cl; 
  lsmestimate treatment “Treatment C vs. Treatment A" -1 0 1 0 0 0/ exp cl; 
  lsmestimate treatment “Treatment C vs. Treatment B" 0 -1 1 0 0 0/ exp cl; 
  lsmestimate treatment “Treatment B vs. Treatment A" -1 1 0 0 0 0/ exp cl; 
  lsmestimate treatment “Treatment F vs. Placebo"0 0 0 0 -1 1/ exp cl; 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South, and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• BDI is the baseline result 
 
The odds ratios, 95% confidence intervals for the odd-ratios, and p-values comparing treatment 
groups will be provided. P-values will not be adjusted for multiplicity. In addition, the odds 
ratios, 95% confidence intervals, and p-values for each of the factors in the model will be 
provided.  
  
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 47 of 70 
 
8.2.1 Statistical/Analytical Issues  
 
8.2.1.1 Handling of Dropouts or Missing Data 
The rules to address missing data rules for specific variables are described in Section 7.2 and 
7.1.1. 
 
8.2.1.2 Blind Review 
A Blind Data Review Meeting is organized just before data base lock to finalize the list of 
protocol deviations which will exclude subjects from the Per Protocol analysis and also to 
address handling of any outstanding data issues. The Data Review Report will describe all 
agreed handling and will be finalized prior to data base lock and unblinding.  The Data Review 
Plan will describe the tables, listings and figures used during this meeting, and falls outside the 
scope of the SAP. 
8.2.1.3 Multi-center Studies 
No adjustment is done for the multiple centers, and no analysis per center is carried out. The 
adjustment in the model will be US region. 
8.2.1.4 Multiple Comparisons/Multiplicity 
Adjustment for multiplicity is applied only to the primary efficacy analysis. The CIs and the p-
values of the comparisons between each dose of CHF 5259 pMDI and placebo for the primary 
efficacy endpoint at Week 6 will be adjusted for multiplicity. The adjustment will be based on 
the parametric simulation method by Edwards and Berry. At each dose level, the superiority of 
CHF 5259 pMDI will be demonstrated by a statistically significant difference (adjusted p-
value < 0.05) favoring CHF 5259 pMDI.  
 
8.3 Specific Methods for Safety Analyses 
Analyses Based on Mixed Models 
The SAS code for the safety endpoints change from baseline (day before V2) in 24-hour 
average, minimum and maximum HR extracted from the Holter recordings will be: 
proc mixed data = <xxx>; 
  class subject treatment visit usregion smoking; 
  model <response> = treatment  visit treatment*visit usregion  smoking  base  base*visit / DDFM=KR;  
  repeated  visit / subject=subject  type=UN; 
  lsmeans treatment*visit / cl OM AT MEANS alpha=0.05 
lsmestimate treatment*visit "Trt A vs Placebo Visit 2"  1 0 0 0 0 0 0 0 -1 0 0 0  /cl alpha=0.05; 
lsmestimate treatment*visit "Trt A vs Placebo Visit 4"  0 1 0 0 0 0 0 0 0 -1 0 0  /cl alpha=0.05; 
… 
lsmestimate treatment *visit "Trt D vs Placebo Visit 2"  0 0 0 0 0 0 1 0 -1 0 0 0  /cl alpha=0.05; 
lsmestimate treatment *visit "Trt D vs Placebo Visit 4"  0 0 0 0 0 0 0 1 0 -1 0 0  /cl alpha=0.05; 
 
lsmestimate treatment *visit "Trt B vs Trt A Visit 2"    -1 0 1 0 0 0 0 0 0 0 0 0  /cl alpha=0.05; 
lsmestimate treatment *visit "Trt B vs Trt A Visit 4"    0 -1 0 1 0 0 0 0 0 0 0 0  /cl alpha=0.05; 
… 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 48 of 70 
 
lsmestimate treatment *visit "Trt F vs Placebo Visit 2"  0 0 0 0 0 0 0 0 1 0 -1 0   /cl alpha=0.05; 
lsmestimate treatment *visit "Trt F vs Placebo Visit 4"  0 0 0 0 0 0 0 0 0 1 0 -1   /cl alpha=0.05; 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• visit is the visit variable (Visit 2 [Day 1] and Visit 4 [week 6]) 
• treatment*visit is the treatment by visit interaction 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• base is the baseline time-matched baseline as defined in Section 7.2.12 
• base*visit is the baseline result by visit interaction. 
• Treatment comparisons will be extended to comparisons between each dose of CHF 
5259 pMDI and Placebo at Visit 2 and Visit 4 and all pairwise comparisons of treatment 
A through treatment D at Visit 2 and Visit 4.  
 
The SAS code for the safety endpoints change from baseline (time-matched on day before V2) 
in ECG parameters extracted from the 24hr Holter (HR, QTcF, QRS and PR) and  change from 
baseline (day before V2) in 24-hour average, minimum and maximum HR extracted from the 
Holter recordings will be: 
 
proc mixed data = <xxx>; 
  class subject treatment timePoint usregion smoking; 
  model <response> = treatment  timePoint  treatment*timePoint usregion  smoking  base  base*timePoint 
timeavgBase / DDFM=KR;  
  repeated  timePoint / subject=subject  type=UN; 
  lsmeans treatment*timePoint   / cl OM AT MEANS alpha=0.1;   
 lsmestimate treatment*timePoint "Trt A vs Placebo 1"    -1 0 0 0 0 0  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  1 0 0 0 
0 0   0 0 0 0 0 0 /cl alpha=0.1; 
 lsmestimate treatment*timePoint "Trt A vs Placebo 2"    0 -1 0 0 0 0  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  0 1 0 0 
0 0   0 0 0 0 0 0 /cl alpha=0.1; 
 lsmestimate treatment*timePoint "Trt A vs Placebo 3"    0 0 -1 0 0 0  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  0 0 1 0 
0 0   0 0 0 0 0 0 /cl alpha=0.1; 
 lsmestimate treatment*timePoint "Trt A vs Placebo 4"    0 0 0 -1 0 0  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  0 0 0 1 
0 0   0 0 0 0 0 0 /cl alpha=0.1; 
 lsmestimate treatment*timePoint "Trt A vs Placebo 5"    0 0 0 0 -1 0  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  0 0 0 0 
1 0   0 0 0 0 0 0 /cl alpha=0.1; 
 lsmestimate treatment*timePoint "Trt A vs Placebo 6"    0 0 0 0 0 -1  0 0 0 0 0 0  0 0 0 0 0 0   0 0 0 0 0 0  0 0 0 0 
0 1   0 0 0 0 0 0 /cl alpha=0.1; 
 
.... 
 
 
run; 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-02 
 
 
Final Version 1.0, 20SEP2018 
 
Page 49 of 70 
 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (GB 12.5 µg) 
2. Treatment B (GB 25 µg) 
3. Treatment C (GB 50 µg) 
4. Treatment D (GB 100 µg) 
5. Placebo 
6. Treatment F (Spiriva 18 µg) 
• timePoint is the time point variable: 6 time points scheduled at Visit 2  +5m, +55m and 
+2.5h and Visit 4  +5m, +55m and +2.5h. 
• treatment*timePoint is the treatment by time point interaction 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South and West Regions). 
• smoking is the smoking status at baseline (ex-smoker, current smoker). 
• base is the baseline time-matched baseline as defined in Section 7.2.12 
• base*timePoint is the baseline result by visit interaction 
• timeavgBase is the time-averaged baseline score be the average of the Day -1 scores at 
+5m, +55m and +2.5h. 
 
Treatment comparisons will be extended for all 6 time points. 
 
9 Interim analyses 
Not applicable. 
 
10 Overview of Tables, Listings and Figures 
Demographics, COPD and smoking history, spirometry and reversibility will be presented 
using all three populations (ITT, Safety, PP). Medical history/concomitant diseases and 
compliance with study treatment will be presented using the ITT and Safety populations.  
Medications, CAT score, BDI, compliance use of e-diary, and protocol deviations will be 
presented using the ITT population. Vital signs, ECG, AEs and laboratory data will be presented 
using the Safety population.  
 
10.1 Disposition of Subjects 
A summary of the number of screened subjects, the number of screening failures and reasons 
for screening failure will be produced for all enrolled subjects. 
A disposition summary of subjects by treatment and overall will include the number (N) of 
subjects randomized with the number (n) and percentage (%) of subjects who completed or 
discontinued the study. A subject is considered as completed if the Study Termination Form in 
the eCRF has “Completed” checked for the question “Specify the subject’s status”. All 
percentages will be based on the number of subjects randomized.  


 
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The reasons for study discontinuation will be also summarized by treatment using absolute 
counts and percentages, based on the number of subjects randomized.  . A Kaplan Meier plot 
will be reported by treatment . 
10.2 Protocol Deviations 
The number of subjects who had at least one Major Protocol Deviation and all Major Protocol 
Deviations will be summarized by absolute counts (n) and percentages (%) by treatment for the 
Safety population. Percentages will be based on the number of subjects in the ITT population. 
The summary will be repeated for Minor Protocol Deviations.   
10.3 Analysis Sets  
The number of subjects in each population will be summarized by treatment and overall, by 
absolute counts (n) and percentages (%) for each treatment group and by US region. 
Percentages will be based on the number of randomized subjects.   
 
10.4 Demographic and Other Baseline Characteristics 
10.4.1 Demographic Characteristics, COPD History and Smoking Habits 
Demographic data, COPD history and smoking habits will be summarized by summary 
statistics and absolute counts (n) and percentages (%) by treatment and overall for the Safety 
population, the ITT population and PP population.  
10.4.2 Medical History 
Medical and Surgical History and Concomitant Diseases will be summarized on a per-subject 
basis (i.e. if a subject reported the same event repeatedly the event will be counted only once at 
the specific level of display). Absolute counts (n) and percentages (%) by treatment and overall 
will be presented for the number of subjects with at least one Medical or Surgical History or 
Concomitant Disease, and per SOC and per PT within SOC, for the ITT and Safety population. 
Percentages will be based on the number of subjects in the population. 
10.4.3 Baseline Subject Characteristics 
Central spirometry and reversibility test data, Physical examination results, ECG results at Visit 
1 and Visit 2 pre-dose, Baseline Dyspnea Index Questionnaire at Visit 1, and the COPD 
Assessment Test at Screening and Visit 2 will be summarized with summary statistics and 
absolute counts (n) and percentages (%) by treatment and overall for the populations described 
in Section 10, above.  
10.4.4 Previous, Maintained and Concomitant Medications 
Previous and maintained medications will be summarized by treatment and overall, while  
concomitant medications will be summarized by treatment (for the assignment of medications 
to a treatment, see section 7.2.7). 
All previous, maintained, and concomitant medications will be presented in the tables and the 
listings.  


 
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Post-treatment medications will be only presented in a listing. 
Previous, maintained and concomitant medications will be summarized on the ITT population 
according to Anatomical Main Group (1st level of ATC), Therapeutic Subgroup (2nd level of 
ATC), Chemical Subgroup (4th level of ATC) and preferred name. 
Absolute counts (n) and percentages (%) will be presented for the number of subjects taking at 
least one medication, and per Anatomical Main Group and per Therapeutic Subgroup within 
Anatomical Main Group and per Chemical Subgroup within Therapeutic Subgroup, for the  ITT 
populations. Percentages will be based on the number of subjects in the population.  
10.5 Study drug / Investigational Medicinal Product  
10.5.1 Background medication 
Daily dose of previous ICS treatment for COPD will be summarized by descriptive statistics 
using absolute counts (n) and percentages (%) of subjects according to the dose category (Low 
Daily Dose and Medium Daily Dose), for the ITT population.  
Similarly, descriptive statistics using only the subjects placed on QVAR® 80 µg will be used to 
calculate the QVAR Estimated Clinical Comparable Dose (µg/day), and the number of morning 
and evening puffs that the subject was instructed to take will be summarized using descriptive 
statistics. 
Exposure and compliance using only the subjects placed on QVAR® 80 µg will be summarized 
by summary statistics and absolute counts (n) and percentages (%) by the treatment that the 
subject will be randomized to and overall during the Run-in Period, and by treatment  during 
the Treatment Period, for ITT populations.  In addition, the number and percentage of subjects 
with either satisfactory (65% to 135%) and unsatisfactory levels (<65% or > 135%) of 
compliance to the background medication will be summarized by the treatment the subject was 
randomized to and overall during the Run-in Period and by treatment and overall during 
Treatment Period for the ITT population.  Compliance to background medication will also be 
categorized in the same manner in the following categories: [0%-10%], (10%-20%], (20%-
30%], (30%-40%], (40%-50%], (50%-60%], (60%-70%], (70%-80%], (80%-90%], (90%-
100%], (100%-110%], (110%-120%], (120%-130%], (130%-140%], >140%. 
10.5.2 Study drug 
Treatment exposure and compliance during the Treatment Period will be summarized by 
summary statistics and absolute counts (n) and percentages (%) by treatment using the ITT and 
Safety populations. In addition the number and percentage of subjects with satisfactory (65% - 
135%) and unsatisfactory (<65%; >135%) levels of compliance to the study drug will be 
summarized by treatment using the ITT and Safety populations.  Compliance to study 
medication will also be categorized in the same manner in the following categories: [0%-10%], 
(10%-20%], (20%-30%], (30%-40%], (40%-50%], (50%-60%], (60%-70%], (70%-80%], 
(80%-90%], (90%-100%], (100%-110%], (110%-120%], (120%-130%], (130%-140%], 
>140%. 
 


 
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10.6 Efficacy Results 
10.6.1 Primary efficacy variable 
The primary endpoint is the change from baseline in FEV1 AUC0-12h at Week 6.  The change 
from baseline in FEV1 AUC0-12h normalized by time will be summarized using descriptive 
statistics and analyzed using a linear mixed model for repeated measurements as outlined in 
Section 8.2. The adjusted means in each treatment group and their corresponding 95% 
confidence intervals (CI), the adjusted mean difference between treatments (active – placebo) 
and their 95% CIs and p-values will be estimated by the model. The CIs and the p-values of the 
comparisons between each dose of CHF 5259 pMDI and placebo at Week 6 will be adjusted 
for multiplicity. The adjustment will be based on the parametric simulation method by Edwards 
and Berry. At each dose level, the superiority of CHF 5259 pMDI versus placebo will be 
demonstrated by a statistically significant difference (adjusted p-value < 0.05) favoring CHF 
5259 pMDI. In addition, the p-values for each of the factors in the model will be displayed.  
Comparisons between the various active doses will be presented based on the model, but not 
adjusted for multiplicity. 
The analysis will be performed using the ITT population (primary analysis) and will be repeated 
using the PP population. 
The mean absolute FEV1 values and the change form baseline will be summarized using 
descriptive statistics with the 95% CI of the mean and will be presented by treatment for the 
ITT and PP population. 
The mean absolute FEV1 values recorded on Day 1 and Week 6 will be plotted over time  for 
each of the treatment groups. These figures will be based on data from subjects in both ITT and 
PP populations (separate graphs for ITT and PP). 
The mean change from baseline FEV1 values on Day 1 and Week 6 will be plotted over time 
for each of the treatment groups. These figures will be based on data from subjects in both ITT 
and PP populations (separate graphs for ITT and PP). 
10.6.2 Secondary efficacy variables 
The following secondary efficacy endpoints will be summarized using descriptive statistics 
with the 95% CI of the mean and will be presented by treatment for the ITT population; in 
addition the following analyses will be performed. There will be no adjustment for multiplicity 
to the CIs or the p-values for any of the secondary efficacy endpoints. The mean change from 
baseline of secondary efficacy endpoints values will be plotted over time for each of the 
treatment groups. 
 
Analysis of Secondary Efficacy Variable 1: Change from baseline in FEV1 AUC0-12h 
normalized by time at Day 1 
The change from baseline in FEV1 AUC0-12h normalized by time on Day 1 will be analyzed 
using a linear mixed model for repeated measurements as outlined in Section 8.2. The adjusted 
means in each treatment group with their corresponding 95% CIs, and the adjusted mean 
difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
 


 
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Analysis of Secondary Efficacy Variable 2a: Change from baseline in FEV1 AUC0-4h 
normalized by time at Day 1 and Week 6 
The change from baseline in FEV1 AUC0-4h normalized by time on Day 1 and Week 6 will be 
analyzed using a linear mixed model for repeated measurements as outlined in Section 8.2. The 
adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
 
Analysis of Secondary Efficacy Variable 2b: Change from baseline in FEV1 peak0-4h 
normalized by time at Day 1 and Week 6 
The change from baseline in FEV1 peak0-4h normalized by time on Day 1 and Week 6 will be 
analyzed using a linear mixed model for repeated measurements as outlined in Section 8.2. The 
adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
 
Analysis of Secondary Efficacy Variable 2c: Change from baseline in pre-dose morning 
FEV1 (average of pre-dose FEV1 measurements) at Week 3 and Week 6 
The change from baseline in pre-dose morning FEV1 normalized by time at Week 3 and Week 
6 will be analyzed using a linear mixed model for repeated measurements as outlined in 
Section 8.2. The adjusted means in each treatment group with their corresponding 95% CIs, 
and the adjusted mean difference between treatments with their corresponding 95% CIs will 
be estimated by the model. In addition, the p-values for each of the factors in the model will 
be displayed. 
 
Analysis of Secondary Efficacy Variable 3a: Change from baseline in FVC AUC0-12h 
normalized by time at Day 1 and Week 6 
The change from baseline in FVC AUC0-12h normalized by time on Day 1 and Week 6 will be 
analyzed using a linear mixed model for repeated measurements as outlined in Section 8.2. The 
adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
The mean absolute FVC values and the change form baseline will be summarized using 
descriptive statistics with the 95% CI of the mean and will be presented by treatment for the 
ITT population. 
 
Analysis of Secondary Efficacy Variable 3b: Change from baseline in FVC AUC0-4h 
normalized by time at Day 1 and Week 6 
The change from baseline in FVC AUC0-4h normalized by time on Day 1 and Week 6 will be 
analyzed using a linear mixed model for repeated measurements as outlined in Section 8.2. The 
adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
 


 
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Analysis of Secondary Efficacy Variable 3c: Change from baseline in FVC peak0-4h at Day 1 
and Week 6 
The change from baseline in FVC peak0-4h normalized by time on Day 1 and Week 6 will be 
analyzed using a linear mixed model for repeated measurements as outlined in Section 8.2. The 
adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
 
Analysis of Secondary Efficacy Variable 4: Time to onset of action (change from baseline in 
post-dose FEV1 ≥ 100 mL) at Day 1 (min) 
Time to onset of action (i.e., change from baseline in post-dose FEV1 ≥ 100 mL at Day 1) will 
be analyzed using a Cox proportional hazard model as outlined in Section 8.2. The 1st quartile, 
median, and 3rd quartile for the time to onset of action in FEV1 will be provided along with the 
number and percentage of subjects who were censored.  The hazard ratios, 95% confidence 
intervals for the hazard-ratios, and p-values comparing each active treatment to placebo will be 
provided.  In addition, the p-values for each of the factors in the model will be provided. 
Comparisons between the various active doses will be presented based on the model. 
A Kaplan-Meier plot of the time to onset of action will also be presented.  
 
Analysis of Secondary Efficacy Variable 5: Change from baseline in pre-dose morning IC at 
Week 3 and Week 6 
The change from baseline in pre-dose morning IC at Week 3 and Week 6 will be analyzed using 
a linear mixed model for repeated measurements as outlined in Section 8.2. The adjusted means 
in each treatment group with their corresponding 95% CIs, and the adjusted mean difference 
between treatments with their corresponding 95% CIs will be estimated by the model. In 
addition, the p-values for each of the factors in the model will be displayed. 
 
Analysis of Secondary Efficacy Variable 6: TDI focal score at Week 3 and Week 6 
The TDI focal score at Week 3 and Week 6 will be analyzed using a linear mixed model for 
repeated measurements as outlined in Section 8.2. The adjusted means in each treatment group 
with their corresponding 95% CIs, and the adjusted mean difference between treatments with 
their corresponding 95% CIs will be estimated by the model. In addition, the p-values for each 
of the factors in the model will be displayed.  
 
Analysis of Secondary Efficacy Variable 7: TDI response (TDI focal score ≥ 1) at Week 3 
and Week 6 
The TDI response at Week 3 and Week 6 will be analyzed using a multiple logistic regression 
model as outlined in Section 8.2. The odds ratios, 95% confidence intervals for the odd-ratios, 
and p-values comparing each active treatment to placebo will be provided.  In addition, the odds 
ratios, 95% confidence intervals, and p-values for each of the factors in the model will be 
provided. The model will be run for Week 3 and Week 6 separately. Comparisons between the 
various active doses will be presented based on the model. 
 


 
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Analysis of Secondary Efficacy Variable 8a: Change from baseline in percentage of rescue 
medication-free days during inter-visit periods and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in the 
percentage of rescue medication-free days will be analyzed using a linear mixed model for 
repeated measurements as outlined in Section 8.2. See Section 7.1 for the definition of the inter-
visit periods. The adjusted means in each treatment group with their corresponding 95% CIs, 
and the adjusted mean difference between treatments with their corresponding 95% CIs will be 
estimated by the model. In addition, the p-values for each of the factors in the model will be 
displayed.  
 
Analysis of Secondary Efficacy Variable 8b: Change from baseline in average use of rescue 
medication (number of puffs/day) during inter-visit periods and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in the 
average use of rescue medication will be analyzed using a linear mixed model for repeated 
measurements as outlined in Section 8.2. See Section 7.1 for the definition of the inter-visit 
periods. The adjusted means in each treatment group with their corresponding 95% CIs, and 
the adjusted mean difference between treatments with their corresponding 95% CIs will be 
estimated by the model. In addition, the p-values for each of the factors in the model will be 
displayed.  
 
Analysis of Secondary Efficacy Variable 8c: Change from baseline in average E-RS total 
score and domain scores during inter-visit periods and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in the 
average E-RS total score and the domain scores will be analyzed using a linear mixed model 
for repeated measurements as outlined in Section 8.2. See Section 7.1 for the definition of the 
inter-visit periods. The adjusted means in each treatment group with their corresponding 95% 
CIs, and the adjusted mean difference between treatments with their corresponding 95% CIs 
will be estimated by the model. In addition, the p-values for each of the factors in the model 
will be displayed. 
10.6.3 Other efficacy variables 
PEF and FEF25%-75% are collected together with the spirometry assessments and will be 
presented in data listings only. 
10.7 Safety Analyses 
All safety analyses described below will be performed on the Safety population. 
10.7.1 Adverse Events 
As defined in the protocol, all AEs starting on or after the date of first study drug intake will be 
classified as TEAEs.  Only TEAEs will be included in the tables. All AEs will be listed.  AE 
onset date will be taken into account when assigning AEs as treatment emergent. Pre-treatment 
AEs (AE onset date < date of first randomized study drug intake) and post-study AEs (AE onset 


 
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date > date of completion/discontinuation) will be included in the subject listings, and flagged, 
but will be excluded from other summaries.  
The number of  TEAEs, ADRs, serious TEAEs, serious ADRs, severe TEAEs, TEAEs leading 
to study drug discontinuation and TEAEs leading to death, and the number and the percentage 
of subjects experiencing TEAEs, ADRs, serious TEAEs, serious ADRs, severe TEAEs, TEAEs 
leading to study drug discontinuation and TEAEs leading to death will be summarized by 
treatment and overall.  
The number and percentage of subjects with at least one AE and the number of AEs will be 
presented by SOC and PT by treatment and overall for treatment-emergent AEs, ADRs, serious 
TEAEs, serious ADRs, severe TEAEs, TEAEs leading to study drug discontinuation and 
TEAEs leading to death. 
Subjects who have multiple events in the same system organ class (SOC) and preferred term 
(PT) will be counted only once in the subject counts. 
 
10.7.2 Vital Signs 
Vital signs (systolic and diastolic blood pressure) and their changes from baseline (pre-dose 
on Day 1) and from pre-dose on Week 6 (for Week 6 post-dose only) will be summarized by 
treatment using descriptive statistics and the 95% CI of the mean. 
 
10.7.3 ECGs  
10.7.3.1 12-Lead ECGs  
Recorded data from the local 12-Lead ECG will be presented in a listing. 
 
10.7.3.2 Holter ECGs  
ECG parameters extracted from the 24hr Holter (HR, QTcF, QRS, and PR) will be summarized 
for the +5 min, +55 min, and +2.5 hour nominal extraction times on Day -1, Day 1 and Week 
6 by treatment using descriptive statistics and the 95% CI of the mean.  The nominal recorded 
value will be used in the calculation.  In addition, their changes from baseline (time-matched 
on the day before V2) will be summarized using descriptive statistics and 90% CI.  The 
summaries will use the triplicate averages obtained at each nominal extraction time. 
Change from baseline (time-matched on day before V2) in ECG parameters extracted from the 
24hr Holter (HR, QTcF, QRS and PR) will be analyzed using a linear mixed model for repeated 
measurements including treatment, time point, treatment by time point interaction, US regions, 
and smoking status at screening as fixed effects, and the baseline value (time-matched on day 
before V2), baseline by time point interaction and time-averaged baseline as covariates. An 
unstructured covariance matrix will be assumed. The adjusted means in each treatment group 
with their corresponding 90% CIs, and the adjusted mean difference between all treatments and 
placebo with their corresponding 90% CIs will be estimated by the model. In addition, the p-
values for each of the factors in the model will be displayed. 


 
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In addition, the number and percentage of subjects with prolonged QTcF will be summarized 
using counts and percentages for each nominal extraction and at any post-dose time point using 
the following thresholds: 
• QTcF >450 ms for males and >470 ms for females 
• QTcF >480 ms for males only 
• QTcF >500 ms 
• Change from baseline in QTcF >30 ms 
• Change from baseline in QTcF >60 ms 
 
For each of the three distinct 24-hour monitoring periods, the HR average, minimum, and 
maximum will be extracted from the Holter recordings and summarized on Day -1, Day 1, and 
Week 6 by treatment using descriptive statistics and the 95% CI of the mean.  In addition, their 
changes from baseline will be summarized using descriptive statistics and 95% CI.   
 
Change from baseline (day before V2) in 24-hour average, minimum and maximum HR 
extracted from the Holter recordings will be analyzed using a linear mixed model for repeated 
measurements including treatment, visit, treatment by visit interaction, US regions and smoking 
status at screening as fixed effects, and the baseline value (day before V2) and baseline by visit 
interaction as covariates. An unstructured covariance matrix will be assumed. The adjusted 
means in each treatment group with their corresponding 95% CIs, and the adjusted mean 
difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. 
The average HR will be calculated on an hourly basis during each 24-hour monitoring period 
and summarized by treatment using descriptive statistics and the 95% CI of the mean. 
The Holter ECG recordings will be scanned for the presence or absence of arrhythmia 
including, but not limited to: 
• Atrial fibrillation, 
• Sinus Pauses, 
• PACs, 
• SVT, 
• PVCs, 
• Ventricular tachycardia, 
• AV Blocks. 
 
In addition, the following will be summarized by treatment using descriptive statistics and the 
95% CI of the mean: 
• Longest Tachycardia Duration (min); 
• Longest Tachycardia Maximum HR (bpm); 
• Fastest Tachycardia Duration (min); 
• Fastest Tachycardia Maximum HR (bpm); 
• Longest Bradycardia Duration (min); 
• Longest Bradycardia Minimum HR (bpm); 
• Slowest Bradycardia Duration (min); 
• Slowest Bradycardia Minimum HR (bpm); 


 
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• Time in Atrial Fibrillation Percentage; 
• Atrial Fibrillation Peak Average Rate (bpm); 
• Supraventricular Total; 
• Ventricular Total; 
 
RR > 2 sec (yes/no: yes if number of RR > 2 sec > 0, no if number of RR > 2 sec = 0) will be 
summarized using counts and percentages. 
  
For ECG analyses, numerical parameters (HR, QTcF, PR and QRS) will not be included in the 
statistical analysis in the following cases:  
• 
patients with a pacemaker already in place at study entry, identified by the 
presence of at least one of the following Preferred Terms in the medical/surgical 
history or concomitant diseases: “Cardiac pacemaker battery replacement”, 
“Cardiac pacemaker evaluation”, “Cardiac pacemaker insertion”, “Cardiac 
pacemaker replacement”, “Electrocardiogram pacemaker spike”, “Pacemaker 
generated 
arrhythmia”, 
“Pacemaker 
generated 
rhythm”, 
“Pacemaker 
syndrome”, “Cardiac assistance device user”;  
• 
patients with a pacemaker implanted during the study, identified by a procedure 
coded with the Preferred Term “Cardiac pacemaker insertion” (other relevant 
cases may be identified in the Data Review Report). In this case, only the 
parameters assessed in a date ≥ start date of the procedure will be excluded from 
the statistical analysis;  
• 
patients with atrial fibrillation as concomitant disease, identified by the presence 
of at least one of the following Preferred Term: “Atrial fibrillation”, “Cardiac 
fibrillation”. 
• 
ECGs with PR=0, since this is indicative of poor quality or inevaluble ECG 
result.  Note that this does not apply to all ECGs for the patient, but only the 
ECGs with PR=0. 
10.7.4 Clinical Laboratory Evaluation 
Shift tables will be presented for hematology and biochemistry parameters  by treatment group 
at Day 1 and Week 6.  
The categories for the shift tables are as follows: 
• Low clinically significant 
• Low not clinically significant 
• Normal 
• High not clinically significant 
• High clinically significant 
 
  In addition, all laboratory data will be listed, with abnormal values flagged. 
 


 
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10.8 Early Termination and Unscheduled Visits 
The handling of the early termination efficacy and safety assessments in the statistical analyses 
will be discussed during the Data Review Meeting and the decisions will be fully documented 
in the Data Review Report. 
 
With regards to unscheduled assessments,these measurements will be evaluated case by case 
during the Data Review Meeting, with handling described in the Data Review Report. 
 
The following rules on data re-allocation will be considered: 
• 
Data collected at multiple visits (spirometry, TDI, vital signs, laboratory data, and Holter 
ECG) recorded at the study termination visit for discontinued patients will be re-allocated 
by selecting the next visit at which the assessment was planned. For each assessment, only 
the visits at which the assessment was scheduled will be considered for re-allocation. This 
means that Holter ECG and laboratory data can be re-allocated only to Visit 4. For example, 
if the last visit performed before the study termination visit was Visit 2, the data recorded 
at the study termination visit will be re-allocated to Visit 3 for spirometry, TDI, and vital 
signs, and to Visit 4 for Holter ECG and laboratory data.  If the study termination visit was 
performed less than 7 days after the preceding visit, then the data recorded at the study 
termination visit will not be re-allocated and they will excluded from the statistical analysis.  
• 
For discontinued patients, efficacy data recorded in the diaries from the last visit performed 
before the study termination visit or the date of discontinuation onwards will be reallocated 
to 
the 
next 
expected 
inter-visit 
period; 
 
• 
in case of missing intermediate visit not due to the re-allocation of data collected at the 
study termination visit (e.g., Visit 3 missing, but Visits 2 and 4 performed), an expected 
date for the missing Visit 3 will be imputed in order to define the inter-visit periods for diary 
data. The expected date for the missing Visit 3 will be imputed as follows: Visit 3 expected 
date = Visit 2 date + 28 days. 
 
• 
Additional unscheduled/optional spirometries will be considered on a case-by-case basis 
and their inclusion in the analysis will be discussed at the DRM and confirmed in the DRR 
prior to data base lock and unblinding.  As a general rule, unscheduled or optional FEV1 
and FVC results which are recorded during the 12 hours post-dose at Visit 2 and Visit 4 will 
be considered in the AUC0-12h calculations, while  results which are recorded during the 
4 hours post-dose at Visit 2 and Visit 4 will be considered in the AUC0-4h and peak0-4h 
calculationsand as eligible for minimum/maximum assessments unless otherwise specified 
in the DRR.  
 
• 
Holter ECG: In case of the memory card was not removed and replaced during Visit 2, such 
that 48 hours are recorded at the Visit 2, Day -1 time point, then the first 24 hours of data 
following the dosing time (first inhalation) will be re-allocated to the Visit 2 time point. 
 
• 
Laboratories: the last assessment before the first randomised study medication intake of 
each parameter will be considered as from Visit 1 in the analysis. For WBC and the 
differential count parameters (lymphocytes, neutrophils, monocytes, eosinophils, 
basophils) the last complete assessment (i.e., with available measurements for all these 
parameters) before first study drug intake will be considered in the analysis. If no complete 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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assessment is available, the last assessment before first study drug intake with the highest 
number of available parameters will be considered in the analysis. 
 
Potential issues of the approach above defined and other decisions regarding data re-allocation 
will be evaluated during the blind review of the data and documented in the Data Review 
Report. 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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11 Table of Contents for the Tables, Listings and Figures 
Key Frist Results (KFR) are identified with an “*”. 
 
Post-Text Tables 
  CSR Section 14.1: Demographic data 
Table 14.1.1.1: Screening Failures (All Enrolled Subjects) 
* Table 14.1.1.2.1: Patient Disposition (All Randomized Subjects) 
Table 14.1.1.2.2: Summary of Subjects by Visit (All Randomized Subjects)  
Table 14.1.1.3.1: Major Protocol Deviations (ITT Population) 
Table 14.1.1.3.1: Major Protocol Deviations (ITT Population) 
* Table 14.1.1.4.1: Summary of Analysis Sets (All randomized patients) 
Table 14.1.1.4.2: Summary of Analysis Sets by US Region (All randomized patients)  
Table 14.1.2.1: Demographic Characteristics (Safety Population) 
Table 14.1.2.2: Demographic Characteristics (ITT Population) 
Table 14.1.2.3: Demographic Characteristics (PP Population) 
Table 14.1.3.2: COPD History and Smoking Habits (ITT Population)  
Table 14.1.3.3: COPD History and Smoking Habits (PP Population)  
Table 14.1.4.1: Medical and Surgical History (Safety Population) 
Table 14.1.4.2: Medical and Surgical History (ITT Population) 
Table 14.1.5.1: Concomitant Diseases (Safety Population)  
Table 14.1.5.2: Concomitant Diseases (ITT Population)  
Table 14.1.6.1: Central Spirometry and Reversibility at Visit 1 (Safety Population)  
Table 14.1.6.2: Central Spirometry and Reversibility at Visit 1 (ITT Population)  
Table 14.1.6.3: Central Spirometry and Reversibility at Visit 1 (PP Population) 
Table 14.1.7: Physical Examination Results at Visit 1 (Safety Population) 
Table 14.1.8.1: Vital Signs Results at Visit 1 (Safety Population) 
Table 14.1.8.2: 12-Lead ECG at Visit 1 and Visit 2 pre dose (Safety Population) 
Table 14.1.9: Baseline Dyspnea Index Questionnaire at Visit 1 (ITT Population)  
Table 14.1.10: COPD Assessment Test at Visit 1 and Visit 2 (ITT Population)  
Table 14.1.11.2: Concomitant Medications (ITT population) 
Table 14.1.11.3: Maintained Medications (ITT population) 
Table 14.1.12.1: Background Medication – Previous COPD Treatment (ITT population)  
Table 14.1.12.2: Background Medication Exposure and Compliance during Run-in Period (ITT population) 
Table 14.1.12.3: Background Medication Exposure and Compliance during Treatment Period (ITT 
population) 
Table 14.1.13.1: Study Treatment Exposure and Compliance (ITT Population) 
Table 14.1.13.2: Study Treatment Exposure and Compliance (Safety Population) 
Table 14.1.14: Compliance with the use of e-Diary (ITT Population) 
CSR Section 14.2: Efficacy Data 
Table 14.2.1.1: Summary of FEV1 AUC0-12h Normalized by Time and the Change from Baseline at Week 6 
(ITT Population) 
* Table 14.2.1.2: Analysis of FEV1 AUC0-12h Normalized by Time at Week 6 (ITT population) 


 
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Table 14.2.1.3: Summary of FEV1 AUC0-12h Normalized by Time and the Change from Baseline at Week 6 
(PP Population) 
* Table 14.2.1.4: Analysis of FEV1 AUC0-12h Normalized by Time at Week 6 - (PP Population) 
Table 14.2.2.1: Summary of FEV1 AUC0-12h Normalized by Time and the Change from Baseline on Day 1 
(ITT Population) 
Table 14.2.2.2: Analysis of FEV1 AUC0-12h Normalized by Time on Day 1 (ITT Population) 
* Table 14.2.3.1: Analysis of FEV1 AUC0-12h Normalized by Time on Day 1 (ITT Population) 
* Table 14.2.4.1.1: Summary of FEV1 at Each Time Point on Day 1, Week 3, and Week 6 (ITT Population) 
Table 14.2.4.1.2: Summary of FEV1 at Each Time Point on Day 1, Week 3, and Week 6 (PP Population) 
Table 14.2.4.2: Summary of Change from Baseline in FVC at Each Time Point on Day 1 and Weeks 3 and 6 
(ITT Population) 
Table 14.2.5.1: Summary of FEV1 AUC0-4h Normalized by Time and the Change from Baseline on Day 1 
and Week 6 (ITT Population) 
* Table 14.2.5.2: Analysis of FEV1 AUC0-4h Normalized by Time on Day 1 and Week 6 (ITT Population) 
Table 14.2.6.1: Summary of FEV1 Peak0-4h and the Change from Baseline on Day 1 and Week 6 (ITT 
Population) 
* Table 14.2.6.2: Analysis of FEV1 Peak0-4h on Day 1 and Week 6 (ITT Population) 
* Table 14.2.7.1: Analysis of Pre-Dose Morning FEV1 at Week 3 and Week 6 (ITT Population) 
Table 14.2.8.1: Summary of Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 100 mL) 
on Day 1 (ITT Population) 
Table 14.2.8.2: Analysis of Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 100 ml) on 
Day 1 (ITT Population) 
Table 14.2.9.1: Summary of FVC at Each Time Point on Day 1, Week 3, and Week 6 (ITT Population) 
Table 14.2.10.1: Summary of Change from Baseline in IC at Each Pre-Dose Time Point on Day 1, Week 3, 
and Week 6 (ITT Population) 
Table 14.2.11.1: Summary of FVC AUC0-12h Normalized by Time and the Change from Baseline on Day 1 
and Week 6 (ITT Population) 
Table 14.2.11.2: Analysis of FVC AUC0-12h Normalized by Time on Day 1 and Week 6 (ITT Population) 
Table 14.2.12.1: Summary of FVC AUC0-4h Normalized by Time and the Change from Baseline on Day 1 
and Week 6 (ITT Population) 
Table 14.2.12.2: Analysis of FVC AUC0-4h Normalized by Time on Day 1 and Week 6 (ITT Population)  
Table 14.2.13.1: Summary of FVC Peak0-4h and the Change from Baseline on Day 1 and Week 6 (ITT 
Population) 
Table 14.2.13.2: Analysis of FVC Peak0-4h on Day 1 and Week 6 (ITT Population) 
Table 14.2.14.1: Summary of IC at Each Pre-dose Time Point on Day 1, Week 3, and Week 6 (ITT 
Population) 
Table 14.2.14.2: Summary of Change from Baseline in IC at Each Time Point on Day 1 and Weeks 3 and 
Week 6 (ITT Population)  
Table 14.2.14.3: Analysis of Pre-Dose Morning IC at Week 3 and Week 6 (ITT Population) 
Table 14.2.15.1: Summary of the TDI Domains, Focal Score, and Response (TDI Focal Score ≥ 1 Unit) at 
Weeks 3 and 6 (ITT Population) 
* Table 14.2.15.2: Analysis of the TDI Focal Score at Weeks 3 and 6 (ITT Population) 
Table 14.2.16.1: Analysis of the TDI Response (TDI Focal Score ≥ 1) at Weeks 3 and 6 (ITT Population)  
Table 14.2.17.1: Summary of the Percentage of Rescue Medication-free Days during Inter-Visit  Periods and 
the Entire Treatment Period (ITT Population)  
Table 14.2.17.2: Analysis of the Percentage of Rescue Medication-free Days during Inter-Visit  Periods and 
the Entire Treatment Period (ITT Population)  
Table 14.2.18.1: Summary of the Average Use of Medication during Inter-Visit  Periods and the Entire 
Treatment Period (ITT Population) 
Table 14.2.18.2: Analysis of the Average Use of Rescue Medication during Inter-Visit  Periods and the Entire 
Treatment Period (ITT Population) 
Table 14.2.19.1: Summary of the E-RS Total and Domain Scores and the Change from Baseline during the 
Inter-Visit Periods and the Entire Treatment                  Period (ITT Population)  


 
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Table 14.2.19.2: Analysis of the E-RS Total during the Inter-Visit  Periods and the Entire Treatment Period 
(ITT Population) 
 
 
CSR Section 14.3: Safety 
* Table 14.3.1.1.1: Summary of Treatment Emergent Adverse Events (Safety Population) 
Table 14.3.1.2.1: Treatment Emergent Adverse Events by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.2.2: Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
* Table 14.3.1.3.1: Adverse Drug Reactions by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.3.2: Serious Adverse Drug Reactions by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.3.3: Severe Adverse Drug Reactions by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.4: Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term (Safety Population)  
Table 14.3.2: Treatment Emergent Adverse Events Leading to Death by System Organ Class and Preferred 
Term (Safety Population)  
Table 14.3.4.1: Vital Signs Results and Changes from Baseline (Safety Population)  
Table 14.3.4.2: Vital Signs Changes from Pre dose (Safety Population) 
Table 14.3.5.1.1: Summary of the 24-hour Holter ECG Results and Changes from Baseline (Safety 
Population) 
Table 14.3.5.1.2: Analysis of the 24-hour Holter ECG Results (Safety Population)  
Table 14.3.5.2.1: 24-hour Holter ECG – Prolonged QTcF (Safety Population - Males) 
Table 14.3.5.2.2: 24-hour Holter ECG - Prolonged QTcF (Safety Population - Females) 
Table 14.3.5.2.3: 12-Lead ECG - Prolonged QTcF – Changes from Baseline (Safety Population)  
Table 14.3.5.3.1: Summary of the 24-hour Holter ECG Average, Minimum, and Maximum Heart Rate Results 
and Changes from Baseline (Safety Population) 
Table 14.3.5.3.2: Analysis of the 24-hour Holter ECG Average, Minimum, and Maximum Heart Rate Results 
(Safety Population) 
Table 14.3.5.4: Summary of the 24-hour Holter ECG Hourly Average Heart Rate Results (Safety Population) 
Table 14.3.5.5: 24-hour Holter ECG Abnormalities (Safety Population)  
Table 14.3.6: Shift Table of Hematology Results (Safety Population)  
Table 14.3.7: Shift Table of Biochemistry Results (Safety Population)  
 
 CSR Section Listings 16: 
Listing 16.1.7: Randomization Schedule (All Randomized Subjects) 
Listing 16.2.1.1: Subject Disposition (All Subjects) 
Listing 16.2.1.2: Visit Dates (All Randomized Subjects)  
Listing 16.2.2.1: Protocol Deviations (All Randomized Subjects) 
Listing 16.2.2.2: Inclusion/Exclusion Criteria Not Met (All Randomized Subjects) 
Listing 16.2.3: Analysis Sets (All Randomized Subjects)  
Listing 16.2.4.1: Subject Demography (All Randomized Subjects) 
Listing 16.2.4.2: COPD History and Smoking Habits (All Randomized Subjects)  
Listing 16.2.4.3.1: Medical and Surgical History (All Randomized Subjects)  
Listing 16.2.4.3.2: Concomitant Diseases (All Randomized Subjects) 
Listing 16.2.4.4: Previous Medications (All Randomized Subjects) 


 
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Listing 16.2.4.5: Concomitant Medications (All Randomized Subjects) 
Listing 16.2.4.6: Maintained Medications (All Randomized Subjects) 
Listing 16.2.4.8: Concomitant Procedures (All Randomized Subjects) 
Listing 16.2.4.9: Reversibility Test (All Randomized Subjects) 
Listing 16.2.4.10: Baseline Dyspnea Index Questionnaire (All Randomized Subjects) 
Listing 16.2.4.11: COPD Assessment Test (All Randomized Subjects) 
Listing 16.2.5.1: Background Medication Administration (All Randomized Subjects) 
Listing 16.2.5.2: Study Drug Administration (All Randomized Subjects) 
Listing 16.2.5.3: Rescue Medication Administration (All Randomized Subjects)  
Listing 16.2.5.4: Background Medication Exposure and Compliance (All Randomized Subjects) 
Listing 16.2.5.5: Study Drug Exposure and Compliance (All Randomized Subjects) 
Listing 16.2.6.2: Peak FEV1 and FVC (All Randomized Subjects) 
Listing 16.2.6.3: Pre-Dose Morning FEV1 and IC Results (All Randomized Subjects) 
Listing 16.2.6.4: FEV1 and FVC AUC0-12h and AUC0-4h Results (All Randomized Subjects) 
Listing 16.2.6.5: Onset of Action (Change from Baseline in FEV1 ≥ 100 mL) on Day 1 (All Randomized 
Subjects) 
Listing 16.2.6.6:Transition Dyspnea Index Questionnaire (All Randomized Subjects) 
Listing 16.2.6.7: Rescue Medication Administration — Derived Variables (All Randomized Subjects) 
Listing 16.2.6.8: E-RS Questionnaire (All Randomized Subjects) 
Listing 16.2.7.1: Pre-Treatment Adverse Events (All Randomized Subjects)  
Listing 16.2.7.2: Treatment Emergent Adverse Events (All Randomized Subjects) 
Listing 16.2.7.3: Serious Treatment Emergent Adverse Events (All Randomized Subjects) 
Listing 16.2.7.4: Adverse Drug Reactions (All Randomized Subjects) 
Listing 16.2.7.5: Serious Adverse Drug Reactions (All Randomized Subjects) 
Listing 16.2.7.6: Severe Treatment Emergent Adverse Events (All Randomized Subjects) 
Listing 16.2.7.7: Treatment Emergent Adverse Events Leading to Study Drug Discontinuation (All 
Randomized Subjects) 
Listing 16.2.7.8: Treatment Emergent Adverse Events Leading to Death (All Randomized Subjects) 
Listing 16.2.7.9: Post-study Adverse Events (All Randomized Subjects) 
Listing 16.2.8.1: Vital Signs (All Randomized Subjects)  
Listing 16.2.8.2.1: 24-hour Holter ECG Results (All Randomized Subjects) 
Listing 16.2.8.2.2: 24-hour Holter ECG – Prolonged QTcF (All Randomized Subjects)  
Listing 16.2.8.2.3: 24-hour Holter ECG Abnormalities (All Randomized Subjects) 
Listing 16.2.8.3.1: Laboratory Results – Hematology (All Randomized Subjects)  
Listing 16.2.8.3.2: Laboratory Results – Biochemistry (All Randomized Subjects) 
Listing 16.2.8.3.3: Laboratory Results – Pregnancy Test (All Randomized Females) 
Listing 16.2.8.4: Physical Examination (All Randomized Subjects) 
Listing 16.2.9: Comments (All Randomized Subjects) 
CSR Section Figure 14: 
Figure 14.1.1: Kaplan-Meier Curves for Time until Discontinuation (All randomized subject) 
Figure 14.2.1.1.1: Mean absolute FEV1 values on Day 1 with 95% Confidence Interval (ITT Population)  
Figure 14.2.1.1.2: Mean absolute FEV1 values on Week 6 with 95% Confidence Interval (ITT Population)  
Figure 14.2.1.1.3: Mean absolute FEV1 values on Day 1 with 95% Confidence Interval (PP Population) 
Figure 14.2.1.1.4: Mean absolute FEV1 values on Week 6 with 95% Confidence Interval (PP Population) 


 
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Figure 14.2.1.2.1: Mean Change from Baseline in FEV1 on Day 1 with 95% Confidence Interval (ITT 
Population) 
Figure 14.2.1.2.2: Mean Change from Baseline in FEV1 on Day 1 with 95% Confidence Interval (ITT 
Population) 
Figure 14.2.1.2.3: Mean Change from Baseline in FEV1 on Day 1 with 95% Confidence Interval (PP 
Population) 
Figure 14.2.1.2.4: Mean Change from Baseline in FEV1 on Day 1 with 95% Confidence Interval (PP 
Population) 
Figure 14.2.4: Kaplan-Meier Curves for Time to Onset of Action (FEV1 ≥ 100 mL) on Day 1 (ITT 
population) 
Figure 14.2.5: Adjusted Mean Change from Baseline in Pre-dose Morning IC with 95% Confidence Interval 
(ITT Population) 
Figure 14.2.6: Adjusted Mean Change from Baseline in TDI Focal Score with 95% Confidence Interval (ITT 
Population) 
Figure 14.2.7: Adjusted Mean Change from Baseline in Percentage of Rescue Medication-free Days with 95% 
Confidence Interval (ITT Population)  
Figure 14.2.8: Adjusted Mean Change from Baseline in Average Use of Rescue Medication with 95% 
Confidence Interval (ITT Population)  
Figure 14.2.9: Adjusted Mean Change from Baseline in E-RS Total Score and Domain Scores with 95% 
Confidence Interval (ITT Population)  
Figure 14.3.1: Forest Plot of Most Common TEAEs with Relative Risk and 95% Confidence Interval (Safety 
Population) 
Figure 14.3.2: Mean Heart Rate from Holter Monitoring over 24 Hours (Safety Population) 
 
 
SAS Outputs Listings: 
 
Listing 16.1.9.1.1: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time at Week 6 (ITT 
population) 
Listing 16.1.9.1.2: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time at Week 6 (PP 
Population) 
Listing 16.1.9.2: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time on Day 1 (ITT 
Population) 
Listing 16.1.9.3: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time on Day 1 (ITT 
Population) 
Listing 16.1.9.4: SAS Output of Analysis of FEV1 AUC0-4h Normalized by Time on Day 1 and Week 6 (ITT 
Population) 
Listing 16.1.9.5: SAS Output of Analysis of FEV1 Peak0-4h on Day 1 and Week 6 (ITT Population) 
Listing 16.1.9.6: SAS Output of Analysis of Pre-Dose Morning FEV1 at Week 3 and Week 6 (ITT 
Population) 
Listing 16.1.9.7: SAS Output of Analysis of Time to Onset of Action (Change from Baseline in Post-dose 
FEV1 ≥ 100 ml) on Day 1 (ITT Population)  
Listing 16.1.9.8: SAS Output of Analysis of FVC AUC0-12h Normalized by Time on Day 1 and Week 6 (ITT 
Population) 
Listing 16.1.9.9: SAS Output of Analysis of FVC AUC0-4h Normalized by Time on Day 1 and Week 6 (ITT 
Population) 
Listing 16.1.9.10: SAS Output of Analysis of FVC Peak0-4h on Day 1 and Week 6 (ITT Population)  
Listing 16.1.9.11: SAS Output of Analysis of Pre-Dose Morning IC at Week 3 and Week 6 (ITT Population)  
Listing 16.1.9.12: SAS Output of Analysis of the TDI Focal Score at Weeks 3 and 6 (ITT Population) 
Listing 16.1.9.13: SAS Output of Analysis of the TDI Response (TDI Focal Score ≥ 1) at Weeks 3 and 6 (ITT 
Population) 
Listing 16.1.9.14: SAS Output of Analysis of the Percentage of Rescue Medication-free Days during Inter-
Visit  Periods and the Entire Treatment Period (ITT Population) 
Listing 16.1.9.15: SAS Output of Analysis of the Average Use of Rescue Medication during Inter-Visit  
Periods and the Entire Treatment Period (ITT Population) 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Listing 16.1.9.16: SAS Output of Analysis of the E-RS Total during the Inter-Visit  Periods and the Entire 
Treatment Period (ITT Population) 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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12 References 
1. Hankinson JL, Eschenbacher B, Townsend M, Stocks J, Quanjer PH. Use of forced 
vital capacity and forced expiratory volume in 1 second quality criteria for 
determining a valid test. European Respiratory Journal 2015, 45(5):1283-92.  
 
2. Leidy NK, Murray LT. Patient-reported outcome (PRO) measures for clinical trials of 
COPD: the EXACT and E-RS. COPD. Jun 2013;10(3):393-398.  
 
3. P.W. Jones, G. Harding, P. Berry, I. Wiklund, W-H. Chen and N. Kline Leidy. 
Development and first validation of the COPD Assessment Test. Eur Respir J 2009, 
34: 648–654.   
 
 


 
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APPENDIX I: EXACT-PRO QUESTIONNAIRE 
 
Scoring Algorithms and Analytical Definitions  
 
COMPUTATIONAL INSTRUCTIONS 
Raw Scores 
Raw scores are assigned to each item response option, as shown below. 
 
Annotated EXACT-PRO for Raw Score Assignment 
The following annotates the raw score values associated with each response category for the 
EXACT-PRO items: 
 
1.  
 
 
 
 
 
 
 
2.  
 
 
 
 
 
 
 
3.  
  
 
 
 
 
 
 
 
4.  
 
 
 
 
 
 
 
5.  
 
 
 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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6.  
 
 
 
 
 
 
 
7.  
 
 
 
 
 
 
 
8.  
 
 
 
 
 
 
 
 
9.  
 
 
 
 
 
 
 
 
 
10.  
 
 
 
 
 
 
 
 
 
11. 
 
 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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